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Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential:

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential: 615514 TAM0010.1177/1758834015615514Therapeutic Advances in Medical OncologyGT Wurz, C-J Kao review-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Novel cancer antigens for personalized 2016, Vol. 8(1) 4 –31 DOI: 10.1177/ immunotherapies: latest evidence and © The Author(s), 2015. Reprints and permissions: clinical potential http://www.sagepub.co.uk/ journalsPermissions.nav Gregory T. Wurz, Chiao-Jung Kao and Michael W. DeGregorio Abstract: The clinical success of monoclonal antibody immune checkpoint modulators such as ipilimumab, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the recently approved agents nivolumab and pembrolizumab, which target programmed cell death receptor 1 (PD-1), has stimulated renewed enthusiasm for anticancer immunotherapy, which was heralded by Science as ‘Breakthrough of the Year’ in 2013. As the potential of cancer immunotherapy has been recognized since the 1890s when William Coley showed that bacterial products could be beneficial in cancer patients, leveraging the immune system in the treatment of cancer is certainly not a new concept; however, earlier attempts to develop effective therapeutic vaccines and antibodies against solid tumors, for example, melanoma, frequently met with failure due in part to self-tolerance and the development of an immunosuppressive tumor microenvironment. Increased knowledge of the mechanisms through which cancer evades the immune system and the identification of tumor-associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of vaccines and monoclonal antibodies targeting specific tumor antigens and immune checkpoints such as CTLA-4 and PD-1. This review first discusses the established targets of currently approved cancer immunotherapies and then focuses on investigational cancer antigens and their clinical potential. Because of the highly heterogeneous nature of tumors, effective anticancer immunotherapy-based treatment regimens will likely require a personalized combination of therapeutic vaccines, antibodies and chemotherapy that fit the specific biology of a patient’s disease. Keywords: antitumor antibody, cancer-testis antigen, cancer vaccine, immunotherapy, oncofetal antigen, tumor-associated antigen Correspondence to: Michael W. DeGregorio, Introduction immune system. Indeed, the first such tumor- Pharm D The possibility that immunotherapy could be associated antigen (TAA), known as melanoma Department of Internal Medicine, Division of useful for the treatment of cancer was first real- antigen 1 (MAGE-1, also known as MAGE-A1), Hematology and Oncology, ized in the 1890s when William B. Coley showed was identified in human melanoma cells by Boon University of California, Davis, 4501 X Street Suite that injecting killed bacterial cultures, known as and colleagues in 1991 [van der Bruggen et  al. 3016, Sacramento, Coley toxins, had beneficial effects in cancer 1991]. Since that seminal discovery, the number CA 95817, USA mwdegregorio@ucdavis. patients [Nauts et al. 1953]. Decades later, stud- of new TAAs has grown steadily to the point edu ies performed in chemically induced sarcoma where there are now over 400 T-cell-defined Gregory T. Wurz, PhD mouse models showed that syngeneic mice human tumor antigenic peptides that have been Department of Internal Medicine, Division of injected with irradiated sarcoma cells displayed identified [Vigneron et  al. 2013]. Until the late Hematology and Oncology, immunity when later challenged with live sar- 20th century, the role of immunosurveillance in University of California, Davis, Sacramento, CA, coma cells [Foley, 1953; Prehn and Main, 1957; cancer control had been the subject of much USA Klein et  al. 1960]. The fact that the immunity debate [Schreiber et al. 2011]; however, two stud- Chiao-Jung Kao, PhD conferred in this manner was tumor-specific sug- ies by Schreiber and colleagues involving inter- Department of Obstetrics and Gynecology, University gested that tumors express unique antigens that feron gamma and tumor immunogenicity in of California, Davis are specifically recognized by the adaptive immunocompetent hosts are considered to have Sacramento, CA, USA 4 http://tam.sagepub.com GT Wurz, C-J Kao et al. played a major role in renewing interest in tumor (T 1) and cytotoxic T lymphocyte (CTL)- immunology [Kaplan et al. 1998; Shankaran et al. mediated] as opposed to humoral [T helper type 2001]. Over the years, a number of different 2 (T 2), antibody-mediated] immune responses approaches to cancer immunotherapy, including in order to be effective [Rosenberg, 2001; antibodies, cytokines, adoptive cell therapy Kirkwood et al. 2012; Melero et al. 2014]. A T 1- (ACT) and therapeutic vaccines, have been polarized immune response involving CTLs and attempted, but the overall response rates have natural killer (NK) cells mediates the elimination been largely disappointing [Kirkwood et al. 2012; of tumor cells, while a T 2-polarized immune Savage et al. 2014]. Only recently, as knowledge response can have deleterious effects by promot- of tumor biology and immunology has improved, ing tumor development and progression has the complex nature of the interactions [Kirkwood et  al. 2012; Curigliano et  al. 2013]. between the immune system and cancer come This is not to say that antibody-based anticancer into focus, which has allowed the development of immunotherapies are ineffective against solid more specifically targeted agents [Kirkwood et al. tumors. Indeed, the past decade has seen the clin- 2012; Galluzzi et al. 2014]. ical development of numerous monoclonal anti- bodies directed at growth factors such as vascular Nonmutated, shared self-antigens constitute the endothelial growth factor A (VEGFA; e.g. bevaci- majority of currently identified TAAs and can be zumab), growth factor receptors such as human classified into three major categories: (a) tumor- epidermal growth factor receptor (EGFR or specific or cancer-testis antigens (CTAs), for exam- HER1; e.g. cetuximab, panitumumab) and ple, MAGE-1, normally found only in the testes but EGFR 2 (HER2; e.g. trastuzumab, pertuzumab), are aberrantly expressed by a number of different and negative immune checkpoint regulators such cancers; (b) differentiation antigens expressed by as cytotoxic T lymphocyte-associated antigen 4 both tumors and the normal differentiated cells (CTLA-4; e.g. ipilimumab) and programmed cell from which the tumors arise, for example, mela- death receptor 1 (PD-1; e.g. nivolumab, pem- noma antigen recognized by T cells (MART-1, also brolizumab) [Sliwkowski and Mellman, 2013]. In known as Melan-A); and (c) self-antigens that are addition to the direct, modulatory effects on sig- overexpressed by tumors, for example, mucin 1 nal transduction, antibody-dependent cellular (MUC1) [Savage et al. 2014]. CTAs were the first cytotoxicity (ADCC), mediated through engage- type of TAA identified, and there are currently over ment of NK cells and macrophages, also likely 200 genes that have been classified as CTAs contributes to the activity of these antibodies [Almeida et al. 2009]. It is believed that the observed [Kohrt et  al. 2012; Sliwkowski and Mellman, antigenicity of CTAs is ascribed to the privileged 2013]. The tumor-targeting monoclonal antibod- immune status of the testis, where the blood–testis ies, perhaps the most commonly utilized form of barrier prevents the entry of immune cells. anticancer immunotherapy [Weiner et  al. 2010; Developing spermatozoa also do not express major Vacchelli et  al. 2014], are examples of passive histocompatibility complex (MHC) class I mole- immunotherapy, while immune checkpoint cules, allowing them to evade immunosurveillance inhibitors are considered to be active immuno- by infiltrating T cells [Whitehurst, 2014]. Thus, therapies [Galluzzi et al. 2014]. CTAs make attractive targets for immunotherapy; however, medullary thymic epithelial cells (mTECs) The recent clinical development and approval of have been reported to express CTAs such as MAGE the immune checkpoint inhibitors ipilimumab, and New York esophageal squamous cell carcinoma which targets CTLA-4, and nivolumab and pem- 1 (NY-ESO-1) [Gotter et al. 2004], which suggests brolizumab, both of which target PD-1, has gen- that central tolerance to CTAs can develop. A tran- erated a great deal of excitement in the field of scriptional regulator known as Aire (autoimmune cancer immunotherapy [Swaika et al. 2015]. In a regulator), which is expressed by mTECs, promotes phase III clinical trial, ipilimumab was the first the promiscuous expression of tissue-restricted anti- immunotherapeutic to significantly improve over- gens such as CTAs [Anderson et al. 2002; Derbinski all survival (OS) in patients with advanced, meta- et al. 2005], resulting in promotion of tolerance to static melanoma [Hodi et  al. 2010], and since TAAs through thymic deletion of self-reactive T then both nivolumab [Robert et  al. 2015a] and cells [Savage et al. 2014]. pembrolizumab [Robert et al. 2015b] have dem- onstrated significant improvement in OS in this In general, active immunotherapy of solid tumors patient population. This review will first discuss requires the induction of cellular [T helper type 1 CTLA-4, PD-1, and other established targets of http://tam.sagepub.com 5 Therapeutic Advances in Medical Oncology 8(1) cancer immunotherapy and then focus on novel months) compared with dacarbazine alone tumor antigens and their clinical potential. [Robert et al. 2011]. Still in clinical development, tremelimumab is Established targets of anticancer another anti-CTLA-4 monoclonal antibody. immunotherapies Unlike ipilimumab, tremelimumab failed to dem- Currently approved anticancer immunotherapies, onstrate any significant clinical benefit in patients including monoclonal antibodies and cancer vac- with advanced melanoma [Ribas et  al. 2013], cines, target a number of different antigens although a survival benefit was revealed in patients including CTLA-4, PD-1, EGFR, HER2, VEGF, achieving higher drug exposures following a ret- VEGF-R2, and PAP (prostatic acid phosphatase). rospective analysis of phase II and III pharma- Another well-known TAA is BCR-ABL (break- cokinetic data [Calabro et  al. 2015]. point cluster region Abelson tyrosine kinase), for Tremelimumab is currently being developed for which several small molecule tyrosine kinase the treatment of malignant mesothelioma inhibitors (TKIs) have been approved and for [Calabro et al. 2015], where it has demonstrated which immunotherapies are currently under long-term clinical benefit in phase II studies development. Monoclonal antibodies are by far [Calabro et  al. 2013, 2015]. The FDA recently the most commonly approved form of antigen- granted tremelimumab Orphan Drug Designation specific anticancer immunotherapy, with only a for this indication. single therapeutic cancer vaccine, sipuleucel-T (trade name Provenge ), which targets the pros- Two new monoclonal antibody-based therapies tate cancer antigen PAP, having received Food targeting PD-1, pembrolizumab (formerly lam- and Drug Administration (FDA) approval to brolizumab) and nivolumab, were approved by date. These immunotherapeutic targets and the the FDA within the last year. The interaction of clinical efficacy of approved treatments are dis- PD-1, expressed on the surface of activated T cussed below. For a comprehensive list of the cells, and PD-L1 on the surface of tumor cells antigen targets of established anticancer immu- results in immunosuppression. An expansion notherapies, refer to Table 1. cohort of a phase I trial [Hamid et al. 2013] com- pared pembrolizumab treatment at doses of 2 or 10 mg in metastatic melanoma patients that had Immune checkpoint blockade: CTLA-4 and progressed on ipilimumab. At both dose levels, PD-1 the overall response rate, which was the primary A great deal of research in cancer immunotherapy endpoint, was 26% and the treatment was well is currently being concentrated on the develop- tolerated [Robert et al. 2014]. The results of this ment of immune checkpoint modulators, particu- study led to accelerated FDA approval of pem- larly those targeting CTLA-4 and PD-1 and its brolizumab for metastatic melanoma in ligands PD-L1/L2. The first checkpoint modula- September 2014, representing the first such tor to be approved, ipilimumab is a monoclonal approval of an anti-PD-1 immunotherapy. Just 3 antibody directed against CTLA-4, a molecule months later, nivolumab received accelerated that downregulates the activation of T cells. A FDA approval for advanced melanoma on the phase III clinical trial in patients with metastatic basis of phase I/II clinical trial data showing a melanoma comparing ipilimumab and gp100 31% overall response rate with a median dura- peptide vaccine monotherapies to the combina- tion of response of two years, 43% two-year sur- tion showed that median OS was significantly vival, and a median OS of approximately 17 increased from 6.4 months (gp100 vaccine alone) months [Topalian et al. 2012, 2014]. A recently to 10.0 months (ipilimumab plus gp100 vaccine). published phase III trial comparing a combina- Ipilimumab monotherapy was equally effective tion of nivolumab and dacarbazine to dacar- [Hodi et al. 2010]. The results of this trial, which bazine alone in patients with metastatic was the first demonstration of an immunothera- melanoma showed significant increases in pro- peutic agent significantly increasing OS in patients gression-free survival (PFS) and OS with the with metastatic melanoma, led to the approval of combination [Robert et al. 2015a]. Clinical trials ipilimumab in 2011. A subsequent phase III trial evaluating the use of nivolumab and pembroli- in patients with metastatic melanoma showed zumab alone and in combination with other that a combination of ipilimumab and dacar- agents such as ipilimumab, TKIs, and anti-PD- bazine significantly increased OS (11.2 versus 9.1 L1 agents for the treatment of a wide variety of 6 http://tam.sagepub.com GT Wurz, C-J Kao et al. Table 1. Antigenic targets of approved immunotherapies. Antigen Cancer Types Targeted Agents References BCR-ABL CML Imatinib, Dasatinib [Isfort et al. 2014; Lindauer and Hochhaus, 2014; Ostendorf et al. ALL Nilotinib, Bosutinib 2014; Waller, 2014; Wehrle et al. 2014] Ponatinib CD19 ALL Blinatumomab [Hoffman and Gore, 2014] CD20 NHL, CLL Rituximab [Sliwkowski and Mellman, 2013; Ai and Advani, 2015] B-cell NHL Ofatumumab pre-B ALL Y-Ibritumomab I-Tositumomab CD30 Hodgkin’s lymphoma Brentuximab vedotin [Sliwkowski and Mellman, 2013; Chen and Chen, 2015] CD33 AML Gemtuzumab [Sliwkowski and Mellman, 2013; Loke et al. 2015] ozogamicin CD52 CLL Alemtuzumab [Skoetz et al. 2012; Sliwkowski and Mellman, 2013] CTLA-4 Unresectable Ipilimumab [Hodi et al. 2010; Robert et al. 2011; Hodi et al. 2014] or metastatic melanoma EGFR CRC Cetuximab [Cunningham et al. 2004; Saltz et al. 2004; Bonner et al. 2006; Van Head and Neck Panitumumab Cutsem et al. 2007; Vermorken et al. 2008; Van Cutsem et al. 2009; Douillard et al. 2010; Price et al. 2014] EpCAM Malignant ascites Catumaxomab [Seimetz, 2011] HER2 Breast Trastuzumab [Slamon et al. 2001; Romond et al. 2005; Bang et al. 2010; Perez Pertuzumab et al. 2011; O’Sullivan and Connolly, 2014; Perez et al. 2014] PAP Prostate Sipuleucel-T [Kantoff et al. 2010a] PD-1 Metastatic Nivolumab [Topalian et al. 2012; Robert et al. 2014; Topalian et al. 2014; melanoma NSCLC Pembrolizumab Garon et al. 2015; Brahmer et al. 2015] VEGF Breast, Cervical Bevacizumab [Hurwitz et al. 2004; Sandler et al. 2006; Escudier et al. 2007; CRC, NSCLC Giantonio et al. 2007; Miller et al. 2007; Friedman et al. 2009; RCC, Ovarian Pujade-Lauraine et al. 2014; Tewari et al. 2014] Glioblastoma VEGF-R2 Gastric Ramucirumab [Fuchs et al. 2014; Garon et al. 2014; Wilke et al. 2014] NSCLC Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; BCR-ABL, breakpoint cluster region Abelson tyrosine ki- nase; CLL, chronic lymphocytic leukemia; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; HER2, human epidermal growth factor receptor 2; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small cell lung cancer; PAP, prostatic acid phosphatase; PD-1, programmed cell death receptor 1; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VEGF-R2, vascular endothelial growth factor receptor 2. other cancers are currently ongoing or com- 58.2% for ipilimumab, differences that were pleted, with promising results [Scott, 2015; highly significant. A response rate of 33.7% was Swaika et al. 2015]. seen with pembrolizumab treatment compared with 11.9% for ipilimumab, with a lower inci- The results of clinical trials involving pembroli- dence of adverse events in patients treated with zumab and nivolumab in the treatment of non- pembrolizumab [Robert et al. 2015b]. In a phase small cell lung cancer (NSCLC) and advanced I study in advanced NSCLC, pembrolizumab melanoma were recently reported. demonstrated antitumor activity, with a response Pembrolizumab was found to be superior to ipil- rate of 45% among patients with a PD-L1 tumor imumab in the treatment of patients with cell expression rate of at least 50%, and a advanced melanoma in a phase III clinical trial response rate of 19% among all patients. Median [Robert et  al. 2015b]. The 6-month PFS rate PFS was 3.7 months among all patients and 6.3 was 47.3% in patients treated with pembroli- months in patients with high PD-L1 expression zumab compared with 26.5% in patients treated [Garon et al. 2015]. The results of this trial led with ipilimumab, and the 12-month survival rate to the recent FDA approval of pembrolizumab for pembrolizumab was 74.1% compared with for NSCLC. http://tam.sagepub.com 7 Therapeutic Advances in Medical Oncology 8(1) Nivolumab was also recently FDA approved for immunotherapy, and indeed several different the treatment of NSCLC based on the results of a monoclonal antibodies as well as small molecule phase III study showing a significant increase in TKIs have been developed and approved OS in patients treated with nivolumab compared [Sliwkowski and Mellman, 2013]. Among these, with docetaxel [Brahmer et  al. 2015]. In previ- gefitinib, erlotinib and afatinib are TKIs approved ously untreated patients with unresectable stage for the treatment of NSCLC. While TKIs are III/IV melanoma, a randomized, double-blind quite effective in treating EGFR mutation-positive phase III trial showed that nivolumab treatment, NSCLC, the development of resistance is virtually either alone or in combination with ipilimumab, universal, commonly through the T790M muta- was superior to ipilimumab alone, with median tion [Pao et al. 2005]. Interestingly, a peptide anti- PFS increasing significantly from 2.9 months gen derived from the T790M EGFR mutation has with ipilimumab to 6.9 and 11.5 months with been reported to be immunogenic and is a poten- nivolumab and the combination, respectively. tial target for antigen-specific immunotherapy Among patients with PD-L1-positive tumors, [Yamada et al. 2013; Ofuji et al. 2015]. median PFS was 14.0 months for nivolumab alone and the combination compared to 3.9 Cetuximab and panitumumab. Approved mono- months for ipilimumab alone [Larkin et al. 2015]. clonal antibodies targeting EGFR include cetux- The combination of nivolumab and ipilimumab imab for colon and head and neck cancers, and recently received accelerated FDA approval for panitumumab for colon cancer. Cetuximab the treatment of BRAF V600 wild-type unresect- received accelerated FDA approval in 2004 for the able or metastatic melanoma based on the treatment of metastatic CRC refractory to irinote- results of a phase II trial [Postow et  al. 2015]. can based on the results of clinical trials showing This was the first approval of an immunotherapy acceptable safety [Saltz et al. 2004] and significant combination for cancer patients. increases in overall response rate and time to pro- gression in patients treated with a combination of Investigational, PD-1-targeted agents still in clini- cetuximab and irinotecan [Cunningham et  al. cal development include pidilizumab, which has 2004]. Phase III clinical trial data reaffirming been evaluated in phase II clinical trials in patients prior results and demonstrating significant with B-cell lymphoma [Armand et  al. 2013] and increases in PFS and OS in patients with refrac- metastatic melanoma [Atkins et  al. 2014], AMP- tory metastatic CRC [Jonker et al. 2007; Sobrero 514 (MEDI0680), being evaluated in ongoing et al. 2008] led to regular FDA approval of single- phase I trials in patients with advanced malignan- agent cetuximab in 2007 for the treatment of che- cies [ClinicalTrials.gov identifiers: NCT02118337; motherapy-refractory metastatic CRC. More NCT02013804], and AMP-224, which is cur- recently, cetuximab received FDA approval in rently being evaluated in a phase I trial [Clini- 2012 as first-line treatment for metastatic CRC calTrials.gov identifier: NCT02298946] in based on the results of the phase III CRYSTAL pati ents with metastatic colorectal cancer (CRC) trial [Van Cutsem et al. 2009] and supporting tri- [Homet Moreno et al. 2015]. als [Bokemeyer et al. 2009, 2012]. A pooled analy- sis of these trials showed that cetuximab combined with chemotherapy significantly increased overall EGFR receptor tyrosine kinase family response rate, PFS and OS in patients with KRAS The human epidermal growth factor receptor wild type, EGFR-expressing metastatic CRC (EGFR or HER1) is a receptor tyrosine kinase [Bokemeyer et al. 2012]. (RTK) that is overexpressed in a variety of differ- ent cancers including lung, breast and colon Cetuximab is also used in the treatment of squa- cancer. Specific mutations in the EGFR proto- mous cell carcinoma of the head and neck oncogene result in the RTK becoming constitu- (SCCHN), having received FDA approval in tively active [Chung, 2015]. Upon activation, 2006 for single-agent use in recurrent/metastatic EGFR stimulates a number of different signaling SCCHN refractory to platinum-based chemo- pathways, for example, MAPK (mitogen-activated therapy, and in combination with radiotherapy protein kinase), PI3K (phosphoinositide 3-kinase) for locally or regionally advanced SCCHN. This and STAT (signal transducer and activator of approval was based on the results of a phase III transcription), which lead to cancer cell prolif- clinical trial showing significant increases in PFS, eration and survival [Hynes and Lane, 2005]. median duration of locoregional control and OS This has made EGFR an attractive target for with cetuximab plus radiotherapy compared to 8 http://tam.sagepub.com GT Wurz, C-J Kao et al. radiotherapy alone in patients with locoregion- et al. 2005; Perez et al. 2011, 2014], trastuzumab ally advanced SCCHN [Bonner et al. 2006], and later received FDA approval in 2006 for the treat- a phase II study in patients with refractory recur- ment of breast cancer in the adjuvant setting in rent/metastatic SCCHN showing a 13% response combination with chemotherapy. Trastuzumab rate and median OS of approximately 6 months was most recently approved in 2010 for the first- with cetuximab monotherapy [Vermorken et  al. line treatment of metastatic gastric or gastro- 2007]. Cetuximab was subsequently approved as esophageal junction adenocarcinoma in first-line therapy in combination with chemo- combination with chemotherapy based on a phase therapy for recurrent/metastatic SCCHN on the III clinical trial showing significantly increased strength of the results of a phase III clinical trial OS following treatment with trastuzumab com- showing significant increases in median OS, PFS bined with chemotherapy [Bang et  al. 2010]. and response rate with the combination of cetux- Currently, trastuzumab in combination with imab and chemotherapy compared with chemo- pembrolizumab is being evaluated in a phase I/II therapy alone in patients with recurrent/ clinical trial in patients with trastuzumab-resis- metastatic SCCHN [Vermorken et  al. 2008]. tant, HER2-positive metastatic breast cancer The activity of cetuximab has also been evalu- [ClinicalTrials.gov identifier: NCT02129556]. It ated in NSCLC, where a meta-analysis of four has been previously shown that trastuzumab and phase II/III clinical trials showed that the combi- anti-PD-1 treatment are synergistic in mice nation of cetuximab and first-line chemotherapy [Stagg et al. 2011]. slightly, yet significantly, increased OS compared with platinum-based chemotherapy alone [Pujol Necitumumab. Still in clinical development, et al. 2014]. necitumumab is a second-generation anti-EGFR monoclonal antibody currently being evaluated Panitumumab is also used in the treatment of for the treatment of NSCLC. Recently published metastatic CRC. The results of a phase III clini- data from a phase III clinical trial in 1093 cal trial showing significant increases in PFS and patients with stage IV squamous NSCLC response rate in patients with chemotherapy- showed that necitumumab in combination with refractory metastatic CRC led to the accelerated chemotherapy as first-line treatment resulted in FDA approval of panitumumab in 2006 [Van a modest survival benefit, with a median OS of Cutsem et  al. 2007]. Panitumumab was most 11.5 months in patients treated with necitu- recently approved in 2014 as first-line treatment mumab plus chemotherapy compared with 9.9 in combination with chemotherapy in KRAS months in patients treated with chemotherapy wild-type, metastatic CRC following the results alone, a difference that was significant [Thatcher of phase III clinical trials showing a significant et  al. 2015]. In patients with stage IV nonsqua- increase in PFS, an increase in OS [Douillard mous NSCLC, however, combining necitu- et  al. 2010], and noninferiority with cetuximab mumab with standard chemotherapy as first-line [Price et al. 2014]. treatment provided no additional clinical benefit compared with chemotherapy alone [Paz-Ares Trastuzumab. Trastuzumab is a monoclonal anti- et al. 2015]. body used for the treatment of breast cancer over- expressing the human EGFR 2 (HER2) oncogene, which includes approximately 15–30% of breast VEGFA and VEGF-R2 cancers and is associated with a poor prognosis Vascular endothelial growth factor A (VEGFA) [Slamon et  al. 1987, 1989]. The FDA first plays a critical role in angiogenesis, and it is the approved trastuzumab in combination with che- target of the monoclonal antibody bevacizumab. motherapy in 1998 for the first-line treatment of In addition to its anti-angiogenic effects [Ferrara patients with metastatic breast cancer. This origi- et al. 2004], bevacizumab has been found to aug- nal approval was based on the results of a phase ment tumor infiltration by T and B lymphocytes III clinical trial showing that treatment with [Manzoni et  al. 2010; Hodi et  al. 2014] and to trastuzumab plus standard chemotherapy signifi- inhibit regulatory T cells (Tregs) [Terme et  al. cantly increased time to progression, response 2013]. Bevacizumab has been FDA approved for rate, duration of response and OS compared with the treatment of CRC (2004), glioblastoma chemotherapy alone [Slamon et al. 2001]. Based (2009), cervical cancer (2014), lung cancer on clinical trials data showing significant increases (2006), renal cell cancer (2009), breast cancer in disease-free survival (DFS) and OS [Romond (2008), and ovarian cancer (2014). http://tam.sagepub.com 9 Therapeutic Advances in Medical Oncology 8(1) Bevacizumab was initially approved for the first- VEGF-R2, also known as KDR (kinase insert line treatment of metastatic CRC in combination domain receptor) and Flk-1 (fetal liver kinase 1), with chemotherapy based on a phase III study is an RTK and the primary receptor through showing significant increases in PFS and median which VEGF mediates its angiogenic, mitogenic, OS compared with chemotherapy alone [Hurwitz and permeability-enhancing effects [Ferrara et al. et  al. 2004]. Shortly thereafter, bevacizumab 2004]. A monoclonal antibody that targets received approval as second-line treatment in VEGF-R2, ramucirumab has received FDA combination with chemotherapy for patients with approval for the second-line treatment of gastric previously treated metastatic CRC following the cancer and NSCLC within the past year. results of a phase III clinical trial showing signifi- Ramucirumab was approved as monotherapy and cant improvement in PFS and median OS in combination with paclitaxel for the treatment [Giantonio et  al. 2007] compared with chemo- of gastric or gastroesophageal junction adenocar- therapy alone. Two years later, another Phase III cinoma after progression on first-line chemother- trial in patients with recurrent or advanced apy based on the results of two phase III trials NSCLC showed significant increases in response showing significant increases in median OS com- rate, PFS and OS following treatment with beva- pared with placebo [Fuchs et al. 2014] and pacli- cizumab plus chemotherapy [Sandler et al. 2006], taxel plus placebo [Wilke et al. 2014]. Efficacy as which led to approval of bevacizumab combined second-line treatment for metastatic NSCLC with chemotherapy as first-line treatment of after progression on platinum-based chemother- recurrent/advanced NSCLC. The approval of apy was also demonstrated in a phase III trial bevacizumab as first-line treatment of metastatic showing significant improvement in PFS and OS breast cancer was supported by the results of a with the combination of docetaxel and ramu- phase III clinical trial in patients with HER2- cirumab compared with docetaxel plus placebo negative metastatic breast cancer showing that [Garon et al. 2014]. treatment with bevacizumab and paclitaxel led to significant increases in PFS and objective response rate (ORR) compared with paclitaxel alone PAP [Miller et al. 2007]. A phase II study used to sup- PAP is the target of the only currently FDA- port the 2009 FDA approval of bevacizumab approved therapeutic anticancer vaccine, sip- combined with chemotherapy for patients with uleucel-T (Provenge ). Sipuleucel-T was recurrent glioblastoma showed that treatment approved for the treatment of asymptomatic and with bevacizumab combined with chemotherapy minimally symptomatic metastatic castration- resulted in improved PFS and ORR, differences resistant prostate cancer in 2010 based on the that were significant compared to expected effects results of the phase III IMPACT trial showing a of salvage chemotherapy [Friedman et al. 2009]. significant increase in median OS in patients The same year, bevacizumab combined with treated with sipuleucel-T compared with those interferon α was approved as first-line treatment treated with placebo [Kantoff et  al. 2010a]. To of metastatic renal cell carcinoma (RCC) based prepare sipuleucel-T, peripheral blood mononu- on phase III data demonstrating significant clear cells from the patient are cultured with a improvement in PFS [Escudier et  al. 2007]. No fusion protein that incorporates PAP and significant improvement in OS was observed in GM-CSF (granulocyte-macrophage colony- this trial [Escudier et  al. 2010]. Most recently, stimulating factor). The patient is then infused bevacizumab was approved in 2014 for the treat- with these cells, and the process is repeated for ment of recurrent or metastatic cervical cancer three cycles. Thus, sipuleucel-T is actually a and recurrent, platinum-refractory ovarian carci- combination of a cell-based vaccine and autolo- noma based on phase III clinical trials showing gous ACT [Melero et al. 2014]. Interestingly, in significant increases in OS and response rate in addition to immune responses against the pri- cervical cancer [Tewari et  al. 2014], and signifi- mary antigenic target PAP, humoral immune cant improvement in PFS and ORR in ovarian responses against several secondary antigens cancer [Pujade-Lauraine et  al. 2014], compared such as PSA (prostate specific antigen), K-ras with chemotherapy alone. Like trastuzumab, bev- and KLK2/hK2 were also observed to be elevated acizumab and anti-PD-1 combination treatment in patients treated with sipuleucel-T but not con- is currently being clinically evaluated trol in the phase III IMPACT trial, and these [ClinicalTrials.gov identifiers: NCT02210117; responses were associated with improved OS NCT02039674; NCT02348008]. [GuhaThakurta et al. 2015]. 10 http://tam.sagepub.com GT Wurz, C-J Kao et al. Investigational tumor antigens and their months of additional follow up, the survival ben- clinical potential efit of tecemotide following concurrent chemora- In addition to the established tumor antigens for diotherapy remained significant [Mitchell et  al. which targeted immunotherapies have already 2015]. These results suggest that the timing of been approved (Table 1), there are numerous radiotherapy, chemotherapy and immunotherapy novel tumor antigens currently being investigated is important and that monitoring immune status as potential targets for new immunotherapies, may be necessary when designing treatment regi- including MUC1, PD-L1, lymphocyte activation mens combining immunotherapy with chemora- gene 3 (LAG-3), T-cell immunoglobulin domain diotherapy [Kao et  al. 2014, 2015]. Another and mucin domain 3 (TIM-3), V-domain immu- phase III trial, recently discontinued, was initi- noglobulin-containing suppressor of T-cell acti- ated to study tecemotide maintenance therapy vation (VISTA), NY-ESO-1, carcinoembryonic following concurrent chemoradiotherapy in antigen (CEA), PSA, MAGE-A3, 5T4, survivin NSCLC [DeGregorio et al. 2014]. and indoleamine-2,3-dioxygenase (IDO1). These selected antigens and their clinical potential as targets for investigational immunotherapies are Immune checkpoints: PD-L1; LAG-3; TIM-3; discussed below. Table 2 includes a more com- VISTA plete listing of tumor antigen targets for which PD-L1. As already mentioned, the development immunotherapies are currently being explored. of immune checkpoint inhibitors is currently the focus of intense research efforts. The interaction of PD-L1, which is expressed on the surface of MUC1 tumor cells, with PD-1 on activated T cells results Mucin 1 (MUC1) is one of the best-characterized in immunosuppression and tumor immune TAAs, and it is overexpressed and aberrantly escape [Iwai et  al. 2002; Swaika et  al. 2015]. glycosylated in over 90% of adenocarcinomas PD-L1 expression has been found to be inducible such as lung and breast cancer [Szabo, 2003; by interferon γ [Muhlbauer et  al. 2006]. Several Brayman et al. 2004]. MUC1 is a transmembrane investigational immunotherapies targeting PD-L1 glycoprotein expressed in several epithelial tissues, are presently in clinical development for meta- but the normal glycosylation pattern shields the static melanoma, NSCLC, RCC and bladder peptide core of the extracellular domain from cancer, among others. immunosurveillance. In cancer, the aberrant underglycosylation of MUC1 leads to exposure BMS-936559 (MDX-1105) is a monoclonal anti- of the immunogenic tandem repeat regions of body that inhibits the binding of PD-L1 to both the core peptide, making MUC1 an attractive PD-1 and CD80. The safety and antitumor activ- target for immunotherapies [Apostolopoulos and ity of BMS-936559 in patients with a variety of McKenzie, 1994; Vlad et al. 2004]. advanced cancers have been evaluated in a phase I clinical trial involving 207 patients [Brahmer While several different MUC1-targeted immuno- et al. 2012]. In NSCLC, an ORR of 10% (all par- therapies have been assessed in clinical trials tial responses) and PFS rate of 31% at 24 weeks [Kimura and Finn, 2013], the most advanced were observed. Patients with RCC showed a 12% agent is tecemotide, an antigen-specific, lipo- ORR and 53% progression-free response rate at some-based, peptide cancer vaccine [Wurz et  al. 24 weeks. In ovarian cancer, an ORR of only 6% 2014] that has been evaluated in a phase III clini- was observed [Brahmer et  al. 2012]. No more cal trial as maintenance therapy for patients with recent clinical data regarding BMS-936559 in locally advanced, unresectable stage IIIA/IIIB cancer therapy have emerged, and it appears that NSCLC who had not progressed following pri- clinical development of this agent for oncology mary chemoradiotherapy [Butts et al. 2014]. The applications has been discontinued [Mullard, results failed to demonstrate significant improve- 2013; Sunshine and Taube, 2015]. ment in OS with tecemotide compared with pla- cebo; however, a predefined subgroup analysis of Atezolizumab (MPDL3280A) is an anti-PD-L1 the patients who received concurrent chemoradi- monoclonal antibody that has demonstrated activ- otherapy followed by tecemotide showed a sig- ity against a variety of advanced cancers in phase I nificant survival benefit, while no survival benefit clinical trials. The Fc region of the antibody is was seen with sequential chemoradiotherapy modified to prevent both ADCC and comple- [Butts et  al. 2014]. After approximately 20 ment-dependent cytotoxicity (CDC) [Lu et  al. http://tam.sagepub.com 11 Therapeutic Advances in Medical Oncology 8(1) Table 2. Antigenic targets of investigational immunotherapies. Antigen Cancer types Targeted agents References A2aR NSCLC PBF-509 [Pinna, 2014] AKAP4 NSCLC Preclinical [Agarwal et al. 2013; Mirandola et al. 2015] Ovarian BAGE Glioblastoma Preclinical [Zhang et al. 2010; Akiyama et al. 2014] Ovarian BORIS Prostate, Lung Preclinical [Okabayashi et al. 2012; Cheema et al. 2014; Lee et al. 2014] Esophageal CD22 ALL Epratuzumab [Raetz et al. 2008; Advani et al. 2014; Annesley and Brown, 2015; Moxetumomab Raetz et al. 2015] Inotuzumab ozogamicin CD73 Advanced solid MEDI9447 [Hay et al. 2015] tumors CD137 Advanced solid Urelumab [Yonezawa et al. 2015] tumors PF-05082566 CEA CRC PANVAC™ [Turriziani et al. 2012; Morse et al. 2013a, 2013b] Ad5-[E1-, E2b-]- CEA(6D) CS1 Multiple myeloma Elotuzumab [Veillette and Guo, 2013] CTLA-4 Malignant Tremelimumab [Calabro et al. 2015] mesothelioma EBAG9 Bladder Preclinical [Miyazaki et al. 2014] EGF NSCLC CIMAvax [Gonzalez et al. 2007; Neninger Vinageras et al. 2008; Cheng and Kananathan, 2012; Ruiz et al. 2014] EGFR NSCLC Necitumumab [Thatcher et al. 2015] GAGE Cervical Preclinical [Kular et al. 2010] GD2 Neuroblastoma Dinutuximab, hu3F8 [Suzuki and Cheung, 2015] Retinoblastoma hu14.18-IL-2, 3F8/ Melanoma other OKT3BsAb solid tumors anti-GD2 CAR GD2-KLH gp100 Melanoma gp100:209-217(210M) [Schwartzentruber et al. 2011] HPV-16 Cervical HPV-16 (E6, E7) [Kenter et al. 2009; Brun et al. 2011; Bagarazzi et al. 2012; SCCHN TG4001, Lm-LLO-E7 Zaravinos, 2014] pNGVL4a-CRT/E7, INO-3112 HSP105 CRC Preclinical [Zappasodi et al. 2011; Kawai et al. 2014; Sawada et al. 2014] Bladder IDH1 Glioma IDH1(R132H) p123-142 [Schumacher et al. 2014] Idiotype NSCLC, Breast Racotumomab [Alfonso et al. 2002, 2014; Diaz et al. 2003] (NeuGcGM3) Melanoma IDO1 Breast, Melanoma Indoximod [Iversen et al. 2014, 2015; Soliman et al. 2014] NSCLC INCB024360 IDO1 peptide vaccine KIR Lymphoma Lirilumab [Kohrt et al. 2014] LAG-3 Breast, Hemato- BMS-986016 [Brignone et al. 2010; Creelan, 2014; Nguyen and Ohashi, 2015] logical, Advanced IMP321 solid tumors LY6K Gastric LY6K-177 peptide [Ishikawa et al. 2014; Yoshitake et al. 2015] SCCHN LY6K, CDCA1, IMP3 MAGE-A3 Melanoma recMAGE-A3 [Kruit et al. 2013; Ulloa-Montoya et al. 2013; Vansteenkiste et al. NSCLC Zastumotide 2013; Melero et al. 2014] MAGE-C2 Gastric, Melanoma Preclinical [Zhang et al. 2013; Ghadban et al. 2014; Reinhard et al. 2014] Multiple myeloma (Continued) 12 http://tam.sagepub.com GT Wurz, C-J Kao et al. Table 2. (Continued) Antigen Cancer types Targeted agents References MAGE-D4 CRC Preclinical [Zhang et al. 2014] Melan-A Melanoma MART-1 (26-35, 27L) [Tarhini et al. 2012; Romano et al. 2014] MET NSCLC Onartuzumab [Scagliotti et al. 2012; Spigel et al. 2013; Stinchcombe, 2014] Tivantinib MUC1 NSCLC, Breast Tecemotide, TG4010 [Kimura and Finn, 2013; Butts et al. 2014; Wurz et al. 2014] Prostate PANVAC™ MUC4 Pancreatic Preclinical [Wu et al. 2009; Torres et al. 2012; Zhu et al. 2014] MUC16 Ovarian Abagovomab [Buzzonetti et al. 2014; Felder et al. 2014] Oregovomab NY-ESO-1 Ovarian NY-ESO-1/ [Robbins et al. 2011; Odunsi et al. 2012; Klein et al. 2015] Melanoma ISCOMATRIX™ rV-NY-ESO-1; rF-NY- ESO-1 PD-1 B-cell lymphoma Pidilizumab [Armand et al. 2013; Homet Moreno et al. 2015] Melanoma, CRC AMP-224, AMP-514 PD-L1 NSCLC, RCC BMS-936559, [Cha et al. 2015; Ibrahim et al. 2015; Sunshine and Taube, 2015; Bladder, Breast Atezolizumab Swaika et al. 2015] Melanoma, SCCHN Durvalumab, Avelumab PRAME NSCLC Preclinical [De Pas et al. 2012] PSA Prostate PROSTVAC -VF [Gulley et al. 2010; Kantoff et al. 2010b; Shore, 2014] ROR1 CLL, Pancreatic Preclinical [Hojjat-Farsangi et al. 2014; Berger et al. 2015; Shabani et al. Lung, Breast 2015] Sialyl-Tn Breast Theratope [Miles et al. 2011; Ibrahim et al. 2013] SPAG-9 Prostate, CRC Preclinical [Garg et al. 2007; Kanojia et al. 2011; Wang et al. 2013; Chen et al. NSCLC, Ovarian 2014] SSX1 Prostate Preclinical [Smith et al. 2011; He et al. 2014] Multiple myeloma Survivin Melanoma EMD640744 [Becker et al. 2012; Lennerz et al. 2014; Pollack et al. 2014] Glioma, Solid Trivalent peptide tumors vaccine Tripeptide vaccine Telomerase Pancreatic Tertomotide [Melero et al. 2014; Staff et al. 2014] TIM-3 Melanoma, NHL Preclinical [Sakuishi et al. 2010; Ngiow et al. 2011; Gao et al. 2012; Fourcade NSCLC et al. 2014; Jiang et al. 2015] VISTA Melanoma, Preclinical [Le Mercier et al. 2014; Lines et al. 2014b] Bladder WT1 Ovarian, Uterine, WT1 peptide vaccine [Coosemans et al. 2014; Di Stasi et al. 2015] AML Multiple myeloma XAGE-1b Prostate DC-based tumor [Zhou et al. 2008; Xie and Wang, 2015] vaccine 5T4 RCC, CRC TroVax [Amato et al. 2010; Zhang et al. 2012; Harrop et al. 2013; Eisen Prostate Naptumomab et al. 2014; Rowe and Cen, 2014; Stern et al. 2014] estafenatox Abbreviations: A2aR, adenosine A2a receptor; AKAP4, A kinase anchor protein 4; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; BAGE, B melanoma antigen; BORIS, brother of the regulator of imprinted sites; CEA, carcinoembryonic antigen; CLL, chronic lymphocytic leukemia; CRC, colorectal cancer; CS1, CD2 subset 1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; EBAG9, estrogen receptor binding site associated antigen 9; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; GAGE, G antigen; GD2, disialoganglioside GD2; gp100, glycoprotein 100; HPV-16, human papillomavirus 16; HSP105, heat-shock protein 105; IDH1, isocitrate dehy- drogenase type 1; IDO1, indoleamine-2,3-dioxygenase 1; KIR, killer cell immunoglobulin-like receptor; LAG-3, lymphocyte activation gene 3; LY6K, lymphocyte antigen 6 complex K; MAGE-A3, melanoma antigen 3; MAGE-C2, melanoma antigen C2; MAGE-D4, melanoma antigen D4; Melan-A/ MART-1, melanoma antigen recognized by T-cells 1; MET, N-methyl-N’-nitroso-guanidine human osteosarcoma transforming gene; MUC1, mucin 1; MUC4, mucin 4; MUC16, mucin 16; NHL, non-Hodgkin lymphoma; NY-ESO-1, New York esophageal squamous cell carcinoma 1; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand 1; PRAME, preferentially expressed antigen of melanoma; PSA, prostate specific antigen; RCC, renal cell carcinoma; ROR1, receptor tyrosine kinase orphan receptor 1; SCCHN, squamous cell carcinoma of the head and neck; SPAG-9, sperm-associated antigen 9; SSX1, synovial sarcoma X-chromosome breakpoint 1; TIM-3, T-cell immunoglobulin domain and mucin domain-3; VISTA, V-domain immunoglobulin-containing suppressor of T-cell activation; WT1, Wilms’ Tumor-1; XAGE-1b, X chromosome antigen 1b. http://tam.sagepub.com 13 Therapeutic Advances in Medical Oncology 8(1) 2014], which prevents the killing of immune cells multiforme is currently underway [Reardon et al. that also express PD-L1, such as activated T cells. 2015]. Durvalumab has also entered a phase III Atezolizumab is currently being evaluated in clinical trial in combination with concurrent patients with locally advanced or metastatic solid chemoradiotherapy in patients with stage III unre- tumors in an ongoing phase I study. In a cohort of sectable NSCLC [ClinicalTrials.gov identifier: patients with metastatic urothelial bladder cancer, NCT02125461] and a phase II/III clinical trial an ORR of 43% was observed at 6 weeks, increas- [ClinicalTrials.gov identifier: NCT02154490] in ing to 52% at 12 weeks of treatment [Powles et al. patients with recurrent stage IIIB/IV squamous 2014]. As there had been no significant advances cell NSCLC [Lee and Chow, 2014; Ibrahim et al. in the treatment of metastatic urothelial cancer in 2015]. Other ongoing phase II and phase III clini- decades, these results led to breakthrough desig- cal trials of durvalumab include third-line treat- nation status by the FDA in June 2014. Updated ment of stage IIIB/IV NSCLC [ClinicalTrials.gov response and survival data from this study after an identifier: NCT02087423], second-line treatment additional 8 months of follow up continued to of SCCHN [ClinicalTrials.gov identifier: show promising PFS and OS results [Petrylak NCT02207530; Ibrahim et  al. 2015] and treat- et al. 2015]. For patients with NSCLC, an ORR ment of advanced NSCLC alone or in combina- of 23% and PFS rate of 45% at 24 weeks was seen tion with tremelimumab [ClinicalTrials.gov with atezolizumab treatment [Herbst et al. 2014], identifier: NCT02352948; Planchard et al. 2015]. and the most recent data continued to show clini- cal benefit in NSCLC [Horn et  al. 2015]. A fourth anti-PD-L1 monoclonal antibody, ave- Atezolizumab has also been studied in combina- lumab (MSB0010718C), is currently in phase I tion with first-line chemotherapy in metastatic development in subjects with metastatic or locally NSCLC patients, and was found to improve ORR advanced solid tumors [ClinicalTrials.gov identi- in all combinations tested in a phase Ib trial [Liu fier: NCT01772004], with a separate phase I et  al. 2015b]. In patients with metastatic mela- trial in Japanese subjects [Lu et al. 2014]. Results noma or RCC, ORRs of 30% and 14%, and PFS of this phase I trial in extensively pretreated rates of 41% and 48% at 24 weeks, respectively, patients with a variety of different tumors have so were observed [Herbst et al. 2014]. Patients in the far demonstrated that avelumab has an accepta- triple-negative breast cancer cohort had an ORR ble safety profile [Kelly et  al. 2015]. A phase Ib of 19% and a PFS rate of 27% at 24 weeks [Emens expansion study in advanced NSCLC patients et al. 2015]. who had progressed after platinum-based chem- otherapy demonstrated increased activity with Preliminary results from two phase II clinical tri- avelumab treatment in patients with PD-L1- als of atezolizumab in patients with advanced positive tumors [Gulley et  al. 2015]. A phase II NSCLC were recently reported. In both chemo- study of avelumab in patients with metastatic therapy-naïve and previously treated patients, an Merkel cell carcinoma is currently underway increasing ORR to atezolizumab treatment was [Kaufman et  al. 2015]. Interestingly, unlike the associated with increasing PD-L1 expression other anti-PD-L1 antibodies being developed, [Spigel et al. 2015]. Compared with docetaxel in avelumab appears to possess ADCC activity previously treated NSCLC, treatment with ate- [Boyerinas et al. 2015]. zolizumab was found to increase OS, PFS and ORR in association with PD-L1 expression [Spira LAG-3. LAG-3 is a negative regulator of effector et  al. 2015]. There are currently several other T-cell function [Sierro et  al. 2011], making it an phase I/II and phase III clinical trials of atezoli- attractive target for immunotherapy. LAG-3 is zumab currently underway [Swaika et al. 2015]. expressed on the membranes of activated T cells and is upregulated on exhausted T cells [Nguyen Durvalumab (MEDI4736) is an anti-PD-L1 and Ohashi, 2015]. Because LAG-3 is also monoclonal antibody similar to atezolizumab, expressed on activated Tregs, LAG-3 blockade with an Fc region modification that prevents may inhibit the suppressive effects of Tregs in ADCC and CDC. In a phase I clinical trial, addition to the direct action on effector cells response rates of 13% and 14% were observed in [Huang et al. 2004]. The major ligand of LAG-3 patients with metastatic NSCLC and SCCHN, is MHC class II, and their interaction may play a respectively [Lee and Chow, 2014]. A phase II role in modulating dendritic cell function [Gold- study [ClinicalTrials.gov identifier: berg and Drake, 2011; Camisaschi et al. 2014]. A NCT02336165] in patients with glioblastoma monoclonal antibody targeting LAG-3, known as 14 http://tam.sagepub.com GT Wurz, C-J Kao et al. BMS-986016, is currently in early phase I clinical elevated VISTA expression. Treatment with an development. Ongoing clinical trials are investi- anti-VISTA monoclonal antibody resulted in gating single agent BMS-986016 for hematologi- tumor growth inhibition, especially in combina- cal malignancies and a combination of nivolumab tion with a tumor vaccine [Le Mercier et al. 2014]. and BMS-986016 in patients with advanced solid In these studies, VISTA blockade was found to be tumors [Creelan, 2014; Nguyen and Ohashi, effective with no detectable expression of VISTA 2015]. In addition to the membrane-bound form and high expression levels of PD-L1 on tumor of LAG-3, the LAG3 gene also codes for a soluble cells. This observation could have important clini- variant, sLAG-3, that functions as an immune cal implications for combination treatments tar- adjuvant [Nguyen and Ohashi, 2015]. A sLAG-3 geting the VISTA and PD-1/PD-L1 checkpoint immunoglobulin fusion protein (IMP321) is in pathways, allowing for potential synergy due to early clinical development as an immune adju- the fact that these pathways operate indepen- vant. In a Phase I clinical trial evaluating a combi- dently [Lines et al. 2014b; Liu et al. 2015a]. nation of taxane-based chemotherapy and IMP321 in women with metastatic breast cancer, a 50% ORR was observed [Brignone et al. 2010]. CTAs: NY-ESO-1 and MAGE-A3 CTAs constitute the majority of the currently TIM-3. TIM-3 is an inhibitory immune check- identified TAAs, and numerous CTAs are being point receptor that limits the duration and magni- investigated as potential targets of new anticancer tude of T 1 CD4+ and CD8+ CTL cellular immunotherapies for a variety of malignancies. responses [Anderson, 2014]. Galectin-9 has been Among these, immunotherapies targeting identified as the ligand for TIM-3, and it is NY-ESO-1 and MAGE-A3 have reached the through this pathway that T 1 immunity may be clinical stage of development. These antigens are suppressed [Zhu et  al. 2005]. The expression of normally expressed only in adult testis germ cells TIM-3 on dysfunctional CD8+ T cells and Tregs and become aberrantly re-expressed in various makes it an attractive target for anticancer immu- cancers such as lung, bladder and melanoma notherapy. Preclinical animal models have shown [Jungbluth et al. 2001]. that antibody inhibition of TIM-3 is very effective in suppressing tumor growth [Ngiow et al. 2011]. NY-ESO-1. NY-ESO-1 is encoded by the CTAG1B Synergistic antitumor effects in multiple cancer gene and was first identified in 1997 [Chen et al. types have been observed in preclinical models 1997]. Expressed in a variety of carcinomas and with the combination of anti-PD-1/PD-L1 and sarcomas, NY-ESO-1 is highly immunogenic and TIM-3 blockade [Sakuishi et  al. 2010; Ngiow is thus a logical target for anticancer immuno- et al. 2011; Jing et al. 2015]. Clinically, increased therapy [Nicholaou et al. 2006; Endo et al. 2015]. expression of TIM-3 and PD-1 in melanoma In a phase I clinical trial in patients with advanced patients has been associated with tumor NY- synovial cell sarcoma and melanoma, subjects ESO-1-specific CD8+ T-cell dysfunction [Four- were administered autologous ACT using cells cade et al. 2014]. In NSCLC, TIM-3 is expressed transduced with a T-cell receptor (TCR) targeting on tumor-infiltrating CD4+ and CD8+ T cells NY-ESO-1. Objective response rates of 67% (4/6) [Gao et  al. 2012], and the presence of CD4+ T and 45% (5/11) were observed for synovial cell cells that express TIM-3 is strongly correlated sarcoma and melanoma patients, respectively with advanced tumor grade in NSCLC [Gao [Robbins et  al. 2011]. Autologous ACT has also et  al. 2012] and poor survival in follicular B-cell been performed using NY-ESO-1-specific CD4+ non-Hodgkin lymphoma [Yang et al. 2012]. Thus, cells [Hunder et al. 2008]. A prime-boost vaccine TIM-3 has great clinical potential as a target of strategy was assessed in patients with stage III/IV novel immunotherapies [Cheng and Ruan, 2015]. melanoma and stage II-IV ovarian carcinoma in a phase II clinical trial. Patients were primed with a VISTA. VISTA is a newly identified negative recombinant NY-ESO-1-expressing vaccinia immune checkpoint regulator [Lines et al. 2014b]. virus and then boosted with an NY-ESO-1-ex- Unlike PD-L1, VISTA is expressed primarily in pressing fowlpox virus. In the melanoma patients, hematopoietic cells in both mice [Wang et  al. CD8+ T-cell responses increased from 40% pre- 2011] and humans [Lines et al. 2014a]. In murine treatment to 88% following vaccination. Median models of melanoma and bladder cancer, leuko- OS was significantly increased in the melanoma cytes within the tumor microenvironment and in and ovarian cancer patients who had immune tumor-draining lymph nodes were found to have responses following treatment [Odunsi et  al. http://tam.sagepub.com 15 Therapeutic Advances in Medical Oncology 8(1) 2012]. An NY-ESO-1-specific vaccine (NY- Oncofetal antigens: CEA and 5T4 ESO-1/ISCOMATRIX™) in combination with Oncofetal antigens are so-called because though cyclophosphamide has also been evaluated in widely expressed during fetal development, nor- advanced melanoma in phase II. Treatment led to mal expression is generally limited in adults. In a significant increase in antigen-specific CD4+ cancer, the expression of these antigens becomes T-cell immune responses [Klein et al. 2015] com- upregulated, making them potential targets for pared to a cohort of patients treated with the vac- immunotherapeutic intervention. cine alone [Nicholaou et al. 2009]. A prime-boost treatment strategy employing NY-ESO-1/ISCO- CEA. CEA is a well-known oncofetal antigen nor- MATRIX™ in high-risk, resected melanoma mally expressed in the stomach, tongue, esopha- patients was found to augment CD8+ T-cell gus, cervix and prostate in adults, but becomes immune responses [Chen et al. 2015]. highly overexpressed in colorectal and gastric can- cers [Beauchemin and Arabzadeh, 2013]. Clini- MAGE-A3. MAGE-A3 is a CTA that has been cally, CEA has been investigated extensively as an extensively clinically investigated as a target for immunotherapeutic target for colorectal and vari- immunotherapy in melanoma and lung cancer. ous other cancers [Turriziani et  al. 2012]. In a In a clinical trial involving nine patients with phase I/II clinical trial, treatment with an adenovi- advanced cancers, five responses were observed ral gene delivery platform encoding the CEA anti- following autologous ACT with T cells trans- gen produced cell-mediated immunity in 61% of duced with anti-MAGE-A3 TCRs. However, patients with advanced CRC and a 48% OS rate neurological toxicities were seen in three patients, at 12 months [Morse et  al. 2013a]. A phase II resulting in two deaths due to previously unknown study in CRC patients who were disease-free fol- expression of MAGE family antigens in the brain lowing metastasectomy and perioperative chemo- [Morgan et al. 2013]. A Phase II study examined therapy compared the effectiveness of autologous vaccination with recombinant MAGE-A3 pro- dendritic cells modified with PANVAC™, a pox- tein combined with either AS15 [a combination vector encoding both CEA and MUC1, to the of QS21 saponin, monophosphoryl lipid A PANVAC™ poxvector administered in combina- (MPL-A), and CpG7909, a Toll-like receptor tion with GM-CSF. Survival and recurrence-free (TLR)-9 agonist, in a liposomal formulation] or survival were similar between the two treatment AS02 (a combination of QS21 saponin and groups, and vaccinated patients overall experi- MPL-A, a TLR-4 agonist) immunostimulants in enced superior survival compared with a contem- patients with stage III/IV melanoma. Trends porary group of patients not treated with towards greater ORR, PFS and median OS were immunotherapy [Morse et al. 2013b]. In a recently observed in the patients who received the AS15 reported phase II trial comparing treatment with immunostimulant compared with AS02 [Kruit PANVAC™ in combination with docetaxel to et  al. 2013]. The peptide vaccine zastumotide docetaxel alone in 48 patients with metastatic (GSK2132231A) is being evaluated in a phase breast cancer, patients treated with the combina- III clinical trial in patients with resected stage tion experienced improved PFS compared with IIIB/IIIC melanoma. This trial failed to demon- docetaxel alone, a result which, while not signifi- strate a significant prolongation of DFS in cant, was suggestive of a clinical benefit [Heery patients with positive expression of MAGE-A3 et  al. 2015]. Increased CEA expression has been [Melero et al. 2014], but it is ongoing in a subset associated with shorter relapse-free survival in of patients who are positive for a predictive breast cancer patients [Saadatmand et al. 2013]. marker of response [Ulloa-Montoya et al. 2013]. A phase II clinical trial of zastumotide 5T4. The oncofetal antigen 5T4 was identified by (GSK1572932A) in patients with resected stage screening for shared surface molecules in human IB/II NSCLC exhibited a trend toward positive trophoblasts and human cancer cells [Stern et al. treatment outcomes compared with placebo 2014]. A heavily glycosylated, membrane-bound [Vansteenkiste et  al. 2013]; however, a large protein, 5T4 is highly expressed in cervical, phase III study in patients with resected stage IB- colorectal, gastric, ovarian, prostate, lung and IIIA NSCLC failed to meet its primary endpoint renal cancers [Southall et  al. 1990]. The expres- of significant prolongation of DFS, resulting in sion of 5T4 has been associated with epithelial termination of the study [Melero et  al. 2014]. mesenchymal transition (EMT), which is involved Clinical development of zastumotide appears to in the metastasis of epithelial cancers [Nieto have been discontinued. and Cano, 2012]. Three different 5T4-based 16 http://tam.sagepub.com GT Wurz, C-J Kao et al. immunotherapeutic strategies are being clinically PSA evaluated: a vaccine known as TroVax (modified PSA is a well-known prostate cancer biomarker vaccinia virus Ankara- MVA), an antibody–supe- that is now a target for antigen-specific immuno- rantigen [Staphylococcal Enterotoxin A (SEA)] therapy. An anticancer vaccine known as fusion protein, and an antibody–drug conjugate PROSTVAC -VF (PSA-TRICOM; rilimogene (ADC) combining a 5T4-specific monoclonal galvacirepvec) has been developed that incorpo- antibody with a tubulin inhibitor. rates three co-stimulatory molecules (CD80, CD54 and CD58, collectively referred to as 5T4 vaccine (TroVax®). Favorable trends toward TRICOM) and two recombinant viral vectors clinical benefit have been observed in early phase encoding PSA transgenes [Singh et  al. 2015]. I and phase II clinical trials of the TroVax Patients are primed with the vaccinia-based vec- 5T4-MVA vaccine in advanced RCC [Zhang tor and then boosted with a fowlpox vector, both et  al. 2012], CRC [Rowe and Cen, 2014], and of which are administered with GM-CSF. Early castration-resistant prostate cancer [Harrop phase I and phase II clinical trials in patients with et  al. 2013]. To determine whether treatment metastatic castration-resistant prostate cancer ® ® with TroVax can improve survival, a phase III (mCRPC) demonstrated that PROSTVAC -VF clinical trial in patients with metastatic RCC is safe, induces a high rate of immune responses compared treatment with TroVax to standard of and has survival benefits [DiPaola et  al. 2006; care treatment [Amato et  al. 2010]. While this Arlen et al. 2007; Gulley et al. 2010]. A double- trial failed to demonstrate any significant effects blind, randomized, controlled phase II clinical of TroVax on OS, a subgroup of patients with trial in patients with mCRPC showed that treat- good prognosis and receiving concurrent IL-2 ment with PROSTVAC -VF significantly experienced a significant survival benefit com- improved OS by 8.5 months compared to treat- pared with placebo. The patients with the great- ment with control vectors [Kantoff et al. 2010b]. est increases in 5T4-specific antibodies also A phase III clinical trial [ClinicalTrials.gov iden- experienced a survival benefit with TroVax tifier: NCT01322490] in 1200 patients with compared with placebo, which is consistent with asymptomatic or minimally symptomatic mCRPC a pooled analysis of prior phase I/II TroVax is currently ongoing [Singh et al. 2015]. studies [Harrop et al. 2010]. 5T4 superantigen–antibody fusion protein (naptu- Survivin momab estafenatox). The tumor-targeted super- Also known as BIRC5 (baculoviral inhibitor of antigen concept employs bacterial superantigens, apoptosis protein repeat-containing 5), survivin is which are the most potent known activators of T an inhibitor of the intrinsic apoptosis pathway cells, to attract and activate large numbers of T that is widely overexpressed in cancers, making it cells to the target [Eisen et  al. 2014]. A phase II an attractive target for antigen-specific immuno- study of the superantigen-antibody fusion protein therapy [Mobahat et  al. 2014]. Peptide cancer targeting 5T4 in RCC showed a significant sur- vaccines targeting survivin have been evaluated in vival benefit [Shaw et al. 2007], which led to the phase I and phase II clinical trials. A phase I study development of ANYARA (naptumomab estafe- of a multi-epitope anti-survivin peptide vaccine natox) [Eisen et  al. 2014]. Naptumomab estafe- (EMD640744) in patients with advanced solid natox has been evaluated in combination with tumors found an antigen-specific T-cell response interferon α in a phase II/III clinical trial involv- in 63% of subjects, and 28% of vaccinated sub- ing patients with advanced RCC. Although the jects achieved stable disease [Lennerz et al. 2014]. study failed to meet its primary endpoint, survival Another phase I study in pediatric brainstem gli- benefits were seen in a subgroup of patients with oma patients using a tripeptide vaccine contain- low levels of IL-6 and normal levels of SEA anti- ing survivin and given in combination with the bodies [Elkord et  al. 2015]. The results of this immunoadjuvant poly-ICLC (polyinosinic- study are still undergoing analysis, and a phase II/ polycytidylic acid stabilized by lysine and carbox- III clinical trial of naptumomab estafenatox in ymethylcellulose) showed evidence of survivin- combination with a TKI for metastatic RCC is specific immune responses and clinical benefit being designed [Stern et al. 2014]. Lastly, promis- [Pollack et al. 2014]. In grade 2 low-grade glioma ing preclinical activity has been seen with an ADC patients, vaccination with survivin and three other targeting 5T4 [Sapra et  al. 2013], and clinical glioma-associated peptides combined with poly- evaluation is now underway [Stern et al. 2014]. ICLC produced robust T 1 immune responses http://tam.sagepub.com 17 Therapeutic Advances in Medical Oncology 8(1) [Okada et al. 2015]. The efficacy of another sur- Discussion vivin-targeted peptide vaccine in metastatic mela- With the recent clinical development and thera- noma patients was evaluated in a phase II clinical peutic successes of immune checkpoint inhibi- trial. Treatment with the vaccine, which contained tors targeting the CTLA-4 and PD-1/PD-L1 three survivin peptide epitopes, significantly pro- pathways, such as ipilimumab, pembrolizumab longed OS in patients with antigen-specific T-cell and nivolumab, enthusiasm surrounding anti- responses [Becker et al. 2012]. cancer immunotherapy has become intense. However, despite the impressive improvements in clinical outcome seen with these agents, the IDO1 response rates remain modest, but encouraging. Upregulation of indolamine-2,3-dioxygenase Clearly, we must expand our knowledge about (IDO1), which catabolizes the essential amino acid how these agents work and the safest way to tryptophan, is a recently discovered mechanism of administer them in order to improve their effi- tumor cell immune escape. Tryptophan is required cacy. With respect to antigen-specific immuno- for normal T-cell function, and its depletion can therapies, the abundance of tumor antigens that lead to immunosuppression [Jiang et  al. 2015]. have been identified has allowed for the devel- The IDO1 enzyme is overexpressed in various opment of multiple monoclonal antibodies and malignancies including breast, NSCLC, prostate peptide cancer vaccines targeting these anti- and gastric cancers [Uyttenhove et al. 2003]. Two gens, but the responses to these agents as well small molecule IDO1 enzyme inhibitors and a remain modest, due in part to mechanisms of peptide-based vaccine are currently being evalu- tumor evasion and immunosuppression, and the ated in clinical trials. Indoximod (1-methly-D- fact that TAA expression profiles are patient- tryptophan) combined with docetaxel was specific. With the availability of checkpoint evaluated in a phase I clinical trial in patients with inhibitors, it is now possible to alter the immu- metastatic solid tumors. The treatment was well nosuppressive tumor microenvironment, which tolerated with evidence of clinical activity [Soliman could potentially increase the efficacy of anti- et al. 2014]. A phase II trial of this agent in combi- gen-specific immunotherapies. It is thus becom- nation with docetaxel as first-line treatment for ing quite clear that in order to derive the metastatic breast cancer is ongoing [ClinicalTrials. maximum benefit from these novel immuno- gov identifier: NCT01792050], in addition to a therapies, we must learn more about how to number of other phase II studies in metastatic mel- best use these agents in combination with chem- anoma, prostate and pancreatic cancers. otherapy and with each other. Numerous clini- cal trials investigating various combinations of The other small molecule IDO1 inhibitor, immunotherapies and chemotherapy are already INCB024360, is currently being evaluated in com- underway. bination with ipilimumab in a phase I/II study [ClinicalTrials.gov identifier: NCT02077114 Another point to consider with the use of cancer (completed)] in metastatic melanoma [Iversen vaccines is that while they are not often associ- et al. 2015], a phase I/II study [ClinicalTrials.gov ated with clinically significant objective responses identifier: NCT02318277] of INCB024360 in or improvements in PFS, they have been shown combination with durvalumab in patients with to significantly prolong OS, and thus OS may be advanced solid tumors [Ibrahim et al. 2015] and the most valid clinical endpoint for assessment a phase Ib study [ClinicalTrials.gov identifier: of the efficacy of these agents [DeGregorio et al. NCT02298153] in stage IIIB/IV NSCLC in 2012; Dillman, 2015]. Ultimately, personalized combination with atezolizumab [Cha et al. 2015]. immunotherapy, whereby patients are screened A peptide vaccine targeting IDO1 was evaluated for the expression of tumor antigens and PD-1/ in a phase I clinical trial in patients with meta- PD-L1 so that they can be matched with the static NSCLC. Median OS was approximately appropriate antigen-specific agent, checkpoint 26 months, and long-lasting disease stabilization inhibitor and chemotherapeutic agent, may be was observed in 47% of patients. A currently the best means of deriving the maximum thera- ongoing phase II study in patients with metastatic peutic benefits from these treatments [Kao et al. melanoma is evaluating the effects of a peptide 2015]. The future of personalized cancer immu- vaccine containing epitopes to survivin and IDO1 notherapy has never been more promising, and in combination with temozolomide [Iversen et al. the results of ongoing clinical trials are eagerly 2014]. awaited. 18 http://tam.sagepub.com GT Wurz, C-J Kao et al. Anderson, M., Venanzi, E., Klein, L., Chen, Z., Funding Berzins, S., Turley, S. et al. (2002) Projection of an This research received no specific grant from any immunological self shadow within the thymus by the funding agency in the public, commercial, or not- Aire protein. Science 298: 1395–1401. for-profit sectors. Annesley, C. and Brown, P. (2015) Novel agents for Conflict of interest statement the treatment of childhood acute leukemia. Ther Adv The author(s) declare(s) that there is no conflict Hematol 6: 61–79. of interest. Apostolopoulos, V. and McKenzie, I. (1994) Cellular mucins: targets for immunotherapy. Crit Rev Immunol 14: 293–309. 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Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential:

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615514 TAM0010.1177/1758834015615514Therapeutic Advances in Medical OncologyGT Wurz, C-J Kao review-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Novel cancer antigens for personalized 2016, Vol. 8(1) 4 –31 DOI: 10.1177/ immunotherapies: latest evidence and © The Author(s), 2015. Reprints and permissions: clinical potential http://www.sagepub.co.uk/ journalsPermissions.nav Gregory T. Wurz, Chiao-Jung Kao and Michael W. DeGregorio Abstract: The clinical success of monoclonal antibody immune checkpoint modulators such as ipilimumab, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the recently approved agents nivolumab and pembrolizumab, which target programmed cell death receptor 1 (PD-1), has stimulated renewed enthusiasm for anticancer immunotherapy, which was heralded by Science as ‘Breakthrough of the Year’ in 2013. As the potential of cancer immunotherapy has been recognized since the 1890s when William Coley showed that bacterial products could be beneficial in cancer patients, leveraging the immune system in the treatment of cancer is certainly not a new concept; however, earlier attempts to develop effective therapeutic vaccines and antibodies against solid tumors, for example, melanoma, frequently met with failure due in part to self-tolerance and the development of an immunosuppressive tumor microenvironment. Increased knowledge of the mechanisms through which cancer evades the immune system and the identification of tumor-associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of vaccines and monoclonal antibodies targeting specific tumor antigens and immune checkpoints such as CTLA-4 and PD-1. This review first discusses the established targets of currently approved cancer immunotherapies and then focuses on investigational cancer antigens and their clinical potential. Because of the highly heterogeneous nature of tumors, effective anticancer immunotherapy-based treatment regimens will likely require a personalized combination of therapeutic vaccines, antibodies and chemotherapy that fit the specific biology of a patient’s disease. Keywords: antitumor antibody, cancer-testis antigen, cancer vaccine, immunotherapy, oncofetal antigen, tumor-associated antigen Correspondence to: Michael W. DeGregorio, Introduction immune system. Indeed, the first such tumor- Pharm D The possibility that immunotherapy could be associated antigen (TAA), known as melanoma Department of Internal Medicine, Division of useful for the treatment of cancer was first real- antigen 1 (MAGE-1, also known as MAGE-A1), Hematology and Oncology, ized in the 1890s when William B. Coley showed was identified in human melanoma cells by Boon University of California, Davis, 4501 X Street Suite that injecting killed bacterial cultures, known as and colleagues in 1991 [van der Bruggen et  al. 3016, Sacramento, Coley toxins, had beneficial effects in cancer 1991]. Since that seminal discovery, the number CA 95817, USA mwdegregorio@ucdavis. patients [Nauts et al. 1953]. Decades later, stud- of new TAAs has grown steadily to the point edu ies performed in chemically induced sarcoma where there are now over 400 T-cell-defined Gregory T. Wurz, PhD mouse models showed that syngeneic mice human tumor antigenic peptides that have been Department of Internal Medicine, Division of injected with irradiated sarcoma cells displayed identified [Vigneron et  al. 2013]. Until the late Hematology and Oncology, immunity when later challenged with live sar- 20th century, the role of immunosurveillance in University of California, Davis, Sacramento, CA, coma cells [Foley, 1953; Prehn and Main, 1957; cancer control had been the subject of much USA Klein et  al. 1960]. The fact that the immunity debate [Schreiber et al. 2011]; however, two stud- Chiao-Jung Kao, PhD conferred in this manner was tumor-specific sug- ies by Schreiber and colleagues involving inter- Department of Obstetrics and Gynecology, University gested that tumors express unique antigens that feron gamma and tumor immunogenicity in of California, Davis are specifically recognized by the adaptive immunocompetent hosts are considered to have Sacramento, CA, USA 4 http://tam.sagepub.com GT Wurz, C-J Kao et al. played a major role in renewing interest in tumor (T 1) and cytotoxic T lymphocyte (CTL)- immunology [Kaplan et al. 1998; Shankaran et al. mediated] as opposed to humoral [T helper type 2001]. Over the years, a number of different 2 (T 2), antibody-mediated] immune responses approaches to cancer immunotherapy, including in order to be effective [Rosenberg, 2001; antibodies, cytokines, adoptive cell therapy Kirkwood et al. 2012; Melero et al. 2014]. A T 1- (ACT) and therapeutic vaccines, have been polarized immune response involving CTLs and attempted, but the overall response rates have natural killer (NK) cells mediates the elimination been largely disappointing [Kirkwood et al. 2012; of tumor cells, while a T 2-polarized immune Savage et al. 2014]. Only recently, as knowledge response can have deleterious effects by promot- of tumor biology and immunology has improved, ing tumor development and progression has the complex nature of the interactions [Kirkwood et  al. 2012; Curigliano et  al. 2013]. between the immune system and cancer come This is not to say that antibody-based anticancer into focus, which has allowed the development of immunotherapies are ineffective against solid more specifically targeted agents [Kirkwood et al. tumors. Indeed, the past decade has seen the clin- 2012; Galluzzi et al. 2014]. ical development of numerous monoclonal anti- bodies directed at growth factors such as vascular Nonmutated, shared self-antigens constitute the endothelial growth factor A (VEGFA; e.g. bevaci- majority of currently identified TAAs and can be zumab), growth factor receptors such as human classified into three major categories: (a) tumor- epidermal growth factor receptor (EGFR or specific or cancer-testis antigens (CTAs), for exam- HER1; e.g. cetuximab, panitumumab) and ple, MAGE-1, normally found only in the testes but EGFR 2 (HER2; e.g. trastuzumab, pertuzumab), are aberrantly expressed by a number of different and negative immune checkpoint regulators such cancers; (b) differentiation antigens expressed by as cytotoxic T lymphocyte-associated antigen 4 both tumors and the normal differentiated cells (CTLA-4; e.g. ipilimumab) and programmed cell from which the tumors arise, for example, mela- death receptor 1 (PD-1; e.g. nivolumab, pem- noma antigen recognized by T cells (MART-1, also brolizumab) [Sliwkowski and Mellman, 2013]. In known as Melan-A); and (c) self-antigens that are addition to the direct, modulatory effects on sig- overexpressed by tumors, for example, mucin 1 nal transduction, antibody-dependent cellular (MUC1) [Savage et al. 2014]. CTAs were the first cytotoxicity (ADCC), mediated through engage- type of TAA identified, and there are currently over ment of NK cells and macrophages, also likely 200 genes that have been classified as CTAs contributes to the activity of these antibodies [Almeida et al. 2009]. It is believed that the observed [Kohrt et  al. 2012; Sliwkowski and Mellman, antigenicity of CTAs is ascribed to the privileged 2013]. The tumor-targeting monoclonal antibod- immune status of the testis, where the blood–testis ies, perhaps the most commonly utilized form of barrier prevents the entry of immune cells. anticancer immunotherapy [Weiner et  al. 2010; Developing spermatozoa also do not express major Vacchelli et  al. 2014], are examples of passive histocompatibility complex (MHC) class I mole- immunotherapy, while immune checkpoint cules, allowing them to evade immunosurveillance inhibitors are considered to be active immuno- by infiltrating T cells [Whitehurst, 2014]. Thus, therapies [Galluzzi et al. 2014]. CTAs make attractive targets for immunotherapy; however, medullary thymic epithelial cells (mTECs) The recent clinical development and approval of have been reported to express CTAs such as MAGE the immune checkpoint inhibitors ipilimumab, and New York esophageal squamous cell carcinoma which targets CTLA-4, and nivolumab and pem- 1 (NY-ESO-1) [Gotter et al. 2004], which suggests brolizumab, both of which target PD-1, has gen- that central tolerance to CTAs can develop. A tran- erated a great deal of excitement in the field of scriptional regulator known as Aire (autoimmune cancer immunotherapy [Swaika et al. 2015]. In a regulator), which is expressed by mTECs, promotes phase III clinical trial, ipilimumab was the first the promiscuous expression of tissue-restricted anti- immunotherapeutic to significantly improve over- gens such as CTAs [Anderson et al. 2002; Derbinski all survival (OS) in patients with advanced, meta- et al. 2005], resulting in promotion of tolerance to static melanoma [Hodi et  al. 2010], and since TAAs through thymic deletion of self-reactive T then both nivolumab [Robert et  al. 2015a] and cells [Savage et al. 2014]. pembrolizumab [Robert et al. 2015b] have dem- onstrated significant improvement in OS in this In general, active immunotherapy of solid tumors patient population. This review will first discuss requires the induction of cellular [T helper type 1 CTLA-4, PD-1, and other established targets of http://tam.sagepub.com 5 Therapeutic Advances in Medical Oncology 8(1) cancer immunotherapy and then focus on novel months) compared with dacarbazine alone tumor antigens and their clinical potential. [Robert et al. 2011]. Still in clinical development, tremelimumab is Established targets of anticancer another anti-CTLA-4 monoclonal antibody. immunotherapies Unlike ipilimumab, tremelimumab failed to dem- Currently approved anticancer immunotherapies, onstrate any significant clinical benefit in patients including monoclonal antibodies and cancer vac- with advanced melanoma [Ribas et  al. 2013], cines, target a number of different antigens although a survival benefit was revealed in patients including CTLA-4, PD-1, EGFR, HER2, VEGF, achieving higher drug exposures following a ret- VEGF-R2, and PAP (prostatic acid phosphatase). rospective analysis of phase II and III pharma- Another well-known TAA is BCR-ABL (break- cokinetic data [Calabro et  al. 2015]. point cluster region Abelson tyrosine kinase), for Tremelimumab is currently being developed for which several small molecule tyrosine kinase the treatment of malignant mesothelioma inhibitors (TKIs) have been approved and for [Calabro et al. 2015], where it has demonstrated which immunotherapies are currently under long-term clinical benefit in phase II studies development. Monoclonal antibodies are by far [Calabro et  al. 2013, 2015]. The FDA recently the most commonly approved form of antigen- granted tremelimumab Orphan Drug Designation specific anticancer immunotherapy, with only a for this indication. single therapeutic cancer vaccine, sipuleucel-T (trade name Provenge ), which targets the pros- Two new monoclonal antibody-based therapies tate cancer antigen PAP, having received Food targeting PD-1, pembrolizumab (formerly lam- and Drug Administration (FDA) approval to brolizumab) and nivolumab, were approved by date. These immunotherapeutic targets and the the FDA within the last year. The interaction of clinical efficacy of approved treatments are dis- PD-1, expressed on the surface of activated T cussed below. For a comprehensive list of the cells, and PD-L1 on the surface of tumor cells antigen targets of established anticancer immu- results in immunosuppression. An expansion notherapies, refer to Table 1. cohort of a phase I trial [Hamid et al. 2013] com- pared pembrolizumab treatment at doses of 2 or 10 mg in metastatic melanoma patients that had Immune checkpoint blockade: CTLA-4 and progressed on ipilimumab. At both dose levels, PD-1 the overall response rate, which was the primary A great deal of research in cancer immunotherapy endpoint, was 26% and the treatment was well is currently being concentrated on the develop- tolerated [Robert et al. 2014]. The results of this ment of immune checkpoint modulators, particu- study led to accelerated FDA approval of pem- larly those targeting CTLA-4 and PD-1 and its brolizumab for metastatic melanoma in ligands PD-L1/L2. The first checkpoint modula- September 2014, representing the first such tor to be approved, ipilimumab is a monoclonal approval of an anti-PD-1 immunotherapy. Just 3 antibody directed against CTLA-4, a molecule months later, nivolumab received accelerated that downregulates the activation of T cells. A FDA approval for advanced melanoma on the phase III clinical trial in patients with metastatic basis of phase I/II clinical trial data showing a melanoma comparing ipilimumab and gp100 31% overall response rate with a median dura- peptide vaccine monotherapies to the combina- tion of response of two years, 43% two-year sur- tion showed that median OS was significantly vival, and a median OS of approximately 17 increased from 6.4 months (gp100 vaccine alone) months [Topalian et al. 2012, 2014]. A recently to 10.0 months (ipilimumab plus gp100 vaccine). published phase III trial comparing a combina- Ipilimumab monotherapy was equally effective tion of nivolumab and dacarbazine to dacar- [Hodi et al. 2010]. The results of this trial, which bazine alone in patients with metastatic was the first demonstration of an immunothera- melanoma showed significant increases in pro- peutic agent significantly increasing OS in patients gression-free survival (PFS) and OS with the with metastatic melanoma, led to the approval of combination [Robert et al. 2015a]. Clinical trials ipilimumab in 2011. A subsequent phase III trial evaluating the use of nivolumab and pembroli- in patients with metastatic melanoma showed zumab alone and in combination with other that a combination of ipilimumab and dacar- agents such as ipilimumab, TKIs, and anti-PD- bazine significantly increased OS (11.2 versus 9.1 L1 agents for the treatment of a wide variety of 6 http://tam.sagepub.com GT Wurz, C-J Kao et al. Table 1. Antigenic targets of approved immunotherapies. Antigen Cancer Types Targeted Agents References BCR-ABL CML Imatinib, Dasatinib [Isfort et al. 2014; Lindauer and Hochhaus, 2014; Ostendorf et al. ALL Nilotinib, Bosutinib 2014; Waller, 2014; Wehrle et al. 2014] Ponatinib CD19 ALL Blinatumomab [Hoffman and Gore, 2014] CD20 NHL, CLL Rituximab [Sliwkowski and Mellman, 2013; Ai and Advani, 2015] B-cell NHL Ofatumumab pre-B ALL Y-Ibritumomab I-Tositumomab CD30 Hodgkin’s lymphoma Brentuximab vedotin [Sliwkowski and Mellman, 2013; Chen and Chen, 2015] CD33 AML Gemtuzumab [Sliwkowski and Mellman, 2013; Loke et al. 2015] ozogamicin CD52 CLL Alemtuzumab [Skoetz et al. 2012; Sliwkowski and Mellman, 2013] CTLA-4 Unresectable Ipilimumab [Hodi et al. 2010; Robert et al. 2011; Hodi et al. 2014] or metastatic melanoma EGFR CRC Cetuximab [Cunningham et al. 2004; Saltz et al. 2004; Bonner et al. 2006; Van Head and Neck Panitumumab Cutsem et al. 2007; Vermorken et al. 2008; Van Cutsem et al. 2009; Douillard et al. 2010; Price et al. 2014] EpCAM Malignant ascites Catumaxomab [Seimetz, 2011] HER2 Breast Trastuzumab [Slamon et al. 2001; Romond et al. 2005; Bang et al. 2010; Perez Pertuzumab et al. 2011; O’Sullivan and Connolly, 2014; Perez et al. 2014] PAP Prostate Sipuleucel-T [Kantoff et al. 2010a] PD-1 Metastatic Nivolumab [Topalian et al. 2012; Robert et al. 2014; Topalian et al. 2014; melanoma NSCLC Pembrolizumab Garon et al. 2015; Brahmer et al. 2015] VEGF Breast, Cervical Bevacizumab [Hurwitz et al. 2004; Sandler et al. 2006; Escudier et al. 2007; CRC, NSCLC Giantonio et al. 2007; Miller et al. 2007; Friedman et al. 2009; RCC, Ovarian Pujade-Lauraine et al. 2014; Tewari et al. 2014] Glioblastoma VEGF-R2 Gastric Ramucirumab [Fuchs et al. 2014; Garon et al. 2014; Wilke et al. 2014] NSCLC Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; BCR-ABL, breakpoint cluster region Abelson tyrosine ki- nase; CLL, chronic lymphocytic leukemia; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; HER2, human epidermal growth factor receptor 2; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small cell lung cancer; PAP, prostatic acid phosphatase; PD-1, programmed cell death receptor 1; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VEGF-R2, vascular endothelial growth factor receptor 2. other cancers are currently ongoing or com- 58.2% for ipilimumab, differences that were pleted, with promising results [Scott, 2015; highly significant. A response rate of 33.7% was Swaika et al. 2015]. seen with pembrolizumab treatment compared with 11.9% for ipilimumab, with a lower inci- The results of clinical trials involving pembroli- dence of adverse events in patients treated with zumab and nivolumab in the treatment of non- pembrolizumab [Robert et al. 2015b]. In a phase small cell lung cancer (NSCLC) and advanced I study in advanced NSCLC, pembrolizumab melanoma were recently reported. demonstrated antitumor activity, with a response Pembrolizumab was found to be superior to ipil- rate of 45% among patients with a PD-L1 tumor imumab in the treatment of patients with cell expression rate of at least 50%, and a advanced melanoma in a phase III clinical trial response rate of 19% among all patients. Median [Robert et  al. 2015b]. The 6-month PFS rate PFS was 3.7 months among all patients and 6.3 was 47.3% in patients treated with pembroli- months in patients with high PD-L1 expression zumab compared with 26.5% in patients treated [Garon et al. 2015]. The results of this trial led with ipilimumab, and the 12-month survival rate to the recent FDA approval of pembrolizumab for pembrolizumab was 74.1% compared with for NSCLC. http://tam.sagepub.com 7 Therapeutic Advances in Medical Oncology 8(1) Nivolumab was also recently FDA approved for immunotherapy, and indeed several different the treatment of NSCLC based on the results of a monoclonal antibodies as well as small molecule phase III study showing a significant increase in TKIs have been developed and approved OS in patients treated with nivolumab compared [Sliwkowski and Mellman, 2013]. Among these, with docetaxel [Brahmer et  al. 2015]. In previ- gefitinib, erlotinib and afatinib are TKIs approved ously untreated patients with unresectable stage for the treatment of NSCLC. While TKIs are III/IV melanoma, a randomized, double-blind quite effective in treating EGFR mutation-positive phase III trial showed that nivolumab treatment, NSCLC, the development of resistance is virtually either alone or in combination with ipilimumab, universal, commonly through the T790M muta- was superior to ipilimumab alone, with median tion [Pao et al. 2005]. Interestingly, a peptide anti- PFS increasing significantly from 2.9 months gen derived from the T790M EGFR mutation has with ipilimumab to 6.9 and 11.5 months with been reported to be immunogenic and is a poten- nivolumab and the combination, respectively. tial target for antigen-specific immunotherapy Among patients with PD-L1-positive tumors, [Yamada et al. 2013; Ofuji et al. 2015]. median PFS was 14.0 months for nivolumab alone and the combination compared to 3.9 Cetuximab and panitumumab. Approved mono- months for ipilimumab alone [Larkin et al. 2015]. clonal antibodies targeting EGFR include cetux- The combination of nivolumab and ipilimumab imab for colon and head and neck cancers, and recently received accelerated FDA approval for panitumumab for colon cancer. Cetuximab the treatment of BRAF V600 wild-type unresect- received accelerated FDA approval in 2004 for the able or metastatic melanoma based on the treatment of metastatic CRC refractory to irinote- results of a phase II trial [Postow et  al. 2015]. can based on the results of clinical trials showing This was the first approval of an immunotherapy acceptable safety [Saltz et al. 2004] and significant combination for cancer patients. increases in overall response rate and time to pro- gression in patients treated with a combination of Investigational, PD-1-targeted agents still in clini- cetuximab and irinotecan [Cunningham et  al. cal development include pidilizumab, which has 2004]. Phase III clinical trial data reaffirming been evaluated in phase II clinical trials in patients prior results and demonstrating significant with B-cell lymphoma [Armand et  al. 2013] and increases in PFS and OS in patients with refrac- metastatic melanoma [Atkins et  al. 2014], AMP- tory metastatic CRC [Jonker et al. 2007; Sobrero 514 (MEDI0680), being evaluated in ongoing et al. 2008] led to regular FDA approval of single- phase I trials in patients with advanced malignan- agent cetuximab in 2007 for the treatment of che- cies [ClinicalTrials.gov identifiers: NCT02118337; motherapy-refractory metastatic CRC. More NCT02013804], and AMP-224, which is cur- recently, cetuximab received FDA approval in rently being evaluated in a phase I trial [Clini- 2012 as first-line treatment for metastatic CRC calTrials.gov identifier: NCT02298946] in based on the results of the phase III CRYSTAL pati ents with metastatic colorectal cancer (CRC) trial [Van Cutsem et al. 2009] and supporting tri- [Homet Moreno et al. 2015]. als [Bokemeyer et al. 2009, 2012]. A pooled analy- sis of these trials showed that cetuximab combined with chemotherapy significantly increased overall EGFR receptor tyrosine kinase family response rate, PFS and OS in patients with KRAS The human epidermal growth factor receptor wild type, EGFR-expressing metastatic CRC (EGFR or HER1) is a receptor tyrosine kinase [Bokemeyer et al. 2012]. (RTK) that is overexpressed in a variety of differ- ent cancers including lung, breast and colon Cetuximab is also used in the treatment of squa- cancer. Specific mutations in the EGFR proto- mous cell carcinoma of the head and neck oncogene result in the RTK becoming constitu- (SCCHN), having received FDA approval in tively active [Chung, 2015]. Upon activation, 2006 for single-agent use in recurrent/metastatic EGFR stimulates a number of different signaling SCCHN refractory to platinum-based chemo- pathways, for example, MAPK (mitogen-activated therapy, and in combination with radiotherapy protein kinase), PI3K (phosphoinositide 3-kinase) for locally or regionally advanced SCCHN. This and STAT (signal transducer and activator of approval was based on the results of a phase III transcription), which lead to cancer cell prolif- clinical trial showing significant increases in PFS, eration and survival [Hynes and Lane, 2005]. median duration of locoregional control and OS This has made EGFR an attractive target for with cetuximab plus radiotherapy compared to 8 http://tam.sagepub.com GT Wurz, C-J Kao et al. radiotherapy alone in patients with locoregion- et al. 2005; Perez et al. 2011, 2014], trastuzumab ally advanced SCCHN [Bonner et al. 2006], and later received FDA approval in 2006 for the treat- a phase II study in patients with refractory recur- ment of breast cancer in the adjuvant setting in rent/metastatic SCCHN showing a 13% response combination with chemotherapy. Trastuzumab rate and median OS of approximately 6 months was most recently approved in 2010 for the first- with cetuximab monotherapy [Vermorken et  al. line treatment of metastatic gastric or gastro- 2007]. Cetuximab was subsequently approved as esophageal junction adenocarcinoma in first-line therapy in combination with chemo- combination with chemotherapy based on a phase therapy for recurrent/metastatic SCCHN on the III clinical trial showing significantly increased strength of the results of a phase III clinical trial OS following treatment with trastuzumab com- showing significant increases in median OS, PFS bined with chemotherapy [Bang et  al. 2010]. and response rate with the combination of cetux- Currently, trastuzumab in combination with imab and chemotherapy compared with chemo- pembrolizumab is being evaluated in a phase I/II therapy alone in patients with recurrent/ clinical trial in patients with trastuzumab-resis- metastatic SCCHN [Vermorken et  al. 2008]. tant, HER2-positive metastatic breast cancer The activity of cetuximab has also been evalu- [ClinicalTrials.gov identifier: NCT02129556]. It ated in NSCLC, where a meta-analysis of four has been previously shown that trastuzumab and phase II/III clinical trials showed that the combi- anti-PD-1 treatment are synergistic in mice nation of cetuximab and first-line chemotherapy [Stagg et al. 2011]. slightly, yet significantly, increased OS compared with platinum-based chemotherapy alone [Pujol Necitumumab. Still in clinical development, et al. 2014]. necitumumab is a second-generation anti-EGFR monoclonal antibody currently being evaluated Panitumumab is also used in the treatment of for the treatment of NSCLC. Recently published metastatic CRC. The results of a phase III clini- data from a phase III clinical trial in 1093 cal trial showing significant increases in PFS and patients with stage IV squamous NSCLC response rate in patients with chemotherapy- showed that necitumumab in combination with refractory metastatic CRC led to the accelerated chemotherapy as first-line treatment resulted in FDA approval of panitumumab in 2006 [Van a modest survival benefit, with a median OS of Cutsem et  al. 2007]. Panitumumab was most 11.5 months in patients treated with necitu- recently approved in 2014 as first-line treatment mumab plus chemotherapy compared with 9.9 in combination with chemotherapy in KRAS months in patients treated with chemotherapy wild-type, metastatic CRC following the results alone, a difference that was significant [Thatcher of phase III clinical trials showing a significant et  al. 2015]. In patients with stage IV nonsqua- increase in PFS, an increase in OS [Douillard mous NSCLC, however, combining necitu- et  al. 2010], and noninferiority with cetuximab mumab with standard chemotherapy as first-line [Price et al. 2014]. treatment provided no additional clinical benefit compared with chemotherapy alone [Paz-Ares Trastuzumab. Trastuzumab is a monoclonal anti- et al. 2015]. body used for the treatment of breast cancer over- expressing the human EGFR 2 (HER2) oncogene, which includes approximately 15–30% of breast VEGFA and VEGF-R2 cancers and is associated with a poor prognosis Vascular endothelial growth factor A (VEGFA) [Slamon et  al. 1987, 1989]. The FDA first plays a critical role in angiogenesis, and it is the approved trastuzumab in combination with che- target of the monoclonal antibody bevacizumab. motherapy in 1998 for the first-line treatment of In addition to its anti-angiogenic effects [Ferrara patients with metastatic breast cancer. This origi- et al. 2004], bevacizumab has been found to aug- nal approval was based on the results of a phase ment tumor infiltration by T and B lymphocytes III clinical trial showing that treatment with [Manzoni et  al. 2010; Hodi et  al. 2014] and to trastuzumab plus standard chemotherapy signifi- inhibit regulatory T cells (Tregs) [Terme et  al. cantly increased time to progression, response 2013]. Bevacizumab has been FDA approved for rate, duration of response and OS compared with the treatment of CRC (2004), glioblastoma chemotherapy alone [Slamon et al. 2001]. Based (2009), cervical cancer (2014), lung cancer on clinical trials data showing significant increases (2006), renal cell cancer (2009), breast cancer in disease-free survival (DFS) and OS [Romond (2008), and ovarian cancer (2014). http://tam.sagepub.com 9 Therapeutic Advances in Medical Oncology 8(1) Bevacizumab was initially approved for the first- VEGF-R2, also known as KDR (kinase insert line treatment of metastatic CRC in combination domain receptor) and Flk-1 (fetal liver kinase 1), with chemotherapy based on a phase III study is an RTK and the primary receptor through showing significant increases in PFS and median which VEGF mediates its angiogenic, mitogenic, OS compared with chemotherapy alone [Hurwitz and permeability-enhancing effects [Ferrara et al. et  al. 2004]. Shortly thereafter, bevacizumab 2004]. A monoclonal antibody that targets received approval as second-line treatment in VEGF-R2, ramucirumab has received FDA combination with chemotherapy for patients with approval for the second-line treatment of gastric previously treated metastatic CRC following the cancer and NSCLC within the past year. results of a phase III clinical trial showing signifi- Ramucirumab was approved as monotherapy and cant improvement in PFS and median OS in combination with paclitaxel for the treatment [Giantonio et  al. 2007] compared with chemo- of gastric or gastroesophageal junction adenocar- therapy alone. Two years later, another Phase III cinoma after progression on first-line chemother- trial in patients with recurrent or advanced apy based on the results of two phase III trials NSCLC showed significant increases in response showing significant increases in median OS com- rate, PFS and OS following treatment with beva- pared with placebo [Fuchs et al. 2014] and pacli- cizumab plus chemotherapy [Sandler et al. 2006], taxel plus placebo [Wilke et al. 2014]. Efficacy as which led to approval of bevacizumab combined second-line treatment for metastatic NSCLC with chemotherapy as first-line treatment of after progression on platinum-based chemother- recurrent/advanced NSCLC. The approval of apy was also demonstrated in a phase III trial bevacizumab as first-line treatment of metastatic showing significant improvement in PFS and OS breast cancer was supported by the results of a with the combination of docetaxel and ramu- phase III clinical trial in patients with HER2- cirumab compared with docetaxel plus placebo negative metastatic breast cancer showing that [Garon et al. 2014]. treatment with bevacizumab and paclitaxel led to significant increases in PFS and objective response rate (ORR) compared with paclitaxel alone PAP [Miller et al. 2007]. A phase II study used to sup- PAP is the target of the only currently FDA- port the 2009 FDA approval of bevacizumab approved therapeutic anticancer vaccine, sip- combined with chemotherapy for patients with uleucel-T (Provenge ). Sipuleucel-T was recurrent glioblastoma showed that treatment approved for the treatment of asymptomatic and with bevacizumab combined with chemotherapy minimally symptomatic metastatic castration- resulted in improved PFS and ORR, differences resistant prostate cancer in 2010 based on the that were significant compared to expected effects results of the phase III IMPACT trial showing a of salvage chemotherapy [Friedman et al. 2009]. significant increase in median OS in patients The same year, bevacizumab combined with treated with sipuleucel-T compared with those interferon α was approved as first-line treatment treated with placebo [Kantoff et  al. 2010a]. To of metastatic renal cell carcinoma (RCC) based prepare sipuleucel-T, peripheral blood mononu- on phase III data demonstrating significant clear cells from the patient are cultured with a improvement in PFS [Escudier et  al. 2007]. No fusion protein that incorporates PAP and significant improvement in OS was observed in GM-CSF (granulocyte-macrophage colony- this trial [Escudier et  al. 2010]. Most recently, stimulating factor). The patient is then infused bevacizumab was approved in 2014 for the treat- with these cells, and the process is repeated for ment of recurrent or metastatic cervical cancer three cycles. Thus, sipuleucel-T is actually a and recurrent, platinum-refractory ovarian carci- combination of a cell-based vaccine and autolo- noma based on phase III clinical trials showing gous ACT [Melero et al. 2014]. Interestingly, in significant increases in OS and response rate in addition to immune responses against the pri- cervical cancer [Tewari et  al. 2014], and signifi- mary antigenic target PAP, humoral immune cant improvement in PFS and ORR in ovarian responses against several secondary antigens cancer [Pujade-Lauraine et  al. 2014], compared such as PSA (prostate specific antigen), K-ras with chemotherapy alone. Like trastuzumab, bev- and KLK2/hK2 were also observed to be elevated acizumab and anti-PD-1 combination treatment in patients treated with sipuleucel-T but not con- is currently being clinically evaluated trol in the phase III IMPACT trial, and these [ClinicalTrials.gov identifiers: NCT02210117; responses were associated with improved OS NCT02039674; NCT02348008]. [GuhaThakurta et al. 2015]. 10 http://tam.sagepub.com GT Wurz, C-J Kao et al. Investigational tumor antigens and their months of additional follow up, the survival ben- clinical potential efit of tecemotide following concurrent chemora- In addition to the established tumor antigens for diotherapy remained significant [Mitchell et  al. which targeted immunotherapies have already 2015]. These results suggest that the timing of been approved (Table 1), there are numerous radiotherapy, chemotherapy and immunotherapy novel tumor antigens currently being investigated is important and that monitoring immune status as potential targets for new immunotherapies, may be necessary when designing treatment regi- including MUC1, PD-L1, lymphocyte activation mens combining immunotherapy with chemora- gene 3 (LAG-3), T-cell immunoglobulin domain diotherapy [Kao et  al. 2014, 2015]. Another and mucin domain 3 (TIM-3), V-domain immu- phase III trial, recently discontinued, was initi- noglobulin-containing suppressor of T-cell acti- ated to study tecemotide maintenance therapy vation (VISTA), NY-ESO-1, carcinoembryonic following concurrent chemoradiotherapy in antigen (CEA), PSA, MAGE-A3, 5T4, survivin NSCLC [DeGregorio et al. 2014]. and indoleamine-2,3-dioxygenase (IDO1). These selected antigens and their clinical potential as targets for investigational immunotherapies are Immune checkpoints: PD-L1; LAG-3; TIM-3; discussed below. Table 2 includes a more com- VISTA plete listing of tumor antigen targets for which PD-L1. As already mentioned, the development immunotherapies are currently being explored. of immune checkpoint inhibitors is currently the focus of intense research efforts. The interaction of PD-L1, which is expressed on the surface of MUC1 tumor cells, with PD-1 on activated T cells results Mucin 1 (MUC1) is one of the best-characterized in immunosuppression and tumor immune TAAs, and it is overexpressed and aberrantly escape [Iwai et  al. 2002; Swaika et  al. 2015]. glycosylated in over 90% of adenocarcinomas PD-L1 expression has been found to be inducible such as lung and breast cancer [Szabo, 2003; by interferon γ [Muhlbauer et  al. 2006]. Several Brayman et al. 2004]. MUC1 is a transmembrane investigational immunotherapies targeting PD-L1 glycoprotein expressed in several epithelial tissues, are presently in clinical development for meta- but the normal glycosylation pattern shields the static melanoma, NSCLC, RCC and bladder peptide core of the extracellular domain from cancer, among others. immunosurveillance. In cancer, the aberrant underglycosylation of MUC1 leads to exposure BMS-936559 (MDX-1105) is a monoclonal anti- of the immunogenic tandem repeat regions of body that inhibits the binding of PD-L1 to both the core peptide, making MUC1 an attractive PD-1 and CD80. The safety and antitumor activ- target for immunotherapies [Apostolopoulos and ity of BMS-936559 in patients with a variety of McKenzie, 1994; Vlad et al. 2004]. advanced cancers have been evaluated in a phase I clinical trial involving 207 patients [Brahmer While several different MUC1-targeted immuno- et al. 2012]. In NSCLC, an ORR of 10% (all par- therapies have been assessed in clinical trials tial responses) and PFS rate of 31% at 24 weeks [Kimura and Finn, 2013], the most advanced were observed. Patients with RCC showed a 12% agent is tecemotide, an antigen-specific, lipo- ORR and 53% progression-free response rate at some-based, peptide cancer vaccine [Wurz et  al. 24 weeks. In ovarian cancer, an ORR of only 6% 2014] that has been evaluated in a phase III clini- was observed [Brahmer et  al. 2012]. No more cal trial as maintenance therapy for patients with recent clinical data regarding BMS-936559 in locally advanced, unresectable stage IIIA/IIIB cancer therapy have emerged, and it appears that NSCLC who had not progressed following pri- clinical development of this agent for oncology mary chemoradiotherapy [Butts et al. 2014]. The applications has been discontinued [Mullard, results failed to demonstrate significant improve- 2013; Sunshine and Taube, 2015]. ment in OS with tecemotide compared with pla- cebo; however, a predefined subgroup analysis of Atezolizumab (MPDL3280A) is an anti-PD-L1 the patients who received concurrent chemoradi- monoclonal antibody that has demonstrated activ- otherapy followed by tecemotide showed a sig- ity against a variety of advanced cancers in phase I nificant survival benefit, while no survival benefit clinical trials. The Fc region of the antibody is was seen with sequential chemoradiotherapy modified to prevent both ADCC and comple- [Butts et  al. 2014]. After approximately 20 ment-dependent cytotoxicity (CDC) [Lu et  al. http://tam.sagepub.com 11 Therapeutic Advances in Medical Oncology 8(1) Table 2. Antigenic targets of investigational immunotherapies. Antigen Cancer types Targeted agents References A2aR NSCLC PBF-509 [Pinna, 2014] AKAP4 NSCLC Preclinical [Agarwal et al. 2013; Mirandola et al. 2015] Ovarian BAGE Glioblastoma Preclinical [Zhang et al. 2010; Akiyama et al. 2014] Ovarian BORIS Prostate, Lung Preclinical [Okabayashi et al. 2012; Cheema et al. 2014; Lee et al. 2014] Esophageal CD22 ALL Epratuzumab [Raetz et al. 2008; Advani et al. 2014; Annesley and Brown, 2015; Moxetumomab Raetz et al. 2015] Inotuzumab ozogamicin CD73 Advanced solid MEDI9447 [Hay et al. 2015] tumors CD137 Advanced solid Urelumab [Yonezawa et al. 2015] tumors PF-05082566 CEA CRC PANVAC™ [Turriziani et al. 2012; Morse et al. 2013a, 2013b] Ad5-[E1-, E2b-]- CEA(6D) CS1 Multiple myeloma Elotuzumab [Veillette and Guo, 2013] CTLA-4 Malignant Tremelimumab [Calabro et al. 2015] mesothelioma EBAG9 Bladder Preclinical [Miyazaki et al. 2014] EGF NSCLC CIMAvax [Gonzalez et al. 2007; Neninger Vinageras et al. 2008; Cheng and Kananathan, 2012; Ruiz et al. 2014] EGFR NSCLC Necitumumab [Thatcher et al. 2015] GAGE Cervical Preclinical [Kular et al. 2010] GD2 Neuroblastoma Dinutuximab, hu3F8 [Suzuki and Cheung, 2015] Retinoblastoma hu14.18-IL-2, 3F8/ Melanoma other OKT3BsAb solid tumors anti-GD2 CAR GD2-KLH gp100 Melanoma gp100:209-217(210M) [Schwartzentruber et al. 2011] HPV-16 Cervical HPV-16 (E6, E7) [Kenter et al. 2009; Brun et al. 2011; Bagarazzi et al. 2012; SCCHN TG4001, Lm-LLO-E7 Zaravinos, 2014] pNGVL4a-CRT/E7, INO-3112 HSP105 CRC Preclinical [Zappasodi et al. 2011; Kawai et al. 2014; Sawada et al. 2014] Bladder IDH1 Glioma IDH1(R132H) p123-142 [Schumacher et al. 2014] Idiotype NSCLC, Breast Racotumomab [Alfonso et al. 2002, 2014; Diaz et al. 2003] (NeuGcGM3) Melanoma IDO1 Breast, Melanoma Indoximod [Iversen et al. 2014, 2015; Soliman et al. 2014] NSCLC INCB024360 IDO1 peptide vaccine KIR Lymphoma Lirilumab [Kohrt et al. 2014] LAG-3 Breast, Hemato- BMS-986016 [Brignone et al. 2010; Creelan, 2014; Nguyen and Ohashi, 2015] logical, Advanced IMP321 solid tumors LY6K Gastric LY6K-177 peptide [Ishikawa et al. 2014; Yoshitake et al. 2015] SCCHN LY6K, CDCA1, IMP3 MAGE-A3 Melanoma recMAGE-A3 [Kruit et al. 2013; Ulloa-Montoya et al. 2013; Vansteenkiste et al. NSCLC Zastumotide 2013; Melero et al. 2014] MAGE-C2 Gastric, Melanoma Preclinical [Zhang et al. 2013; Ghadban et al. 2014; Reinhard et al. 2014] Multiple myeloma (Continued) 12 http://tam.sagepub.com GT Wurz, C-J Kao et al. Table 2. (Continued) Antigen Cancer types Targeted agents References MAGE-D4 CRC Preclinical [Zhang et al. 2014] Melan-A Melanoma MART-1 (26-35, 27L) [Tarhini et al. 2012; Romano et al. 2014] MET NSCLC Onartuzumab [Scagliotti et al. 2012; Spigel et al. 2013; Stinchcombe, 2014] Tivantinib MUC1 NSCLC, Breast Tecemotide, TG4010 [Kimura and Finn, 2013; Butts et al. 2014; Wurz et al. 2014] Prostate PANVAC™ MUC4 Pancreatic Preclinical [Wu et al. 2009; Torres et al. 2012; Zhu et al. 2014] MUC16 Ovarian Abagovomab [Buzzonetti et al. 2014; Felder et al. 2014] Oregovomab NY-ESO-1 Ovarian NY-ESO-1/ [Robbins et al. 2011; Odunsi et al. 2012; Klein et al. 2015] Melanoma ISCOMATRIX™ rV-NY-ESO-1; rF-NY- ESO-1 PD-1 B-cell lymphoma Pidilizumab [Armand et al. 2013; Homet Moreno et al. 2015] Melanoma, CRC AMP-224, AMP-514 PD-L1 NSCLC, RCC BMS-936559, [Cha et al. 2015; Ibrahim et al. 2015; Sunshine and Taube, 2015; Bladder, Breast Atezolizumab Swaika et al. 2015] Melanoma, SCCHN Durvalumab, Avelumab PRAME NSCLC Preclinical [De Pas et al. 2012] PSA Prostate PROSTVAC -VF [Gulley et al. 2010; Kantoff et al. 2010b; Shore, 2014] ROR1 CLL, Pancreatic Preclinical [Hojjat-Farsangi et al. 2014; Berger et al. 2015; Shabani et al. Lung, Breast 2015] Sialyl-Tn Breast Theratope [Miles et al. 2011; Ibrahim et al. 2013] SPAG-9 Prostate, CRC Preclinical [Garg et al. 2007; Kanojia et al. 2011; Wang et al. 2013; Chen et al. NSCLC, Ovarian 2014] SSX1 Prostate Preclinical [Smith et al. 2011; He et al. 2014] Multiple myeloma Survivin Melanoma EMD640744 [Becker et al. 2012; Lennerz et al. 2014; Pollack et al. 2014] Glioma, Solid Trivalent peptide tumors vaccine Tripeptide vaccine Telomerase Pancreatic Tertomotide [Melero et al. 2014; Staff et al. 2014] TIM-3 Melanoma, NHL Preclinical [Sakuishi et al. 2010; Ngiow et al. 2011; Gao et al. 2012; Fourcade NSCLC et al. 2014; Jiang et al. 2015] VISTA Melanoma, Preclinical [Le Mercier et al. 2014; Lines et al. 2014b] Bladder WT1 Ovarian, Uterine, WT1 peptide vaccine [Coosemans et al. 2014; Di Stasi et al. 2015] AML Multiple myeloma XAGE-1b Prostate DC-based tumor [Zhou et al. 2008; Xie and Wang, 2015] vaccine 5T4 RCC, CRC TroVax [Amato et al. 2010; Zhang et al. 2012; Harrop et al. 2013; Eisen Prostate Naptumomab et al. 2014; Rowe and Cen, 2014; Stern et al. 2014] estafenatox Abbreviations: A2aR, adenosine A2a receptor; AKAP4, A kinase anchor protein 4; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; BAGE, B melanoma antigen; BORIS, brother of the regulator of imprinted sites; CEA, carcinoembryonic antigen; CLL, chronic lymphocytic leukemia; CRC, colorectal cancer; CS1, CD2 subset 1; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; EBAG9, estrogen receptor binding site associated antigen 9; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; GAGE, G antigen; GD2, disialoganglioside GD2; gp100, glycoprotein 100; HPV-16, human papillomavirus 16; HSP105, heat-shock protein 105; IDH1, isocitrate dehy- drogenase type 1; IDO1, indoleamine-2,3-dioxygenase 1; KIR, killer cell immunoglobulin-like receptor; LAG-3, lymphocyte activation gene 3; LY6K, lymphocyte antigen 6 complex K; MAGE-A3, melanoma antigen 3; MAGE-C2, melanoma antigen C2; MAGE-D4, melanoma antigen D4; Melan-A/ MART-1, melanoma antigen recognized by T-cells 1; MET, N-methyl-N’-nitroso-guanidine human osteosarcoma transforming gene; MUC1, mucin 1; MUC4, mucin 4; MUC16, mucin 16; NHL, non-Hodgkin lymphoma; NY-ESO-1, New York esophageal squamous cell carcinoma 1; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand 1; PRAME, preferentially expressed antigen of melanoma; PSA, prostate specific antigen; RCC, renal cell carcinoma; ROR1, receptor tyrosine kinase orphan receptor 1; SCCHN, squamous cell carcinoma of the head and neck; SPAG-9, sperm-associated antigen 9; SSX1, synovial sarcoma X-chromosome breakpoint 1; TIM-3, T-cell immunoglobulin domain and mucin domain-3; VISTA, V-domain immunoglobulin-containing suppressor of T-cell activation; WT1, Wilms’ Tumor-1; XAGE-1b, X chromosome antigen 1b. http://tam.sagepub.com 13 Therapeutic Advances in Medical Oncology 8(1) 2014], which prevents the killing of immune cells multiforme is currently underway [Reardon et al. that also express PD-L1, such as activated T cells. 2015]. Durvalumab has also entered a phase III Atezolizumab is currently being evaluated in clinical trial in combination with concurrent patients with locally advanced or metastatic solid chemoradiotherapy in patients with stage III unre- tumors in an ongoing phase I study. In a cohort of sectable NSCLC [ClinicalTrials.gov identifier: patients with metastatic urothelial bladder cancer, NCT02125461] and a phase II/III clinical trial an ORR of 43% was observed at 6 weeks, increas- [ClinicalTrials.gov identifier: NCT02154490] in ing to 52% at 12 weeks of treatment [Powles et al. patients with recurrent stage IIIB/IV squamous 2014]. As there had been no significant advances cell NSCLC [Lee and Chow, 2014; Ibrahim et al. in the treatment of metastatic urothelial cancer in 2015]. Other ongoing phase II and phase III clini- decades, these results led to breakthrough desig- cal trials of durvalumab include third-line treat- nation status by the FDA in June 2014. Updated ment of stage IIIB/IV NSCLC [ClinicalTrials.gov response and survival data from this study after an identifier: NCT02087423], second-line treatment additional 8 months of follow up continued to of SCCHN [ClinicalTrials.gov identifier: show promising PFS and OS results [Petrylak NCT02207530; Ibrahim et  al. 2015] and treat- et al. 2015]. For patients with NSCLC, an ORR ment of advanced NSCLC alone or in combina- of 23% and PFS rate of 45% at 24 weeks was seen tion with tremelimumab [ClinicalTrials.gov with atezolizumab treatment [Herbst et al. 2014], identifier: NCT02352948; Planchard et al. 2015]. and the most recent data continued to show clini- cal benefit in NSCLC [Horn et  al. 2015]. A fourth anti-PD-L1 monoclonal antibody, ave- Atezolizumab has also been studied in combina- lumab (MSB0010718C), is currently in phase I tion with first-line chemotherapy in metastatic development in subjects with metastatic or locally NSCLC patients, and was found to improve ORR advanced solid tumors [ClinicalTrials.gov identi- in all combinations tested in a phase Ib trial [Liu fier: NCT01772004], with a separate phase I et  al. 2015b]. In patients with metastatic mela- trial in Japanese subjects [Lu et al. 2014]. Results noma or RCC, ORRs of 30% and 14%, and PFS of this phase I trial in extensively pretreated rates of 41% and 48% at 24 weeks, respectively, patients with a variety of different tumors have so were observed [Herbst et al. 2014]. Patients in the far demonstrated that avelumab has an accepta- triple-negative breast cancer cohort had an ORR ble safety profile [Kelly et  al. 2015]. A phase Ib of 19% and a PFS rate of 27% at 24 weeks [Emens expansion study in advanced NSCLC patients et al. 2015]. who had progressed after platinum-based chem- otherapy demonstrated increased activity with Preliminary results from two phase II clinical tri- avelumab treatment in patients with PD-L1- als of atezolizumab in patients with advanced positive tumors [Gulley et  al. 2015]. A phase II NSCLC were recently reported. In both chemo- study of avelumab in patients with metastatic therapy-naïve and previously treated patients, an Merkel cell carcinoma is currently underway increasing ORR to atezolizumab treatment was [Kaufman et  al. 2015]. Interestingly, unlike the associated with increasing PD-L1 expression other anti-PD-L1 antibodies being developed, [Spigel et al. 2015]. Compared with docetaxel in avelumab appears to possess ADCC activity previously treated NSCLC, treatment with ate- [Boyerinas et al. 2015]. zolizumab was found to increase OS, PFS and ORR in association with PD-L1 expression [Spira LAG-3. LAG-3 is a negative regulator of effector et  al. 2015]. There are currently several other T-cell function [Sierro et  al. 2011], making it an phase I/II and phase III clinical trials of atezoli- attractive target for immunotherapy. LAG-3 is zumab currently underway [Swaika et al. 2015]. expressed on the membranes of activated T cells and is upregulated on exhausted T cells [Nguyen Durvalumab (MEDI4736) is an anti-PD-L1 and Ohashi, 2015]. Because LAG-3 is also monoclonal antibody similar to atezolizumab, expressed on activated Tregs, LAG-3 blockade with an Fc region modification that prevents may inhibit the suppressive effects of Tregs in ADCC and CDC. In a phase I clinical trial, addition to the direct action on effector cells response rates of 13% and 14% were observed in [Huang et al. 2004]. The major ligand of LAG-3 patients with metastatic NSCLC and SCCHN, is MHC class II, and their interaction may play a respectively [Lee and Chow, 2014]. A phase II role in modulating dendritic cell function [Gold- study [ClinicalTrials.gov identifier: berg and Drake, 2011; Camisaschi et al. 2014]. A NCT02336165] in patients with glioblastoma monoclonal antibody targeting LAG-3, known as 14 http://tam.sagepub.com GT Wurz, C-J Kao et al. BMS-986016, is currently in early phase I clinical elevated VISTA expression. Treatment with an development. Ongoing clinical trials are investi- anti-VISTA monoclonal antibody resulted in gating single agent BMS-986016 for hematologi- tumor growth inhibition, especially in combina- cal malignancies and a combination of nivolumab tion with a tumor vaccine [Le Mercier et al. 2014]. and BMS-986016 in patients with advanced solid In these studies, VISTA blockade was found to be tumors [Creelan, 2014; Nguyen and Ohashi, effective with no detectable expression of VISTA 2015]. In addition to the membrane-bound form and high expression levels of PD-L1 on tumor of LAG-3, the LAG3 gene also codes for a soluble cells. This observation could have important clini- variant, sLAG-3, that functions as an immune cal implications for combination treatments tar- adjuvant [Nguyen and Ohashi, 2015]. A sLAG-3 geting the VISTA and PD-1/PD-L1 checkpoint immunoglobulin fusion protein (IMP321) is in pathways, allowing for potential synergy due to early clinical development as an immune adju- the fact that these pathways operate indepen- vant. In a Phase I clinical trial evaluating a combi- dently [Lines et al. 2014b; Liu et al. 2015a]. nation of taxane-based chemotherapy and IMP321 in women with metastatic breast cancer, a 50% ORR was observed [Brignone et al. 2010]. CTAs: NY-ESO-1 and MAGE-A3 CTAs constitute the majority of the currently TIM-3. TIM-3 is an inhibitory immune check- identified TAAs, and numerous CTAs are being point receptor that limits the duration and magni- investigated as potential targets of new anticancer tude of T 1 CD4+ and CD8+ CTL cellular immunotherapies for a variety of malignancies. responses [Anderson, 2014]. Galectin-9 has been Among these, immunotherapies targeting identified as the ligand for TIM-3, and it is NY-ESO-1 and MAGE-A3 have reached the through this pathway that T 1 immunity may be clinical stage of development. These antigens are suppressed [Zhu et  al. 2005]. The expression of normally expressed only in adult testis germ cells TIM-3 on dysfunctional CD8+ T cells and Tregs and become aberrantly re-expressed in various makes it an attractive target for anticancer immu- cancers such as lung, bladder and melanoma notherapy. Preclinical animal models have shown [Jungbluth et al. 2001]. that antibody inhibition of TIM-3 is very effective in suppressing tumor growth [Ngiow et al. 2011]. NY-ESO-1. NY-ESO-1 is encoded by the CTAG1B Synergistic antitumor effects in multiple cancer gene and was first identified in 1997 [Chen et al. types have been observed in preclinical models 1997]. Expressed in a variety of carcinomas and with the combination of anti-PD-1/PD-L1 and sarcomas, NY-ESO-1 is highly immunogenic and TIM-3 blockade [Sakuishi et  al. 2010; Ngiow is thus a logical target for anticancer immuno- et al. 2011; Jing et al. 2015]. Clinically, increased therapy [Nicholaou et al. 2006; Endo et al. 2015]. expression of TIM-3 and PD-1 in melanoma In a phase I clinical trial in patients with advanced patients has been associated with tumor NY- synovial cell sarcoma and melanoma, subjects ESO-1-specific CD8+ T-cell dysfunction [Four- were administered autologous ACT using cells cade et al. 2014]. In NSCLC, TIM-3 is expressed transduced with a T-cell receptor (TCR) targeting on tumor-infiltrating CD4+ and CD8+ T cells NY-ESO-1. Objective response rates of 67% (4/6) [Gao et  al. 2012], and the presence of CD4+ T and 45% (5/11) were observed for synovial cell cells that express TIM-3 is strongly correlated sarcoma and melanoma patients, respectively with advanced tumor grade in NSCLC [Gao [Robbins et  al. 2011]. Autologous ACT has also et  al. 2012] and poor survival in follicular B-cell been performed using NY-ESO-1-specific CD4+ non-Hodgkin lymphoma [Yang et al. 2012]. Thus, cells [Hunder et al. 2008]. A prime-boost vaccine TIM-3 has great clinical potential as a target of strategy was assessed in patients with stage III/IV novel immunotherapies [Cheng and Ruan, 2015]. melanoma and stage II-IV ovarian carcinoma in a phase II clinical trial. Patients were primed with a VISTA. VISTA is a newly identified negative recombinant NY-ESO-1-expressing vaccinia immune checkpoint regulator [Lines et al. 2014b]. virus and then boosted with an NY-ESO-1-ex- Unlike PD-L1, VISTA is expressed primarily in pressing fowlpox virus. In the melanoma patients, hematopoietic cells in both mice [Wang et  al. CD8+ T-cell responses increased from 40% pre- 2011] and humans [Lines et al. 2014a]. In murine treatment to 88% following vaccination. Median models of melanoma and bladder cancer, leuko- OS was significantly increased in the melanoma cytes within the tumor microenvironment and in and ovarian cancer patients who had immune tumor-draining lymph nodes were found to have responses following treatment [Odunsi et  al. http://tam.sagepub.com 15 Therapeutic Advances in Medical Oncology 8(1) 2012]. An NY-ESO-1-specific vaccine (NY- Oncofetal antigens: CEA and 5T4 ESO-1/ISCOMATRIX™) in combination with Oncofetal antigens are so-called because though cyclophosphamide has also been evaluated in widely expressed during fetal development, nor- advanced melanoma in phase II. Treatment led to mal expression is generally limited in adults. In a significant increase in antigen-specific CD4+ cancer, the expression of these antigens becomes T-cell immune responses [Klein et al. 2015] com- upregulated, making them potential targets for pared to a cohort of patients treated with the vac- immunotherapeutic intervention. cine alone [Nicholaou et al. 2009]. A prime-boost treatment strategy employing NY-ESO-1/ISCO- CEA. CEA is a well-known oncofetal antigen nor- MATRIX™ in high-risk, resected melanoma mally expressed in the stomach, tongue, esopha- patients was found to augment CD8+ T-cell gus, cervix and prostate in adults, but becomes immune responses [Chen et al. 2015]. highly overexpressed in colorectal and gastric can- cers [Beauchemin and Arabzadeh, 2013]. Clini- MAGE-A3. MAGE-A3 is a CTA that has been cally, CEA has been investigated extensively as an extensively clinically investigated as a target for immunotherapeutic target for colorectal and vari- immunotherapy in melanoma and lung cancer. ous other cancers [Turriziani et  al. 2012]. In a In a clinical trial involving nine patients with phase I/II clinical trial, treatment with an adenovi- advanced cancers, five responses were observed ral gene delivery platform encoding the CEA anti- following autologous ACT with T cells trans- gen produced cell-mediated immunity in 61% of duced with anti-MAGE-A3 TCRs. However, patients with advanced CRC and a 48% OS rate neurological toxicities were seen in three patients, at 12 months [Morse et  al. 2013a]. A phase II resulting in two deaths due to previously unknown study in CRC patients who were disease-free fol- expression of MAGE family antigens in the brain lowing metastasectomy and perioperative chemo- [Morgan et al. 2013]. A Phase II study examined therapy compared the effectiveness of autologous vaccination with recombinant MAGE-A3 pro- dendritic cells modified with PANVAC™, a pox- tein combined with either AS15 [a combination vector encoding both CEA and MUC1, to the of QS21 saponin, monophosphoryl lipid A PANVAC™ poxvector administered in combina- (MPL-A), and CpG7909, a Toll-like receptor tion with GM-CSF. Survival and recurrence-free (TLR)-9 agonist, in a liposomal formulation] or survival were similar between the two treatment AS02 (a combination of QS21 saponin and groups, and vaccinated patients overall experi- MPL-A, a TLR-4 agonist) immunostimulants in enced superior survival compared with a contem- patients with stage III/IV melanoma. Trends porary group of patients not treated with towards greater ORR, PFS and median OS were immunotherapy [Morse et al. 2013b]. In a recently observed in the patients who received the AS15 reported phase II trial comparing treatment with immunostimulant compared with AS02 [Kruit PANVAC™ in combination with docetaxel to et  al. 2013]. The peptide vaccine zastumotide docetaxel alone in 48 patients with metastatic (GSK2132231A) is being evaluated in a phase breast cancer, patients treated with the combina- III clinical trial in patients with resected stage tion experienced improved PFS compared with IIIB/IIIC melanoma. This trial failed to demon- docetaxel alone, a result which, while not signifi- strate a significant prolongation of DFS in cant, was suggestive of a clinical benefit [Heery patients with positive expression of MAGE-A3 et  al. 2015]. Increased CEA expression has been [Melero et al. 2014], but it is ongoing in a subset associated with shorter relapse-free survival in of patients who are positive for a predictive breast cancer patients [Saadatmand et al. 2013]. marker of response [Ulloa-Montoya et al. 2013]. A phase II clinical trial of zastumotide 5T4. The oncofetal antigen 5T4 was identified by (GSK1572932A) in patients with resected stage screening for shared surface molecules in human IB/II NSCLC exhibited a trend toward positive trophoblasts and human cancer cells [Stern et al. treatment outcomes compared with placebo 2014]. A heavily glycosylated, membrane-bound [Vansteenkiste et  al. 2013]; however, a large protein, 5T4 is highly expressed in cervical, phase III study in patients with resected stage IB- colorectal, gastric, ovarian, prostate, lung and IIIA NSCLC failed to meet its primary endpoint renal cancers [Southall et  al. 1990]. The expres- of significant prolongation of DFS, resulting in sion of 5T4 has been associated with epithelial termination of the study [Melero et  al. 2014]. mesenchymal transition (EMT), which is involved Clinical development of zastumotide appears to in the metastasis of epithelial cancers [Nieto have been discontinued. and Cano, 2012]. Three different 5T4-based 16 http://tam.sagepub.com GT Wurz, C-J Kao et al. immunotherapeutic strategies are being clinically PSA evaluated: a vaccine known as TroVax (modified PSA is a well-known prostate cancer biomarker vaccinia virus Ankara- MVA), an antibody–supe- that is now a target for antigen-specific immuno- rantigen [Staphylococcal Enterotoxin A (SEA)] therapy. An anticancer vaccine known as fusion protein, and an antibody–drug conjugate PROSTVAC -VF (PSA-TRICOM; rilimogene (ADC) combining a 5T4-specific monoclonal galvacirepvec) has been developed that incorpo- antibody with a tubulin inhibitor. rates three co-stimulatory molecules (CD80, CD54 and CD58, collectively referred to as 5T4 vaccine (TroVax®). Favorable trends toward TRICOM) and two recombinant viral vectors clinical benefit have been observed in early phase encoding PSA transgenes [Singh et  al. 2015]. I and phase II clinical trials of the TroVax Patients are primed with the vaccinia-based vec- 5T4-MVA vaccine in advanced RCC [Zhang tor and then boosted with a fowlpox vector, both et  al. 2012], CRC [Rowe and Cen, 2014], and of which are administered with GM-CSF. Early castration-resistant prostate cancer [Harrop phase I and phase II clinical trials in patients with et  al. 2013]. To determine whether treatment metastatic castration-resistant prostate cancer ® ® with TroVax can improve survival, a phase III (mCRPC) demonstrated that PROSTVAC -VF clinical trial in patients with metastatic RCC is safe, induces a high rate of immune responses compared treatment with TroVax to standard of and has survival benefits [DiPaola et  al. 2006; care treatment [Amato et  al. 2010]. While this Arlen et al. 2007; Gulley et al. 2010]. A double- trial failed to demonstrate any significant effects blind, randomized, controlled phase II clinical of TroVax on OS, a subgroup of patients with trial in patients with mCRPC showed that treat- good prognosis and receiving concurrent IL-2 ment with PROSTVAC -VF significantly experienced a significant survival benefit com- improved OS by 8.5 months compared to treat- pared with placebo. The patients with the great- ment with control vectors [Kantoff et al. 2010b]. est increases in 5T4-specific antibodies also A phase III clinical trial [ClinicalTrials.gov iden- experienced a survival benefit with TroVax tifier: NCT01322490] in 1200 patients with compared with placebo, which is consistent with asymptomatic or minimally symptomatic mCRPC a pooled analysis of prior phase I/II TroVax is currently ongoing [Singh et al. 2015]. studies [Harrop et al. 2010]. 5T4 superantigen–antibody fusion protein (naptu- Survivin momab estafenatox). The tumor-targeted super- Also known as BIRC5 (baculoviral inhibitor of antigen concept employs bacterial superantigens, apoptosis protein repeat-containing 5), survivin is which are the most potent known activators of T an inhibitor of the intrinsic apoptosis pathway cells, to attract and activate large numbers of T that is widely overexpressed in cancers, making it cells to the target [Eisen et  al. 2014]. A phase II an attractive target for antigen-specific immuno- study of the superantigen-antibody fusion protein therapy [Mobahat et  al. 2014]. Peptide cancer targeting 5T4 in RCC showed a significant sur- vaccines targeting survivin have been evaluated in vival benefit [Shaw et al. 2007], which led to the phase I and phase II clinical trials. A phase I study development of ANYARA (naptumomab estafe- of a multi-epitope anti-survivin peptide vaccine natox) [Eisen et  al. 2014]. Naptumomab estafe- (EMD640744) in patients with advanced solid natox has been evaluated in combination with tumors found an antigen-specific T-cell response interferon α in a phase II/III clinical trial involv- in 63% of subjects, and 28% of vaccinated sub- ing patients with advanced RCC. Although the jects achieved stable disease [Lennerz et al. 2014]. study failed to meet its primary endpoint, survival Another phase I study in pediatric brainstem gli- benefits were seen in a subgroup of patients with oma patients using a tripeptide vaccine contain- low levels of IL-6 and normal levels of SEA anti- ing survivin and given in combination with the bodies [Elkord et  al. 2015]. The results of this immunoadjuvant poly-ICLC (polyinosinic- study are still undergoing analysis, and a phase II/ polycytidylic acid stabilized by lysine and carbox- III clinical trial of naptumomab estafenatox in ymethylcellulose) showed evidence of survivin- combination with a TKI for metastatic RCC is specific immune responses and clinical benefit being designed [Stern et al. 2014]. Lastly, promis- [Pollack et al. 2014]. In grade 2 low-grade glioma ing preclinical activity has been seen with an ADC patients, vaccination with survivin and three other targeting 5T4 [Sapra et  al. 2013], and clinical glioma-associated peptides combined with poly- evaluation is now underway [Stern et al. 2014]. ICLC produced robust T 1 immune responses http://tam.sagepub.com 17 Therapeutic Advances in Medical Oncology 8(1) [Okada et al. 2015]. The efficacy of another sur- Discussion vivin-targeted peptide vaccine in metastatic mela- With the recent clinical development and thera- noma patients was evaluated in a phase II clinical peutic successes of immune checkpoint inhibi- trial. Treatment with the vaccine, which contained tors targeting the CTLA-4 and PD-1/PD-L1 three survivin peptide epitopes, significantly pro- pathways, such as ipilimumab, pembrolizumab longed OS in patients with antigen-specific T-cell and nivolumab, enthusiasm surrounding anti- responses [Becker et al. 2012]. cancer immunotherapy has become intense. However, despite the impressive improvements in clinical outcome seen with these agents, the IDO1 response rates remain modest, but encouraging. Upregulation of indolamine-2,3-dioxygenase Clearly, we must expand our knowledge about (IDO1), which catabolizes the essential amino acid how these agents work and the safest way to tryptophan, is a recently discovered mechanism of administer them in order to improve their effi- tumor cell immune escape. Tryptophan is required cacy. With respect to antigen-specific immuno- for normal T-cell function, and its depletion can therapies, the abundance of tumor antigens that lead to immunosuppression [Jiang et  al. 2015]. have been identified has allowed for the devel- The IDO1 enzyme is overexpressed in various opment of multiple monoclonal antibodies and malignancies including breast, NSCLC, prostate peptide cancer vaccines targeting these anti- and gastric cancers [Uyttenhove et al. 2003]. Two gens, but the responses to these agents as well small molecule IDO1 enzyme inhibitors and a remain modest, due in part to mechanisms of peptide-based vaccine are currently being evalu- tumor evasion and immunosuppression, and the ated in clinical trials. Indoximod (1-methly-D- fact that TAA expression profiles are patient- tryptophan) combined with docetaxel was specific. With the availability of checkpoint evaluated in a phase I clinical trial in patients with inhibitors, it is now possible to alter the immu- metastatic solid tumors. The treatment was well nosuppressive tumor microenvironment, which tolerated with evidence of clinical activity [Soliman could potentially increase the efficacy of anti- et al. 2014]. A phase II trial of this agent in combi- gen-specific immunotherapies. It is thus becom- nation with docetaxel as first-line treatment for ing quite clear that in order to derive the metastatic breast cancer is ongoing [ClinicalTrials. maximum benefit from these novel immuno- gov identifier: NCT01792050], in addition to a therapies, we must learn more about how to number of other phase II studies in metastatic mel- best use these agents in combination with chem- anoma, prostate and pancreatic cancers. otherapy and with each other. Numerous clini- cal trials investigating various combinations of The other small molecule IDO1 inhibitor, immunotherapies and chemotherapy are already INCB024360, is currently being evaluated in com- underway. bination with ipilimumab in a phase I/II study [ClinicalTrials.gov identifier: NCT02077114 Another point to consider with the use of cancer (completed)] in metastatic melanoma [Iversen vaccines is that while they are not often associ- et al. 2015], a phase I/II study [ClinicalTrials.gov ated with clinically significant objective responses identifier: NCT02318277] of INCB024360 in or improvements in PFS, they have been shown combination with durvalumab in patients with to significantly prolong OS, and thus OS may be advanced solid tumors [Ibrahim et al. 2015] and the most valid clinical endpoint for assessment a phase Ib study [ClinicalTrials.gov identifier: of the efficacy of these agents [DeGregorio et al. NCT02298153] in stage IIIB/IV NSCLC in 2012; Dillman, 2015]. Ultimately, personalized combination with atezolizumab [Cha et al. 2015]. immunotherapy, whereby patients are screened A peptide vaccine targeting IDO1 was evaluated for the expression of tumor antigens and PD-1/ in a phase I clinical trial in patients with meta- PD-L1 so that they can be matched with the static NSCLC. Median OS was approximately appropriate antigen-specific agent, checkpoint 26 months, and long-lasting disease stabilization inhibitor and chemotherapeutic agent, may be was observed in 47% of patients. A currently the best means of deriving the maximum thera- ongoing phase II study in patients with metastatic peutic benefits from these treatments [Kao et al. melanoma is evaluating the effects of a peptide 2015]. The future of personalized cancer immu- vaccine containing epitopes to survivin and IDO1 notherapy has never been more promising, and in combination with temozolomide [Iversen et al. the results of ongoing clinical trials are eagerly 2014]. awaited. 18 http://tam.sagepub.com GT Wurz, C-J Kao et al. Anderson, M., Venanzi, E., Klein, L., Chen, Z., Funding Berzins, S., Turley, S. et al. (2002) Projection of an This research received no specific grant from any immunological self shadow within the thymus by the funding agency in the public, commercial, or not- Aire protein. Science 298: 1395–1401. for-profit sectors. Annesley, C. and Brown, P. (2015) Novel agents for Conflict of interest statement the treatment of childhood acute leukemia. Ther Adv The author(s) declare(s) that there is no conflict Hematol 6: 61–79. of interest. Apostolopoulos, V. and McKenzie, I. (1994) Cellular mucins: targets for immunotherapy. Crit Rev Immunol 14: 293–309. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 18, 2015

Keywords: antitumor antibody; cancer-testis antigen; cancer vaccine; immunotherapy; oncofetal antigen; tumor-associated antigen

References