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How do I steer this thing? Using dendritic cell targeted vaccination to more effectively guide the antitumor immune response with combination immunotherapy

How do I steer this thing? Using dendritic cell targeted vaccination to more effectively guide... Mounting an immune response sufficient to eradicate a tumor is the goal of modern immunotherapy. Single agent therapies with checkpoint inhibitors or costimulatory molecule agonists are effective only for a small portion of all treated patients. Combined therapy, e.g., CTLA-4 and PD-1 checkpoint blockade, is a more effective treatment modality, but in preclinical studies OX40 agonism with CTLA-4 blockade using monoclonal antibodies (aOX40/aCTLA-4) failed to induce tumor regression of larger, more established tumors. We hypothesized that administration of a vaccine with a tumor-associated antigen targeted to the appropriate antigen presenting cell could make combined aOX40/aCTLA-4 therapy more effective. We administered an antibody-based vaccine targeting HER2 to the DEC-205 endocytic receptor on cross-presenting dendritic cells (anti-DEC-205/HER2; aDEC-205/HER2) and a potent adjuvant (poly (I:C)) to assist with maturation, along with aOX40/aCTLA-4 therapy. This therapy induced complete regression of established tumors and a pronounced infiltration of effector CD8 and CD4 T cells, with no effect on regulatory T cell infiltration compared to aOX40/aCTLA-4 alone. To be maximally effective, this therapy required expression of both OX40 and CTLA-4 on CD8 T cells. These data indicate that vaccination targeting cross-presenting dendritic cells with a tumor-associated antigen is a highly effective immunization strategy that can overcome some of the limitations of current systemic immunotherapeutic approaches that lack defined tumor-directed antigenic targets. Keywords: Immunotherapy, Cytotoxic CD8 T cell, OX40, CTLA-4, Checkpoint blockade, Co-stimulation, Dendritic cell, Vaccine, Anergy, Tolerance Background anti-OX40 monoclonal antibodies (aOX40) induced tumor Immunotherapy is quickly garnering attention and enthusi- regression by boosting effector CD8 and CD4 T cell expan- asm as some patients with metastatic disease have achieved sion and function [2–6]. Another successful approach is the long-term remission. However, combinations of immuno- blockade of a co-inhibitory molecule, CTLA-4, which limits therapies and/or targeted therapies will be needed to an active immune response. Our previous research has achieve complete tumor regression for a larger portion of demonstrated that combination aOX40/aCTLA-4 therapy patients. Our lab has been investigating the efficacy of significantly improved survival in preclinical models [7]. OX40 agonism in combination with CTLA-4 blockade. Surprisingly, this therapy also induced a profound Th2 bias OX40 is costimulatory molecule expressed by both CD4 in CD4 T cells. It is known that TCR-mediated recognition and CD8 T cells following T cell receptor (TCR) ligation [1]. of low-affinity antigens can promote a Th2 bias, which Preclinical data demonstrate that treatment with agonist limits an effective antitumor immune response, and that promoting a Th1 bias results in more favorable outcomes for patients [8–13]. In order to circumvent a Th2 bias and * Correspondence: William.redmond@providence.org Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, promote a more robust Th1 response, we opted to augment Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR a CD8 T cell response directly via DEC205 expressing 97213, USA cross-presenting dendritic cells (DCs) [14]. It was previously Department of Molecular Microbiology and Immunology, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA © 2016 Linch and Redmond. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Linch and Redmond Journal for ImmunoTherapy of Cancer (2016) 4:31 Page 2 of 4 demonstrated that mice defective in cross-presentation have function of this population following combined aOX40/ impaired tumor rejection and that in cancer, DC function is aCTLA-4 treatment. Furthermore, CD4 T cells were frequently impaired [15, 16]. We hypothesized that vaccin- required to induce a potent CD8 T cell response. A key ob- ation targeting a tumor-associated antigen toward cross- servationwemadeinour previous studywas that aOX40/ presenting dendritic cells (aDEC-205/HER2 with poly (I: C)) aCTLA-4 therapy was not sufficient to improve survival of combined with aOX40/aCTLA-4 immunotherapy would mice with larger, more established tumors. Notably, when promote a robust effector CD8 T cell response capable of aDEC-205/HER2 vaccination was combined with aOX40/ clearing established tumors. aCTLA-4, we observed regression of established tumors (100-150 mm ). This corresponded with a significant in- Main text crease in inflammatory cytokine and chemokine production To elaborate on our previous studies, we tested the effect of by CD4 and CD8 T cells, and a notable decrease in Th2 combination aOX40/aCTLA-4 therapy on antigen-specific cytokines from CD4 T cells, which we had observed previ- T cell expansion and the kinetics of this response. Combin- ously. The triple combination induced profound CD8 and ation aOX40/aCTLA-4 therapy significantly increased the CD4 effector T cell infiltration in the tumor. It is known that frequency, function, and persistence of antigen-specific CD8 T cell anergy is a major obstacle to effective antitumor T cells in the periphery over time. To determine whether immunity. To investigate whether this triple combination this was a direct or indirect effect on CD8 T cells, we used could overcome T cell anergy, we combined a mouse model OX40-deficient and human CTLA-4 knock-in transgenic of anergy using POET-1 (probasin ovalbumin expressing -/- mice. OX40 OT-I cells had a significantly reduced ability transgenic-1) combined with a spontaneous prostate cancer to proliferate, differentiate into effector cells, and produce model – TRAMP (transgenic adenocarcinoma of the mouse inflammatory cytokines following combination therapy, in- prostate) transgenic mice [18, 19]. POET-1 mice express dicating the requirement for OX40. To determine whether membrane-bound ovalbumin (mOVA) in the prostate CTLA-4 expression on CD8 T cells was required for the driven by the rat probasin promoter. Thus, POET-1 x efficacy of combination therapy, we used transgenic mice in TRAMP (TRAMP-OVA) mice express mOVA as a self/ which the extracellular portion of the mouse CTLA-4 tumor-associated antigen that renders ovalbumin-specific receptor is swapped with the human version (huCTLA-4 CD8 T cells anergic. Combined aOX40/aCTLA-4 therapy mice), rendering them unresponsive to anti-mouse CTLA-4 with aDEC-205/OVA vaccination rescued anergic tumor- antagonism [17]. Surprisingly, CTLA-4 expression on CD8 specific CD8 T cells and significantly improved their activa- T cells was required to induce maximal expansion and tion, proliferation, and cytokine production (Fig. 1). Fig. 1 Vaccination using aDEC-205/HER2 combined with adjuvant poly (I:C) induces dendritic cell maturation and costimulatory molecule expression, thereby resulting in more efficient antigen presentation to CD8 T cells. Activation of CD8 T cells via the T cell receptor (TCR) and OX40 using an OX40 agonist induces robust CTL activation, while CTLA-4 blockade releases the brakes on the activated CTL. Effector CD8 T cells can now traffic into the tumor, where they accumulate and induce cancer cell death using cytolytic granule proteins. T cell activation and cancer cell death leads to increased cytokine (IFN-γ,TNF-α, IL-2) and chemokine (CCL3/MIP-1α; CCL4/MIP-1β; CCL5/RANTES) production leading to additional recruitment of effector T cells. OX40 agonism and CTLA-4 blockade also lead to CD4 T cell activation and expansion. Together, this robust T cell response results in tumor eradication and improved long-term survival Linch and Redmond Journal for ImmunoTherapy of Cancer (2016) 4:31 Page 3 of 4 Conclusions molecules in preventing rampant autoimmunity. Perhaps Our recent studies suggest that finding appropriate vac- combining a method of vaccination with a checkpoint cination methods to combine with checkpoint inhibitors inhibitor and a costimulatory molecule agonist, such as (e.g., aCTLA-4) and costimulatory molecule agonism monoclonal antibodies activating OX40, 4-1BB, or GITR, (e.g., aOX40) will be more effective at reducing tumor will provide greater efficacy for patients, as it may more burden and improving survival than any single agent. In easily direct the immune response in the direction desir- particular, the use of aOX40/aCTLA-4 alone was insuffi- ed—away from normal self-antigens and toward a tumor- cient to eliminate larger, more established tumors, which associated antigen. In the growing age of bioinformatics may be due to increased Th2-associated cytokines or and personalized medicine, it seems that personalized tumor-induced anergy [7]. One possible explanation for vaccination is becoming a more feasible possibility for the reduced efficacy of combination therapy in the patients. Combining vaccination using a patient’sown absence of vaccination is because it relies on TCR- tumor-associated neoepitopes with checkpoint inhibition mediated recognition of endogenous antigens. Due to and/or costimulatory molecule agonism will likely pro- mechanisms of central and peripheral tolerance the mote a more directed T cell response and may benefit a majority of these T cells are likely to be of low affinity majority of patients, even with a minimal baseline pres- for their respective tumor-associated antigens. In the ence of T cells. In fact, it is in this scenario where the absence of competition from T cells with higher affinity efficacy of OX40 agonists may truly shine. or an abundance of antigen, a Th2 response predominates [20, 21]. By administering both an adjuvant to promote Ethical approval and consent to participate DC maturation and a tumor-associated antigen targeted Not applicable. to an endocytic receptor present on DCs, we were able to very effectively prime an antitumor cytotoxic T lympho- Consent for publication cyte (CTL) response. CTL activation through the TCR is Not applicable. known to induce expression of both OX40 and CTLA-4 receptors, thus providing targets for aOX40/aCTLA-4 Availability of supporting data therapy. This triple combination—using OX40 agonism to Not applicable. step on the gas, CTLA-4 blockade to release the brakes, Abbreviations and vaccination using aDEC-205/HER2 to steer the im- CTL: cytotoxic T lymphocyte; DC: dendritic cell; TCR: T cell receptor; mune response in the right direction—was able to gener- TIL: tumor infiltrating lymphocyte. ate profound CTL infiltration into the tumor leading to Competing interests tumor regression (Fig. 1). One possible explanation for the W.L.R has received commercial research grants, consulting fees, and/or observed increase in Th1 polarization and concomitant royalties from Bristol-Myers Squibb, Merck, Galectin Therapeutics, and Nektar Therapeutics. S.N.L has received royalties from Galectin Therapeutics. reduction in Th2 cytokine production following triple No non-financial competing interests exist for any of the authors. combination therapy is that CTL-mediated cancer cell death will release an abundance of antigens, including Authors’ contributions SNL and WLR drafted the manuscript and edited the final version. Both those derived from over-expressed and/or mutated self- authors reviewed and approved the final manuscript. proteins. CD4 T cell recognition of these epitopes on ma- ture antigen presenting cells expressing the appropriate Authors’ information Not applicable. costimulatory molecules would favor a Th1-polarized re- sponse. These and previous data also suggest an effect on Acknowledgements CD8 T cell differentiation as a possible mechanism for the The authors would like to thank Diego Barragan-Echenique for his assistance in designing the figure. increased efficacy of the therapy. Our lab is currently investigating the molecular mechanisms underlying this Funding process. Currently, there are multiple clinical trials testing This work was supported by grants from the NIH 1R21CA190790 (W.L.R.), various combinations of immune-based therapeutic mo- Susan G. Komen CCR15329664 (W.L.R.), and the American Cancer Society 2014 Roaring Fork Valley Postdoctoral Fellowship PF1424901LIB (S.N.L.). dalities, including checkpoint inhibitors, targeted therapy with small molecule inhibitors, adoptive cell therapy, Received: 1 April 2016 Accepted: 9 May 2016 and standard of care chemotherapy or radiation. Dual treatment with CTLA-4 and PD-1 blockade (ipilimumab References and nivolumab, respectively) was recently approved, and 1. Redmond WL, Ruby CE, Weinberg AD. The role of OX40-mediated while it improves the overall response rate, the majority of co-stimulation in T-cell activation and survival. Crit Rev Immunol. 2009;29(3):187–201. patients succumb to their disease. The incidence of Grade 2. Gough MJ et al. Adjuvant therapy with agonistic antibodies to CD134 3-4 toxicities also increases with dual therapy, which is (OX40) increases local control after surgical or radiation therapy of not surprising given the importance of these two cancer in mice. J Immunother. 2010;33(8):798–809. Linch and Redmond Journal for ImmunoTherapy of Cancer (2016) 4:31 Page 4 of 4 3. Gough MJ et al. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res. 2008;68(13):5206–15. 4. Redmond WL, Gough MJ, Charbonneau B, Ratliff TL, Weinberg AD. Defects in the acquisition of CD8 T cell effector function after priming with tumor or soluble antigen can be overcome by the addition of an OX40 agonist. J Immunol. 2007;179(11):7244–53. 5. Redmond WL, Gough MJ, Weinberg AD. Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo. Eur J Immunol. 2009;39(8):2184–94. 6. Ruby CE, Redmond WL, Haley D, Weinberg AD. Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur J Immunol. 2007;37(1):157–66. 7. Redmond WL, Linch SL, Kasiewicz MJ. Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity. Cancer Immunol Res. 2014;2(2):142–53. 8. Pfeiffer C et al. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995;181(4):1569–74. 9. Tao X, Grant C, Constant S, Bottomly K. Induction of IL-4-producing CD4+ T cells by antigenic peptides altered for TCR binding. J Immunol. 1997;158(9):4237–44. 10. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. 11. Tatsumi T et al. Disease-associated bias in T helper type 1 (Th1)/Th2 CD4 (+) T cell responses against MAGE-6 in HLA-DRB10401 (+) patients with renal cell carcinoma or melanoma. J Exp Med. 2002;196(5):619–28. 12. Shiao SL et al. TH2-Polarized CD4+ T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res. 2015;3(5):518–25. 13. Ochi A et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209(9):1671–87. 14. Tsuji T et al. Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity. J Immunol. 2011;186(2):1218–27. 15. Hildner K et al. Batf3 deficiency reveals a critical role for CD8alpha + dendritic cells in cytotoxic T cell immunity. Science. 2008;322(5904):1097–100. 16. Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005;83(5):451–61. 17. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717–25. 18. Lees JR et al. Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8+ T cells. Immunology. 2006;117(2):248–61. 19. Hurwitz AA, Foster BA, Allison JP, Greenberg NM, Kwon ED. The TRAMP mouse as a model for prostate cancer. In: Coligan JE et al. editors. Current protocols in immunology. 2001. Chapter 20: Unit 20 25. 20. Milner JD, Fazilleau N, McHeyzer-Williams M, Paul W. Cutting edge: lack of high affinity competition for peptide in polyclonal CD4+ responses unmasks IL-4 production. J Immunol. 2010;184(12):6569–73. 21. Van Panhuys N, Klauschen F, Germain RN. T-cell-receptor-dependent signal intensity dominantly controls CD4 (+) T cell polarization In Vivo. Immunity. 2014;41(1):63–74. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

How do I steer this thing? Using dendritic cell targeted vaccination to more effectively guide the antitumor immune response with combination immunotherapy

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Publisher
Springer Journals
Copyright
Copyright © 2016 by Linch and Redmond.
Subject
Medicine & Public Health; Oncology; Immunology
eISSN
2051-1426
DOI
10.1186/s40425-016-0135-z
pmid
27330804
Publisher site
See Article on Publisher Site

Abstract

Mounting an immune response sufficient to eradicate a tumor is the goal of modern immunotherapy. Single agent therapies with checkpoint inhibitors or costimulatory molecule agonists are effective only for a small portion of all treated patients. Combined therapy, e.g., CTLA-4 and PD-1 checkpoint blockade, is a more effective treatment modality, but in preclinical studies OX40 agonism with CTLA-4 blockade using monoclonal antibodies (aOX40/aCTLA-4) failed to induce tumor regression of larger, more established tumors. We hypothesized that administration of a vaccine with a tumor-associated antigen targeted to the appropriate antigen presenting cell could make combined aOX40/aCTLA-4 therapy more effective. We administered an antibody-based vaccine targeting HER2 to the DEC-205 endocytic receptor on cross-presenting dendritic cells (anti-DEC-205/HER2; aDEC-205/HER2) and a potent adjuvant (poly (I:C)) to assist with maturation, along with aOX40/aCTLA-4 therapy. This therapy induced complete regression of established tumors and a pronounced infiltration of effector CD8 and CD4 T cells, with no effect on regulatory T cell infiltration compared to aOX40/aCTLA-4 alone. To be maximally effective, this therapy required expression of both OX40 and CTLA-4 on CD8 T cells. These data indicate that vaccination targeting cross-presenting dendritic cells with a tumor-associated antigen is a highly effective immunization strategy that can overcome some of the limitations of current systemic immunotherapeutic approaches that lack defined tumor-directed antigenic targets. Keywords: Immunotherapy, Cytotoxic CD8 T cell, OX40, CTLA-4, Checkpoint blockade, Co-stimulation, Dendritic cell, Vaccine, Anergy, Tolerance Background anti-OX40 monoclonal antibodies (aOX40) induced tumor Immunotherapy is quickly garnering attention and enthusi- regression by boosting effector CD8 and CD4 T cell expan- asm as some patients with metastatic disease have achieved sion and function [2–6]. Another successful approach is the long-term remission. However, combinations of immuno- blockade of a co-inhibitory molecule, CTLA-4, which limits therapies and/or targeted therapies will be needed to an active immune response. Our previous research has achieve complete tumor regression for a larger portion of demonstrated that combination aOX40/aCTLA-4 therapy patients. Our lab has been investigating the efficacy of significantly improved survival in preclinical models [7]. OX40 agonism in combination with CTLA-4 blockade. Surprisingly, this therapy also induced a profound Th2 bias OX40 is costimulatory molecule expressed by both CD4 in CD4 T cells. It is known that TCR-mediated recognition and CD8 T cells following T cell receptor (TCR) ligation [1]. of low-affinity antigens can promote a Th2 bias, which Preclinical data demonstrate that treatment with agonist limits an effective antitumor immune response, and that promoting a Th1 bias results in more favorable outcomes for patients [8–13]. In order to circumvent a Th2 bias and * Correspondence: William.redmond@providence.org Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, promote a more robust Th1 response, we opted to augment Providence Portland Medical Center, 4805 NE Glisan St. 2N35, Portland, OR a CD8 T cell response directly via DEC205 expressing 97213, USA cross-presenting dendritic cells (DCs) [14]. It was previously Department of Molecular Microbiology and Immunology, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA © 2016 Linch and Redmond. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Linch and Redmond Journal for ImmunoTherapy of Cancer (2016) 4:31 Page 2 of 4 demonstrated that mice defective in cross-presentation have function of this population following combined aOX40/ impaired tumor rejection and that in cancer, DC function is aCTLA-4 treatment. Furthermore, CD4 T cells were frequently impaired [15, 16]. We hypothesized that vaccin- required to induce a potent CD8 T cell response. A key ob- ation targeting a tumor-associated antigen toward cross- servationwemadeinour previous studywas that aOX40/ presenting dendritic cells (aDEC-205/HER2 with poly (I: C)) aCTLA-4 therapy was not sufficient to improve survival of combined with aOX40/aCTLA-4 immunotherapy would mice with larger, more established tumors. Notably, when promote a robust effector CD8 T cell response capable of aDEC-205/HER2 vaccination was combined with aOX40/ clearing established tumors. aCTLA-4, we observed regression of established tumors (100-150 mm ). This corresponded with a significant in- Main text crease in inflammatory cytokine and chemokine production To elaborate on our previous studies, we tested the effect of by CD4 and CD8 T cells, and a notable decrease in Th2 combination aOX40/aCTLA-4 therapy on antigen-specific cytokines from CD4 T cells, which we had observed previ- T cell expansion and the kinetics of this response. Combin- ously. The triple combination induced profound CD8 and ation aOX40/aCTLA-4 therapy significantly increased the CD4 effector T cell infiltration in the tumor. It is known that frequency, function, and persistence of antigen-specific CD8 T cell anergy is a major obstacle to effective antitumor T cells in the periphery over time. To determine whether immunity. To investigate whether this triple combination this was a direct or indirect effect on CD8 T cells, we used could overcome T cell anergy, we combined a mouse model OX40-deficient and human CTLA-4 knock-in transgenic of anergy using POET-1 (probasin ovalbumin expressing -/- mice. OX40 OT-I cells had a significantly reduced ability transgenic-1) combined with a spontaneous prostate cancer to proliferate, differentiate into effector cells, and produce model – TRAMP (transgenic adenocarcinoma of the mouse inflammatory cytokines following combination therapy, in- prostate) transgenic mice [18, 19]. POET-1 mice express dicating the requirement for OX40. To determine whether membrane-bound ovalbumin (mOVA) in the prostate CTLA-4 expression on CD8 T cells was required for the driven by the rat probasin promoter. Thus, POET-1 x efficacy of combination therapy, we used transgenic mice in TRAMP (TRAMP-OVA) mice express mOVA as a self/ which the extracellular portion of the mouse CTLA-4 tumor-associated antigen that renders ovalbumin-specific receptor is swapped with the human version (huCTLA-4 CD8 T cells anergic. Combined aOX40/aCTLA-4 therapy mice), rendering them unresponsive to anti-mouse CTLA-4 with aDEC-205/OVA vaccination rescued anergic tumor- antagonism [17]. Surprisingly, CTLA-4 expression on CD8 specific CD8 T cells and significantly improved their activa- T cells was required to induce maximal expansion and tion, proliferation, and cytokine production (Fig. 1). Fig. 1 Vaccination using aDEC-205/HER2 combined with adjuvant poly (I:C) induces dendritic cell maturation and costimulatory molecule expression, thereby resulting in more efficient antigen presentation to CD8 T cells. Activation of CD8 T cells via the T cell receptor (TCR) and OX40 using an OX40 agonist induces robust CTL activation, while CTLA-4 blockade releases the brakes on the activated CTL. Effector CD8 T cells can now traffic into the tumor, where they accumulate and induce cancer cell death using cytolytic granule proteins. T cell activation and cancer cell death leads to increased cytokine (IFN-γ,TNF-α, IL-2) and chemokine (CCL3/MIP-1α; CCL4/MIP-1β; CCL5/RANTES) production leading to additional recruitment of effector T cells. OX40 agonism and CTLA-4 blockade also lead to CD4 T cell activation and expansion. Together, this robust T cell response results in tumor eradication and improved long-term survival Linch and Redmond Journal for ImmunoTherapy of Cancer (2016) 4:31 Page 3 of 4 Conclusions molecules in preventing rampant autoimmunity. Perhaps Our recent studies suggest that finding appropriate vac- combining a method of vaccination with a checkpoint cination methods to combine with checkpoint inhibitors inhibitor and a costimulatory molecule agonist, such as (e.g., aCTLA-4) and costimulatory molecule agonism monoclonal antibodies activating OX40, 4-1BB, or GITR, (e.g., aOX40) will be more effective at reducing tumor will provide greater efficacy for patients, as it may more burden and improving survival than any single agent. In easily direct the immune response in the direction desir- particular, the use of aOX40/aCTLA-4 alone was insuffi- ed—away from normal self-antigens and toward a tumor- cient to eliminate larger, more established tumors, which associated antigen. In the growing age of bioinformatics may be due to increased Th2-associated cytokines or and personalized medicine, it seems that personalized tumor-induced anergy [7]. One possible explanation for vaccination is becoming a more feasible possibility for the reduced efficacy of combination therapy in the patients. Combining vaccination using a patient’sown absence of vaccination is because it relies on TCR- tumor-associated neoepitopes with checkpoint inhibition mediated recognition of endogenous antigens. Due to and/or costimulatory molecule agonism will likely pro- mechanisms of central and peripheral tolerance the mote a more directed T cell response and may benefit a majority of these T cells are likely to be of low affinity majority of patients, even with a minimal baseline pres- for their respective tumor-associated antigens. In the ence of T cells. In fact, it is in this scenario where the absence of competition from T cells with higher affinity efficacy of OX40 agonists may truly shine. or an abundance of antigen, a Th2 response predominates [20, 21]. By administering both an adjuvant to promote Ethical approval and consent to participate DC maturation and a tumor-associated antigen targeted Not applicable. to an endocytic receptor present on DCs, we were able to very effectively prime an antitumor cytotoxic T lympho- Consent for publication cyte (CTL) response. CTL activation through the TCR is Not applicable. known to induce expression of both OX40 and CTLA-4 receptors, thus providing targets for aOX40/aCTLA-4 Availability of supporting data therapy. This triple combination—using OX40 agonism to Not applicable. step on the gas, CTLA-4 blockade to release the brakes, Abbreviations and vaccination using aDEC-205/HER2 to steer the im- CTL: cytotoxic T lymphocyte; DC: dendritic cell; TCR: T cell receptor; mune response in the right direction—was able to gener- TIL: tumor infiltrating lymphocyte. ate profound CTL infiltration into the tumor leading to Competing interests tumor regression (Fig. 1). One possible explanation for the W.L.R has received commercial research grants, consulting fees, and/or observed increase in Th1 polarization and concomitant royalties from Bristol-Myers Squibb, Merck, Galectin Therapeutics, and Nektar Therapeutics. S.N.L has received royalties from Galectin Therapeutics. reduction in Th2 cytokine production following triple No non-financial competing interests exist for any of the authors. combination therapy is that CTL-mediated cancer cell death will release an abundance of antigens, including Authors’ contributions SNL and WLR drafted the manuscript and edited the final version. Both those derived from over-expressed and/or mutated self- authors reviewed and approved the final manuscript. proteins. CD4 T cell recognition of these epitopes on ma- ture antigen presenting cells expressing the appropriate Authors’ information Not applicable. costimulatory molecules would favor a Th1-polarized re- sponse. These and previous data also suggest an effect on Acknowledgements CD8 T cell differentiation as a possible mechanism for the The authors would like to thank Diego Barragan-Echenique for his assistance in designing the figure. increased efficacy of the therapy. Our lab is currently investigating the molecular mechanisms underlying this Funding process. Currently, there are multiple clinical trials testing This work was supported by grants from the NIH 1R21CA190790 (W.L.R.), various combinations of immune-based therapeutic mo- Susan G. Komen CCR15329664 (W.L.R.), and the American Cancer Society 2014 Roaring Fork Valley Postdoctoral Fellowship PF1424901LIB (S.N.L.). dalities, including checkpoint inhibitors, targeted therapy with small molecule inhibitors, adoptive cell therapy, Received: 1 April 2016 Accepted: 9 May 2016 and standard of care chemotherapy or radiation. Dual treatment with CTLA-4 and PD-1 blockade (ipilimumab References and nivolumab, respectively) was recently approved, and 1. Redmond WL, Ruby CE, Weinberg AD. The role of OX40-mediated while it improves the overall response rate, the majority of co-stimulation in T-cell activation and survival. Crit Rev Immunol. 2009;29(3):187–201. patients succumb to their disease. The incidence of Grade 2. Gough MJ et al. Adjuvant therapy with agonistic antibodies to CD134 3-4 toxicities also increases with dual therapy, which is (OX40) increases local control after surgical or radiation therapy of not surprising given the importance of these two cancer in mice. J Immunother. 2010;33(8):798–809. Linch and Redmond Journal for ImmunoTherapy of Cancer (2016) 4:31 Page 4 of 4 3. Gough MJ et al. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res. 2008;68(13):5206–15. 4. Redmond WL, Gough MJ, Charbonneau B, Ratliff TL, Weinberg AD. Defects in the acquisition of CD8 T cell effector function after priming with tumor or soluble antigen can be overcome by the addition of an OX40 agonist. J Immunol. 2007;179(11):7244–53. 5. Redmond WL, Gough MJ, Weinberg AD. Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo. Eur J Immunol. 2009;39(8):2184–94. 6. Ruby CE, Redmond WL, Haley D, Weinberg AD. Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur J Immunol. 2007;37(1):157–66. 7. Redmond WL, Linch SL, Kasiewicz MJ. Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity. Cancer Immunol Res. 2014;2(2):142–53. 8. Pfeiffer C et al. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995;181(4):1569–74. 9. Tao X, Grant C, Constant S, Bottomly K. Induction of IL-4-producing CD4+ T cells by antigenic peptides altered for TCR binding. J Immunol. 1997;158(9):4237–44. 10. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. 11. Tatsumi T et al. Disease-associated bias in T helper type 1 (Th1)/Th2 CD4 (+) T cell responses against MAGE-6 in HLA-DRB10401 (+) patients with renal cell carcinoma or melanoma. J Exp Med. 2002;196(5):619–28. 12. Shiao SL et al. TH2-Polarized CD4+ T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res. 2015;3(5):518–25. 13. Ochi A et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209(9):1671–87. 14. Tsuji T et al. Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity. J Immunol. 2011;186(2):1218–27. 15. Hildner K et al. Batf3 deficiency reveals a critical role for CD8alpha + dendritic cells in cytotoxic T cell immunity. Science. 2008;322(5904):1097–100. 16. Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005;83(5):451–61. 17. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717–25. 18. Lees JR et al. Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8+ T cells. Immunology. 2006;117(2):248–61. 19. Hurwitz AA, Foster BA, Allison JP, Greenberg NM, Kwon ED. The TRAMP mouse as a model for prostate cancer. In: Coligan JE et al. editors. Current protocols in immunology. 2001. Chapter 20: Unit 20 25. 20. Milner JD, Fazilleau N, McHeyzer-Williams M, Paul W. Cutting edge: lack of high affinity competition for peptide in polyclonal CD4+ responses unmasks IL-4 production. J Immunol. 2010;184(12):6569–73. 21. Van Panhuys N, Klauschen F, Germain RN. T-cell-receptor-dependent signal intensity dominantly controls CD4 (+) T cell polarization In Vivo. Immunity. 2014;41(1):63–74. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support � Convenient online submission � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit

Journal

Journal for ImmunoTherapy of CancerSpringer Journals

Published: Jun 21, 2016

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