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The 2014 San Antonio Breast Cancer Symposium: A successful lift-off for breast immunotherapy?

The 2014 San Antonio Breast Cancer Symposium: A successful lift-off for breast immunotherapy? www.nature.com/npjbcancer All rights reserved 2374-4677/15 MEETING REPORT OPEN The 2014 San Antonio Breast Cancer Symposium: A successful lift-off for breast immunotherapy? 1 1 1 David B Page , Jarushka Naidoo and Heather L McArthur Therapeutic immune checkpoint antibodies promote potentially durable cancer control by modulating key regulatory factors of the endogenous anti-tumor immune response. The first clinical trial data of these agents in breast cancer were presented at the 2014 San Antonio Breast Cancer Symposium, with seemingly modest response rates compared with metastatic melanoma and Hodgkin’s lymphoma. In this article, we review the San Antonio immunotherapy data, drawing key analogies to historical experiences in metastatic melanoma that support an enthusiastic outlook for immunotherapy in breast cancer. npj Breast Cancer (2015) 1, 15001; doi:10.1038/npjbcancer.2015.1; published online 2 June 2015 INTRODUCTION therapy in breast cancer. Herein, we review the developments to date and potential future directions for immunotherapy in breast Modern immunotherapy has markedly transformed the treatment cancer. landscape for metastatic melanoma as evidenced by the recent rapid-fire food and drug administration (FDA) approval of three immunologic ‘checkpoint antibodies’ (ipilimumab, pembrolizu- THE TIL STORY: REPEATED CREDENCE FOR BREAST mab, and nivolumab). These checkpoint antibodies function by IMMUNOTHERAPY binding and blocking key immune regulatory proteins, cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1), In 2013, leaders in the field convened at the first annual San or programmed death ligand 1 (PD-L1), thereby ‘releasing Antonio TILs working group to develop a standardized metric by the brakes’ on lymphocytes and permitting a robust immune which to measure TILs using hematoxylin and eosin (H&E). Using response against the tumor. The most recently approved anti- these consensus guidelines, Dr Edith Perez presented a retro- body, nivolumab, produced a 40% durable objective response rate spective analysis of TILs in patients with HER2-positive early-stage and a near-doubling of 1-year overall survival compared with breast cancer who received adjuvant chemotherapy +/ − trastu- 3 4 conventional chemotherapy. zumab in the ECOG N9831 trial at SABCS 2014. Two key findings In light of these impressive results, investigators have been were presented, one confirmatory and the other novel. The keen to evaluate immune checkpoint antibodies in other tumor confirmatory finding, illustrated previously in several adjuvant 9,10 types. The clinical activity of anti-PD-1/L1 therapy was recently data sets, was that TIL quantity by H&E is prognostic, with reported across a growing list of malignancies, including non- increasing stromal TILs correlating with improved outcome follow- small cell lung cancer, renal cell carcinoma, gastric cancer, ing chemotherapy both as continuous and binary variables. Hodgkin’s lymphoma, and bladder cancer. To date, limited These data suggest that anti-tumor immunity contributes toward clinical trial data have been presented for breast cancer. However, cure in early-stage breast cancer, and provides a compelling recent observations that tumor-infiltrating lymphocytes (TILs) rationale to investigate immunotherapy in early-stage breast are both prognostic and predictive supports the hypotheses cancer, particularly in patients with low TILs and a high risk of that the immune system is implicated in the biology of breast relapse. cancer, mediates favorable outcomes, and that immunotherapy The novel finding was that the prognostic association was less may be used as a rational therapeutic modality to enhance apparent in trastuzumab-treated patients. From the previously outcomes. reported FinHer study of chemotherapy with or without a shorter The emerging role of immunotherapy in breast cancer was duration of trastuzumab, stromal TILs as a continuous variable evidenced by a number of presentations at this year’s San Antonio was associated with improved outcome following trastuzumab. Breast Cancer Symposium (SABCS). First, retrospective analyses of The N9831 analysis, however, failed to confirm this finding. The TILs provided additional evidence that anti-tumor immunity FinHer data set also suggested that TIL-high tumors benefited to a mediates survival in breast cancer. Next, the first unequivocal greater degree from trastuzumab, in contrast to the N9831 data cases of objective response to immune checkpoint blockade in set that demonstrated TIL-low tumors benefited from trastu- metastatic breast cancer were reported from two independent zumab and TIL-high tumors fared equally well, with or without 5,6 phase I clinical trials with anti-PD-1/L1 therapy. Finally, prelimi- trastuzumab. nary data were presented illustrating how novel combination One way to come to terms with these discrepancies is to strategies—such as immune checkpoint blockade with tumor conceptually ‘re-classify’ trastuzumab as a bona fide immuno- cryoablation—might be used to enhance response to immuno- therapy, which is supported by preclinical observations that Memorial Sloan Kettering Cancer Center, Breast Medicine Service, New York, NY, USA. Correspondence: DB Page (paged@mskcc.org) Received 21 January 2015; accepted 21 January 2015 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited San Antonio 2014: Immunotherapy Update DB Page et al trastuzumab activity is mediated by both innate (antigen non- development of new lesions. In melanoma, we know that many specific) and adaptive (antigen-specific) immunity. As such, the long-term survivors, who received immune checkpoint blockade, first discrepancy—that TILs are less prognostic in trastuzumab- develop new lesions that are successfully managed with radiation treated patients—could be explained by the possibility that or surgery without additional systemic therapy. These observa- trastuzumab serves to immunologically rescue ‘low-TIL’ tumors, tions provide hope that survival benefit in breast cancer may thereby improving their prognosis and diminishing the impor- exceed the apparent benefit using conventional response criteria. tance of baseline TIL density. The second discrepancy—that ‘high- Furthermore, in contrast to Coley’s toxins and the early TIL’ tumors did not benefit from the addition of trastuzumab in ipilimumab experience, both MPDL3280A and pembrolizumab 5,6 the N9831 data set—is likely explained by the excellent prognosis were safe and well tolerated. Minimal grade 3-4 adverse events of these patients irrespective of trastuzumab, potentially because were reported (MPDL3280A: 8% adrenal insufficiency; pembroli- of pre-existing anti-tumor immunity. While the FinHer data set zumab: 3% anemia, headache, aseptic meningitis, pyrexia, and demonstrated benefit with trastuzumab in the high-TIL subgroup, decreased fibrinogen). One death occurred in the pembrolizumab the subgroup was small (n = 22) with only six events across two trial; however, this death was attributed to disseminated arms. So given this data, the ‘take-home’ message from N9831 is intravascular coagulation, which is not generally observed with that the ‘high-TIL’ patient—characterized by excellent baseline anti-PD-1 therapy. The toxicity profiles reported at SABCS 2014 tumor immunogenicity—fares well with standard-of-care echo the larger body of clinical evidence that anti-PD-1/PD-L1 is chemotherapy alone, whereas patients with lower TIL quantities extremely safe and may provide clinical activity while preserving benefit from the addition of trastuzumab, with the caveat that quality of life in heavily pre-treated patients. these findings are discordant with those from the smaller FinHer study. A meta-analysis of the data from all the pivotal adjuvant PERSONALIZED IMMUNOTHERAPY: THE FUTURE IN BREAST chemotherapy/trastuzumab trials would further refine these CANCER observations and may further delineate which patients could potentially benefit from modern immunotherapy strategies. Despite our calls for optimism, these trials also suggest that a ‘one- size-fits-all’ immunotherapy approach may not succeed across tumor types, or across breast cancer subtypes. For example, both THE POWER OF THE ANECDOTE: FROM COLEY’S TOXIN TO of the aforementioned anti-PD-1/L1 antibody phase I breast cancer PEMBROLIZUMAB trials excluded patients with PD-L1-negative tumors. Because More than a century ago, a surgeon named William Coley noticed PD-L1 positivity is likely to enrich for response, an anti-PD-1/L1 that one of his cancer patients experienced a remission after a trial in an unselected population might achieve even fewer serious infection. With further investigation he learned that other objective responses than reported. However, the significance and physicians had observed similar responses. He consequently definition of PD-L1 positivity remains highly controversial. It was developed ‘Coley’s toxin,’ a cocktail of bacterial products that originally believed that tumors expressing PD-L1 would be most could induce marked tumor regressions when injected into likely to respond to anti-PD1/PD-L1 therapy. However, recent sarcomas, albeit with somewhat inconsistent results, and with data suggest that PD-L1 positivity of infiltrating immune cells is the unfortunate side effect of sepsis in some. With these efforts, better associated with response, and that PD-L1 may be a marker 20,21 he is largely credited as being the founder of cancer immu- of prior T-cell activation rather than tumor immune escape. notherapy. More than a century later, initial experiments of However, PD-L1 expression alone, or TIL quantity by H&E staining ipilimumab in metastatic melanoma were remarkably similar to alone, is unlikely to adequately predict response to immuno- the Coley’s toxin experience, characterized by frequent toxicities therapy. More nuanced studies of TILs may provide an under- (including life-threatening immune colitis) and infrequent objec- standing of the mechanisms of immune resistance in breast 14,15 tive responses (10.9–15.2%). Akin to William Coley, modern cancer, and may guide rational therapeutic targeting of molecules immunotherapists used anecdotes of complete responses, implicated in tumor immune evasion and escape. A recent analysis delayed responses, and durable stable disease to sustain enthu- of baseline tumor biopsies preceding anti-PD-L1 therapy serves to 16 20 siasm for modern immune checkpoint blockade strategies. illustrate this concept. Tumors that responded to anti-PD-L1 Thanks to these unwavering efforts, ipilimumab was ultimately therapy were generally characterized by high-TIL density and PD- FDA approved in metastatic melanoma on the basis of durable L1 positivity. In contrast, tumors that progressed following PD-L1 survival benefit, with many ipilimumab-treated patients surviving therapy were characterized by one of several profiles: some 14,15 free of disease for more than 10 years. Furthermore, we have ‘immunologically ignorant’ tumors exhibited low-TIL density and learned, through experience, how to safely manage the toxicities PD-L1 negativity; other ‘immunologically non-functional’ tumors of ipilimumab. contained more TILs but were PD-L1-negative; finally, a third In some ways, this year’s initial reports of immune checkpoint group of ‘immunologically excluded’ tumors contained dense, blockade in breast cancer echo these historical experiences. PD-L1-positive lymphocytes at the leading edge of the tumor, but Reports from a phase I study of MPDL3280A, an anti-PD-L1 with no intratumoral TILs. While these findings have not yet been antibody, and a phase I study of pembrolizumab, an anti-PD-1 validated in larger studies, they highlight the principle that a antibody, in triple-negative breast cancer were modest, with singular biomarker may be inadequate to predict response to media headlines emphasizing that the objective response rates in immunotherapy. Furthermore, the lack of a standardized assay for breast cancer (33 and 19%) paled in comparison with melanoma PD-L1 and the dynamic nature of PD-L1 expression remain 3 17 (40%) and Hodgkin’s lymphoma (87%). However, if we draw ongoing challenges in this field. analogies to melanoma experience with ipilimumab, we have How can we forge ahead to optimize immunotherapy in breast reason to remain optimistic. The first similarity to ipilimumab in cancer? First, as a field, we must acknowledge and embrace the melanoma is that objective responses to anti-PD1/PD-L1 therapy complexity of immunology. Despite the prognostic considerations in breast cancer appeared to be durable, with several patients of TILs, the TIL is not a singular entity: TILs comprises multiple cell treated for more than 11 months. Second, in addition to the types, some capable of killing tumor (and protecting from relapse) reports of complete (n = 2) and partial (n = 6) responders, a notable and others capable of promoting tumor growth. Similarly, proportion of patients experienced response kinetics similar to the immunotherapy is not a singular entity: aside from anti-PD-1/L1, melanoma population, with unconventional but durable clinical dozens of other immunotherapeutic targets are being evaluated benefit seen in 8 patients (26%, 11%) who achieved stable disease, in phase I studies, many of which have strong pre-clinical rationale and several with prolonged tumor regression after initial in breast cancer. For example, some breast cancers, particularly npj Breast Cancer (2015) 15001 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited Low Low Negave San Antonio 2014: Immunotherapy Update DB Page et al PD-L1 TILs TILs TIL phenotype PD-1/PD-L1 sensive Excluded Non-funconal Ignorant Example Tumor - associated macrophages or other Inadequate angen Mechanism of T-cell exhauson suppressive cells presentaon immune evasion Immunizaon An-PD-1/PD-L1 plus second immunotherapy Proposed An-PD-1/PD-L1 (vaccine, cryo- immunotherapies (example, an-CSF-R1 or an-CTLA4) immunotherapy) Figure 1. Conceptualization of how multiple immunologic biomarkers could be used to personalize immunotherapy. CSF-1R, colony- stimulating factor 1 receptor; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TILs, tumour-infiltrating lymphocytes. the cancers that are PD-L1-positive but resistant to anti-PD-1/L1, FUNDING might develop immune resistance by recruiting tumor-associated The authors declare that no funding was received. macrophages (TAMs)—suppressive macrophages that are asso- ciated with adverse prognosis in breast cancer. Antibodies REFERENCES targeting colony-stimulating factor 1 receptor, a growth factor 1 Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response receptor for TAMs, are undergoing phase I evaluation and may of T cells to stimulation. J Exp Med 1995; 182: 459–465. ultimately be effective in overcoming this resistance mechanism. 2 Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. Engage- For these reasons, we must expand our efforts beyond the H&E TIL ment of the PD-1 immunoinhibitory receptor by a novel B7 family member biomarker and anti-PD-1/PD-L1 therapeutic antibodies. leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: One potential way forward is to integrate independently 1027–1034. validated immune-based biomarkers, and to use these data to 3 Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al. Nivolumab in personalize immunotherapy using a variety of novel agents and previously untreated melanoma without BRAF mutation. N Engl J Med 2015; 372: 320–330. combination therapies. For example, if we assume that PD-L1 4 Perez EA, Ballman KV, Anderson SK, Thompson EA, Badve SS, Bailey H et al. expression and TIL quantity are binary variables, we can conceive Stromal tumor-infiltrating lymphocytes(S-TILs): In the alliance N9831 trial S-TILs are of four distinct immune phenotypes, each which may benefit from associated with chemotherapy benefit but not associated with trastuzumab benefit. a distinct immunotherapeutic strategy (Figure 1). While the San Antonio Breast Cancer Symposium: San Antonio, TX, 2014, December 8-13, TIL-high, PD-L1 positive tumors may respond to anti-PD-1/L1 therapy alone, other tumors may require novel agents or 5 Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. combination approaches. Perhaps the ‘immunologically ignorant’ San Antonio Breast Cancer Symposium: San Antonio, TX, 2014, December 8-13, cancers—with minimal or no TILs or PD-L1—might benefit from an immunization strategy to induce a de novo immune response 6 Emens LA, Braiteh FS, Cassier PA, Delord J, Eder JP, Shen X et al. Inhibition of PD-L1 against the tumor and promote influx of TILs. One such by MPDL3280A leads to clinical activity in patients with metastastic triple-negative immunization strategy employs tumor cryoablation plus check- breast cancer. 2014 San Antonio Breast Cancer Symposium: San Antonio, TX, 2014, point antibody to generate tumor antigen release followed by December 8-13, 2014. T-cell activation. In a pilot clinical study presented at SABCS, 7 Page DB, Yuan J, Diab A, Dong Z, Ginsberg A, Wong P et al. Integrated immuno- logic assessment of tumor infiltrating lymphocytes (TILs) and peripheral blood to treatment with cryoablation plus ipilimumab led to production of assess synergy of cryoablation (cryo) plus ipilimumab (ipi) in early stage breast interferon gamma and proliferation of T-cell clones. Because cancer (ESBC) patietns (pts). 2014 San Antonio Breast Cancer Symposium: San interferon gamma is associated with upregulation of PD-L1, cryo- Antonio, TX, 2014, December 8-14, 2014. immunotherapy might be particularly suitable for the ‘immuno- 8 Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G et al. Har- logically ignorant’ tumors that exhibit low TILs and PD-L1 monization of the evaluation of tumor infiltrating lymphocytes (TILs) in breast negativity at baseline. cancer: recommendations by an international TILs-working group 2014. Ann While anti-PD-1/PD-L1 alone may not be a ‘one-size-fits-all’ drug Oncol 2015; 26: 259–271. 9 Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D et al. Tumor infiltrating for breast cancer, combinatorial strategies and novel agents might lymphocytes is prognostic and predictive for trastuzumab benefit in early breast make all tumors—TIL low or TIL high, PD-L1 negative or PD-L1 cancer: results from the FinHER trial. Ann Oncol 2014; 25: 1544–1550. positive—amenable to an immunotherapeutic approach. In 10 Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN et al. Prognostic summary, while fraught with challenges, breast cancer immuno- value of tumor-infiltrating lymphocytes in triple-negative breast cancers from therapy has ‘lifted-off,’ and in our opinion, is here to stay. Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199. J Clin Oncol 2014; 32: 2959–2966. 11 LoiS,Michiels S,Salgado R, Sirtaine N, JoseV,Fumagalli D et al. Tumor infiltrating COMPETING INTERESTS lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer. The authors declare no conflict of interest. San Antonio Breast Cancer Symposium, 2013, December 10-14, San Antonio, TX, 2013. © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited npj Breast Cancer (2015) 15001 Posive High High San Antonio 2014: Immunotherapy Update DB Page et al 12 Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X et al. The 19 Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. therapeutic effect of anti-HER2/neu antibody depends on both innate and Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J adaptive immunity. Cancer Cell 2010; 18:160–170. Med 2012; 366: 2443–2454. 13 Coley WB. The Treatment of inoperable sarcoma by bacterial toxins (the mixed 20 Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS et al. Predictive toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. 1910; 3:1–48. Nature 2014; 515:563–567. 14 Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C et al. Ipilimumab 21 Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E et al. PD-1 identifies the plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin 2011; 364: 2517–2526. Invest 2014; 124: 2246–2259. 15 Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. 22 Galluzzi L, Vacchelli E, Bravo-San Pedro JM, Buque A, Senovilla L, Baracco EE et al. Classi- Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J fication of current anticancer immunotherapies. Oncotarget 2014; 5: 12472–12508. Med 2010; 363: 711–723. 23 Ding ZC, Lu X, Yu M, Lemos H, Huang L, Chandler P et al. Immunosuppressive 16 Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C et al. Guidelines for the myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell evaluation of immune therapy activity in solid tumors: immune-related response responses through the PD-1-PD-L1 axis. Cancer Res 2014; 74: 3441–3453. criteria. Clin Cancer Res 2009; 15:7412–7420. 17 Armand P, Ansell SM, Lesokhin AM, Halwani A, Millenson MM, Schuster SJ et al. This work is licensed under a Creative Commons Attribution- Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma—Preliminary Safety, Effiacy, and Biomarker Results of a Phase I Study. 56th ASH Annual Meeting NonCommercial-NoDerivatives 4.0 International License. The images and Exposition; 2014 December 6-9, 2014; San Francisco, CA. or other third party material in this article are included in the article’s Creative Commons 18 Page DB, Naidoo J, Momtaz P, Bogatch K, Kuk D, Panageas K et al. Patterns of long- license, unless indicated otherwise in the credit line; if the material is not included under term survival following ipilimumab (Ipi): the Memorial Sloan Kettering Cancer Cetner the Creative Commons license, users will need to obtain permission from the license 10-year metastatic melanoma (MM) experience. SITC 2014: National Harbor, MD, holder to reproduce the material. To view a copy of this license, visit http:// 2014, November 7-9, 2014. creativecommons.org/licenses/by-nc-nd/4.0/ npj Breast Cancer (2015) 15001 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

The 2014 San Antonio Breast Cancer Symposium: A successful lift-off for breast immunotherapy?

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www.nature.com/npjbcancer All rights reserved 2374-4677/15 MEETING REPORT OPEN The 2014 San Antonio Breast Cancer Symposium: A successful lift-off for breast immunotherapy? 1 1 1 David B Page , Jarushka Naidoo and Heather L McArthur Therapeutic immune checkpoint antibodies promote potentially durable cancer control by modulating key regulatory factors of the endogenous anti-tumor immune response. The first clinical trial data of these agents in breast cancer were presented at the 2014 San Antonio Breast Cancer Symposium, with seemingly modest response rates compared with metastatic melanoma and Hodgkin’s lymphoma. In this article, we review the San Antonio immunotherapy data, drawing key analogies to historical experiences in metastatic melanoma that support an enthusiastic outlook for immunotherapy in breast cancer. npj Breast Cancer (2015) 1, 15001; doi:10.1038/npjbcancer.2015.1; published online 2 June 2015 INTRODUCTION therapy in breast cancer. Herein, we review the developments to date and potential future directions for immunotherapy in breast Modern immunotherapy has markedly transformed the treatment cancer. landscape for metastatic melanoma as evidenced by the recent rapid-fire food and drug administration (FDA) approval of three immunologic ‘checkpoint antibodies’ (ipilimumab, pembrolizu- THE TIL STORY: REPEATED CREDENCE FOR BREAST mab, and nivolumab). These checkpoint antibodies function by IMMUNOTHERAPY binding and blocking key immune regulatory proteins, cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1), In 2013, leaders in the field convened at the first annual San or programmed death ligand 1 (PD-L1), thereby ‘releasing Antonio TILs working group to develop a standardized metric by the brakes’ on lymphocytes and permitting a robust immune which to measure TILs using hematoxylin and eosin (H&E). Using response against the tumor. The most recently approved anti- these consensus guidelines, Dr Edith Perez presented a retro- body, nivolumab, produced a 40% durable objective response rate spective analysis of TILs in patients with HER2-positive early-stage and a near-doubling of 1-year overall survival compared with breast cancer who received adjuvant chemotherapy +/ − trastu- 3 4 conventional chemotherapy. zumab in the ECOG N9831 trial at SABCS 2014. Two key findings In light of these impressive results, investigators have been were presented, one confirmatory and the other novel. The keen to evaluate immune checkpoint antibodies in other tumor confirmatory finding, illustrated previously in several adjuvant 9,10 types. The clinical activity of anti-PD-1/L1 therapy was recently data sets, was that TIL quantity by H&E is prognostic, with reported across a growing list of malignancies, including non- increasing stromal TILs correlating with improved outcome follow- small cell lung cancer, renal cell carcinoma, gastric cancer, ing chemotherapy both as continuous and binary variables. Hodgkin’s lymphoma, and bladder cancer. To date, limited These data suggest that anti-tumor immunity contributes toward clinical trial data have been presented for breast cancer. However, cure in early-stage breast cancer, and provides a compelling recent observations that tumor-infiltrating lymphocytes (TILs) rationale to investigate immunotherapy in early-stage breast are both prognostic and predictive supports the hypotheses cancer, particularly in patients with low TILs and a high risk of that the immune system is implicated in the biology of breast relapse. cancer, mediates favorable outcomes, and that immunotherapy The novel finding was that the prognostic association was less may be used as a rational therapeutic modality to enhance apparent in trastuzumab-treated patients. From the previously outcomes. reported FinHer study of chemotherapy with or without a shorter The emerging role of immunotherapy in breast cancer was duration of trastuzumab, stromal TILs as a continuous variable evidenced by a number of presentations at this year’s San Antonio was associated with improved outcome following trastuzumab. Breast Cancer Symposium (SABCS). First, retrospective analyses of The N9831 analysis, however, failed to confirm this finding. The TILs provided additional evidence that anti-tumor immunity FinHer data set also suggested that TIL-high tumors benefited to a mediates survival in breast cancer. Next, the first unequivocal greater degree from trastuzumab, in contrast to the N9831 data cases of objective response to immune checkpoint blockade in set that demonstrated TIL-low tumors benefited from trastu- metastatic breast cancer were reported from two independent zumab and TIL-high tumors fared equally well, with or without 5,6 phase I clinical trials with anti-PD-1/L1 therapy. Finally, prelimi- trastuzumab. nary data were presented illustrating how novel combination One way to come to terms with these discrepancies is to strategies—such as immune checkpoint blockade with tumor conceptually ‘re-classify’ trastuzumab as a bona fide immuno- cryoablation—might be used to enhance response to immuno- therapy, which is supported by preclinical observations that Memorial Sloan Kettering Cancer Center, Breast Medicine Service, New York, NY, USA. Correspondence: DB Page (paged@mskcc.org) Received 21 January 2015; accepted 21 January 2015 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited San Antonio 2014: Immunotherapy Update DB Page et al trastuzumab activity is mediated by both innate (antigen non- development of new lesions. In melanoma, we know that many specific) and adaptive (antigen-specific) immunity. As such, the long-term survivors, who received immune checkpoint blockade, first discrepancy—that TILs are less prognostic in trastuzumab- develop new lesions that are successfully managed with radiation treated patients—could be explained by the possibility that or surgery without additional systemic therapy. These observa- trastuzumab serves to immunologically rescue ‘low-TIL’ tumors, tions provide hope that survival benefit in breast cancer may thereby improving their prognosis and diminishing the impor- exceed the apparent benefit using conventional response criteria. tance of baseline TIL density. The second discrepancy—that ‘high- Furthermore, in contrast to Coley’s toxins and the early TIL’ tumors did not benefit from the addition of trastuzumab in ipilimumab experience, both MPDL3280A and pembrolizumab 5,6 the N9831 data set—is likely explained by the excellent prognosis were safe and well tolerated. Minimal grade 3-4 adverse events of these patients irrespective of trastuzumab, potentially because were reported (MPDL3280A: 8% adrenal insufficiency; pembroli- of pre-existing anti-tumor immunity. While the FinHer data set zumab: 3% anemia, headache, aseptic meningitis, pyrexia, and demonstrated benefit with trastuzumab in the high-TIL subgroup, decreased fibrinogen). One death occurred in the pembrolizumab the subgroup was small (n = 22) with only six events across two trial; however, this death was attributed to disseminated arms. So given this data, the ‘take-home’ message from N9831 is intravascular coagulation, which is not generally observed with that the ‘high-TIL’ patient—characterized by excellent baseline anti-PD-1 therapy. The toxicity profiles reported at SABCS 2014 tumor immunogenicity—fares well with standard-of-care echo the larger body of clinical evidence that anti-PD-1/PD-L1 is chemotherapy alone, whereas patients with lower TIL quantities extremely safe and may provide clinical activity while preserving benefit from the addition of trastuzumab, with the caveat that quality of life in heavily pre-treated patients. these findings are discordant with those from the smaller FinHer study. A meta-analysis of the data from all the pivotal adjuvant PERSONALIZED IMMUNOTHERAPY: THE FUTURE IN BREAST chemotherapy/trastuzumab trials would further refine these CANCER observations and may further delineate which patients could potentially benefit from modern immunotherapy strategies. Despite our calls for optimism, these trials also suggest that a ‘one- size-fits-all’ immunotherapy approach may not succeed across tumor types, or across breast cancer subtypes. For example, both THE POWER OF THE ANECDOTE: FROM COLEY’S TOXIN TO of the aforementioned anti-PD-1/L1 antibody phase I breast cancer PEMBROLIZUMAB trials excluded patients with PD-L1-negative tumors. Because More than a century ago, a surgeon named William Coley noticed PD-L1 positivity is likely to enrich for response, an anti-PD-1/L1 that one of his cancer patients experienced a remission after a trial in an unselected population might achieve even fewer serious infection. With further investigation he learned that other objective responses than reported. However, the significance and physicians had observed similar responses. He consequently definition of PD-L1 positivity remains highly controversial. It was developed ‘Coley’s toxin,’ a cocktail of bacterial products that originally believed that tumors expressing PD-L1 would be most could induce marked tumor regressions when injected into likely to respond to anti-PD1/PD-L1 therapy. However, recent sarcomas, albeit with somewhat inconsistent results, and with data suggest that PD-L1 positivity of infiltrating immune cells is the unfortunate side effect of sepsis in some. With these efforts, better associated with response, and that PD-L1 may be a marker 20,21 he is largely credited as being the founder of cancer immu- of prior T-cell activation rather than tumor immune escape. notherapy. More than a century later, initial experiments of However, PD-L1 expression alone, or TIL quantity by H&E staining ipilimumab in metastatic melanoma were remarkably similar to alone, is unlikely to adequately predict response to immuno- the Coley’s toxin experience, characterized by frequent toxicities therapy. More nuanced studies of TILs may provide an under- (including life-threatening immune colitis) and infrequent objec- standing of the mechanisms of immune resistance in breast 14,15 tive responses (10.9–15.2%). Akin to William Coley, modern cancer, and may guide rational therapeutic targeting of molecules immunotherapists used anecdotes of complete responses, implicated in tumor immune evasion and escape. A recent analysis delayed responses, and durable stable disease to sustain enthu- of baseline tumor biopsies preceding anti-PD-L1 therapy serves to 16 20 siasm for modern immune checkpoint blockade strategies. illustrate this concept. Tumors that responded to anti-PD-L1 Thanks to these unwavering efforts, ipilimumab was ultimately therapy were generally characterized by high-TIL density and PD- FDA approved in metastatic melanoma on the basis of durable L1 positivity. In contrast, tumors that progressed following PD-L1 survival benefit, with many ipilimumab-treated patients surviving therapy were characterized by one of several profiles: some 14,15 free of disease for more than 10 years. Furthermore, we have ‘immunologically ignorant’ tumors exhibited low-TIL density and learned, through experience, how to safely manage the toxicities PD-L1 negativity; other ‘immunologically non-functional’ tumors of ipilimumab. contained more TILs but were PD-L1-negative; finally, a third In some ways, this year’s initial reports of immune checkpoint group of ‘immunologically excluded’ tumors contained dense, blockade in breast cancer echo these historical experiences. PD-L1-positive lymphocytes at the leading edge of the tumor, but Reports from a phase I study of MPDL3280A, an anti-PD-L1 with no intratumoral TILs. While these findings have not yet been antibody, and a phase I study of pembrolizumab, an anti-PD-1 validated in larger studies, they highlight the principle that a antibody, in triple-negative breast cancer were modest, with singular biomarker may be inadequate to predict response to media headlines emphasizing that the objective response rates in immunotherapy. Furthermore, the lack of a standardized assay for breast cancer (33 and 19%) paled in comparison with melanoma PD-L1 and the dynamic nature of PD-L1 expression remain 3 17 (40%) and Hodgkin’s lymphoma (87%). However, if we draw ongoing challenges in this field. analogies to melanoma experience with ipilimumab, we have How can we forge ahead to optimize immunotherapy in breast reason to remain optimistic. The first similarity to ipilimumab in cancer? First, as a field, we must acknowledge and embrace the melanoma is that objective responses to anti-PD1/PD-L1 therapy complexity of immunology. Despite the prognostic considerations in breast cancer appeared to be durable, with several patients of TILs, the TIL is not a singular entity: TILs comprises multiple cell treated for more than 11 months. Second, in addition to the types, some capable of killing tumor (and protecting from relapse) reports of complete (n = 2) and partial (n = 6) responders, a notable and others capable of promoting tumor growth. Similarly, proportion of patients experienced response kinetics similar to the immunotherapy is not a singular entity: aside from anti-PD-1/L1, melanoma population, with unconventional but durable clinical dozens of other immunotherapeutic targets are being evaluated benefit seen in 8 patients (26%, 11%) who achieved stable disease, in phase I studies, many of which have strong pre-clinical rationale and several with prolonged tumor regression after initial in breast cancer. For example, some breast cancers, particularly npj Breast Cancer (2015) 15001 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited Low Low Negave San Antonio 2014: Immunotherapy Update DB Page et al PD-L1 TILs TILs TIL phenotype PD-1/PD-L1 sensive Excluded Non-funconal Ignorant Example Tumor - associated macrophages or other Inadequate angen Mechanism of T-cell exhauson suppressive cells presentaon immune evasion Immunizaon An-PD-1/PD-L1 plus second immunotherapy Proposed An-PD-1/PD-L1 (vaccine, cryo- immunotherapies (example, an-CSF-R1 or an-CTLA4) immunotherapy) Figure 1. Conceptualization of how multiple immunologic biomarkers could be used to personalize immunotherapy. CSF-1R, colony- stimulating factor 1 receptor; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TILs, tumour-infiltrating lymphocytes. the cancers that are PD-L1-positive but resistant to anti-PD-1/L1, FUNDING might develop immune resistance by recruiting tumor-associated The authors declare that no funding was received. macrophages (TAMs)—suppressive macrophages that are asso- ciated with adverse prognosis in breast cancer. Antibodies REFERENCES targeting colony-stimulating factor 1 receptor, a growth factor 1 Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response receptor for TAMs, are undergoing phase I evaluation and may of T cells to stimulation. J Exp Med 1995; 182: 459–465. ultimately be effective in overcoming this resistance mechanism. 2 Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. 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The images and Exposition; 2014 December 6-9, 2014; San Francisco, CA. or other third party material in this article are included in the article’s Creative Commons 18 Page DB, Naidoo J, Momtaz P, Bogatch K, Kuk D, Panageas K et al. Patterns of long- license, unless indicated otherwise in the credit line; if the material is not included under term survival following ipilimumab (Ipi): the Memorial Sloan Kettering Cancer Cetner the Creative Commons license, users will need to obtain permission from the license 10-year metastatic melanoma (MM) experience. SITC 2014: National Harbor, MD, holder to reproduce the material. To view a copy of this license, visit http:// 2014, November 7-9, 2014. creativecommons.org/licenses/by-nc-nd/4.0/ npj Breast Cancer (2015) 15001 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited

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npj Breast CancerSpringer Journals

Published: Jun 2, 2015

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