Evolving synergistic combinations of targeted immunotherapies to combat cancer

Nature Reviews Cancer

Volumn 15, Issue 8, 2015, Pages 457-472

  Melero, Ignacio ^a   Berman, David M ^b   Aznar, M Angela ^c   Korman, Alan J ^d   Gracia, José Luis Pérez ^a   Haanen, John ^d  

^a UNIVERSITY OF NAVARRA   (Spain)

^b BRISTOL MYERS SQUIBB   (United States)

^c Bristol Myers Squibb   (United States)

^d NETHERLANDS CANCER INSTITUTE   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; ATEZOLIZUMAB; CETUXIMAB; LIRILUMAB; NIVOLUMAB; PEMBROLIZUMAB; PIDILIZUMAB; RITUXIMAB; TRASTUZUMAB; TUMOR MARKER;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; DRUG POTENTIATION; HUMAN; IMMUNOMODULATION; LYMPHOCYTE ACTIVATION; NEOPLASM; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; REVIEW; TUMOR MICROENVIRONMENT; VASCULAR ENDOTHELIUM; ANIMAL; CLINICAL TRIAL (TOPIC); IMMUNOLOGY; IMMUNOTHERAPY; METABOLISM; MOLECULARLY TARGETED THERAPY; MULTIMODALITY CANCER THERAPY; NEOPLASMS;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; COMBINED MODALITY THERAPY; HUMANS; IMMUNOTHERAPY; MOLECULAR TARGETED THERAPY; NEOPLASMS; TUMOR MARKERS, BIOLOGICAL; TUMOR MICROENVIRONMENT;

EID: 84937846973     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3973     Document Type: Review

References (183)

1. Dustin, M. L. The immunological synapse. Cancer Immunol. Res. 2, 1023-1033 (2014)
2. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012)
3. White, A. L. et al. Interaction with FcRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J. Immunol. 187, 1754-1763 (2011)
4. Li, F. &Ravetch, J. V. Antitumour activities of agonistic anti-TNFR antibodies require differential FcRIIB coengagement in vivo. Proc. Natl Acad. Sci. USA 110, 19501-19506 (2013)
5. White, A. L. et al. Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies. Cancer Cell 27, 138-148 (2015)
6. Melero, I. et al. Immunostimulatory monoclonal antibodies for cancer therapy. Nat. Rev. Cancer 7, 95-106 (2007)
7. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 25, 711-723 (2010)
8. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517-2526 (2011)
9. Mellman, I., Coukos, G. &Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480-489 (2011)
10. Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P. &Wolchok, J. D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65, 185-202 (2014)
11. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122-133 (2013)
12. Kim, Y. H. et al. Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity. Cancer Res. 68, 7264-7269 (2008)
13. Knight, D. A. et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J. Clin. Invest. 123, 1371-1381 (2013)
14. Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728-734 (2005)
15. Newcomb, E. W. et al. Radiotherapy enhances antitumour effect of anti-CD137 therapy in a mouse glioma model. Radiat. Res. 173, 426-432 (2010)
16. Yasuda, S. et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin. Exp. Immunol. 172, 500-506 (2013)
17. Hodi, F. S. et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol. Res. 2, 632-642 (2014)
18. Kwon, E. D. et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-Associated antigen 4 (CTLA-4) blockade immunotherapy. Proc. Natl Acad. Sci. USA 96, 15074-15079 (1999)
19. Gangadhar, T. C. &Vonderheide, R. H. Mitigating the toxic effects of anticancer immunotherapy. Nat. Rev. Clin. Oncol. 11, 91-99 (2014)
20. Zwirner, N. W., Croci, D. O., Domaica, C. I. &Rabinovich, G. A. Overcoming the hurdles of tumor immunity by targeting regulatory pathways in innate and adaptive immune cells. Curr. Pharm. Des. 16, 255-267 (2010)
21. Perez-Gracia, J. L., Labiano, S., Rodriguez-Ruiz, M. E., Sanmamed, M. F. &Melero, I. Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Curr. Opin. Immunol. 27, 89-97 (2014)
22. Rosenberg, S. A. &Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62-68 (2015)
23. Kershaw, M. H., Westwood, J. A. &Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer. 13, 525-541 (2013)
24. Morales-Kastresana, A., Labiano, S., Quetglas, J. I. &Melero, I. Better performance of CARs deprived of the PD-1 brake. Clin. Cancer Res. 19, 5546-5548 (2013)
25. Weigelin, B. et al. Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. Proc. Natl Acad. Sci. USA 2 (Suppl 3), P95 (2015)
26. Krummel, M. F. &Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459-465 (1995)
27. Gabriel, E. M. &Lattime, E. C. Anti-CTL-Associated antigen 4: are regulatory T cells a target? Clin. Cancer Res. 13, 785-788 (1995)
28. Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32-42 (2013)
29. Simpson, T. R. et al. Fc-dependent depletion of tumour-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695-1710 (2013)
30. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600-603 (2011)
31. Schadendorf, D. et al. Pooled analysis of long-term survival data from Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889-1894 (2015)
32. Kwon, E. D. et al. Ipilimumab versus placebo after radiotherapy in patients with post-docetaxel metastatic castration-resistant prostate cancer (CA184-043): a multicenter, randomized, double-blind phase 3 trial. Lancet Oncol. 15, 700-712 (2014)
33. Ribas, A. et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31, 616-622 (2013)
34. Okazaki, T. et al. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212-1218 (2013)
35. Butte, M. J., Keir, M. E., Phamduy, T. B., Sharpe, A. H. &Freeman, G. J. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111-112 (2007)
36. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687 (2006)
37. Flies, D. B., Sandler, B. J., Sznol, M. &Chen, L. Blockade of the B7-H1/PD-1 pathway for cancer immunotherapy. J. Biol. Med. 84, 409-421 (2011)
38. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443-2454 (2012)
39. Sznol, M. &Chen, L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin. Cancer Res. 19, 1021-1034 (2013)
40. Hamid, O. et al. Safety and tumour responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134-144 (2013)
41. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109-1117 (2014)
42. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521-2532 (2015)
43. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018-2028 (2015)
44. Berger, R. et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 3044-3051 (2008)
45. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563-567 (2014)
46. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670-684 (2007)
47. Sierro, S., Romero, P. &Speiser, D. E. The CD4-like molecule LAG-3, biology and therapeutic applications. Expert Opin. Ther. Targets 15, 91-101 (2011)
48. Kouo, T. et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol. Res. 3, 412-423 (2015)
49. Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoural immune escape. Cancer Res. 72, 917-927 (2012)
50. Anderson, A. C. Tim-3, a negative regulator of anti-tumour immunity. Curr. Opin. Immunol. 24, 213-216 (2012)
51. Sanchez-Fueyo, A. et al. Tim-3 inhibits T helper type 1-mediated auto-And alloimmune responses and promotes immunological tolerance. Nat. Immunol. 4, 1093-1101 (2003)
52. Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumour antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175-2186 (2010)
53. Gao, X. et al. TIM-3 expression characterizes regulatory T cells in tumour tissues and is associated with lung cancer progression. PLoS ONE 7, e30676 (2012)
54. Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumour immunity. J. Exp. Med. 207, 2187-2194 (2010)
55. Huang, Y. H. et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517, 386-390 (2015)
56. Wang, C., Lin, G. H., McPherson, A. J. &Watts, T. H. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol. Rev. 229, 192-215 (2009)
57. Melero, I. et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med. 3, 682-685 (1997)
58. Shuford, W. W. et al. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47-55 (1997
59. Vinay, D. S. &Kwon, B. S. Immunotherapy of cancer with 4-1BB. Mol. Cancer Ther. 11, 1062-1070 (2012)
60. Fisher, T. S. et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol. Immunother. 61, 1721-1733 (2012)
61. Houot, R. et al. Targeting immune effector cells to promote antibody-induced cytotoxicity in cancer immunotherapy. Trends Immunol. 32, 510-516 (2011)
62. Kohrt, H. E. et al. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood 117, 2423-2432 (2011)
63. Kohrt, H. E. et al. Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668-2682 (2014)
64. Kohrt, H. E. et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 122, 1066-1075 (2012)
65. Ko, K. et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J. Exp. Med. 202, 885-891 (2005)
66. Schaer, D. A., Murphy, J. T. &Wolchok, J. D. Modulation of GITR for cancer immunotherapy. Curr. Opin. Immunol. 24, 217-224 (2012)
67. McHugh, R. S. et al. CD4+ CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311-323 (2002)
68. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. &Sakaguchi, S. Stimulation of CD25+ CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135-142 (2002)
69. Zhou, P., L'italien L., Hodges, D. &Schebye, X. M. Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J. Immunol. 179, 7365-7375 (2007)
70. Houot, R. &Levy, R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood 113, 3546-3552 (2009)
71. Ruby, C. E., Redmond, W. L., Haley, D. &Weinberg, A. D. Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur. J. Immunol. 37, 157-166 (2007)
72. Piconese, S., Valzasina, B. &Colombo, M. P. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J. Exp. Med. 205, 825-839 (2008)
73. Weinberg, A. D., Morris, N. P., Kovacsovics-Bankowski, M., Urba, W. J. &Curti, B. D. Science gone translational: the OX40 agonist story. Immunol. Rev. 244, 218-231 (2011)
74. Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189-7198 (2013)
75. Quezada, S. A., Jarvinen, L. Z., Lind, E. F. &Noelle, R. J. CD40/CD154 interactions at the interface of tolerance and immunity. Annu. Rev. Immunol. 22, 307-328 (2004)
76. Vonderheide, R. H. &Glennie, M. J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035-1043 (2013)
77. Vonderheide, R. H. et al. Clinical activity and immune modulation in cancer patients treated with CP-870, 893, a novel CD40 agonist monoclonal antibody. J. Clin. Oncol. 25, 876-883 (2007)
78. Denoeud, J. &Moser, M. Role of CD27/CD70 pathway of activation in immunity and tolerance. J. Leukoc. Biol. 89, 195-203 (2011)
79. Hintzen, R. Q. et al. Characterization of the human CD27 ligand, a novel member of the TNF gene family. J. Immunol. 152, 1762-1773 (1994)
80. Hintzen, R. Q. et al. Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation. J. Immunol. 154, 2612-2623 (1995)
81. Yang, F. C. et al. CD27/CD70 interaction directly induces natural killer cell killing activity. Immunology 88, 289-293 (1996)
82. Tesselaar, K., Gravestein, L. A., Van Schijndel, G. M., Borst, J. &Van Lier, R. A. Characterization of murine CD70, the ligand of the TNF receptor family member CD27. J. Immunol. 159, 4959-4965 (1997)
83. Hendriks, J., Xiao, Y. &Borst, J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J. Exp. Med. 198, 1369-1380 (2003)
84. Bullock, T. N. J. &Yagita, H. Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. J. Immunol. 174, 710-717 (2005)
85. Taraban, V. Y., Rowley, T. F., Tough, D. F. &Al-Shamkhani, A. Requirement for CD70 in CD4+ Th cell-dependent and innate receptor-mediated CD8+ T cell priming. J. Immunol. 177, 2969-2975 (2006)
86. Parham, P. MHC class I molecules and KIRs in human history, health and survival. Nat. Rev. Immunol. 5, 201-214 (2005)
87. Falco, M., Moretta, L., Moretta, A. &Bottino, C. KIR and KIR ligand polymorphism: a new area for clinical applications? Tissue Antigens 82, 363-373 (2013)
88. Karre, K. Natural killer cell recognition of missing self. Nat. Immunol. 9, 477-480 (2008)
89. Vey, N. et al. A Phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood 120, 4317-4323 (2012)
90. Masilamani, M., Nguyen, C., Kabat, J., Borrego, F. &Coligan, J. E. CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J. Immunol. 177, 3590-3596 (2006)
91. Chan, C. J. et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat. Immunol. 15, 431-438 (2014)
92. Kroemer, G., Galluzzi, L., Kepp, O. &Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51-72 (2013)
93. Melero, I., Rouzaut, A., Motz, G. T. &Coukos, G. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 4, 522-526 (2014)
94. Sznol, M. et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). American Society of Clinical Oncology [online] http://meetinglibrary.asco.org/content/126008-144 (2014)
95. Hodi, F. S. et al. Ipilimumab plus sargramostim versus ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA 312, 1744-1753 (2014)
96. Lynch, T. J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase II study. J. Clin. Oncol. 30, 2046-2054 (2012)
97. Reck, M. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter Phase 2 trial. Ann. Oncol. 24, 75-83 (2013)
98. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 21, 2006-2017 (2015)
99. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 372, 2006-2017 (2015)
100. Kim, J. M. &Ashkenazi, A. Fc? receptors enable anticancer action of proapoptotic and immune-modulatory antibodies. J. Exp. Med. 210, 1647-1651 (2013)
101. Wang, C. et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol. Res. 2, 846-856 (2014)
102. Korman, A. et al. Activity of anti-PD-1 in murine tumor models: role of "host" PD-L1 and synergistic effect of anti-PD-1 and anti-CTLA-4. J. Immunol. [online] http://www.jimmunol.org/cgi/content/meeting-Abstract/178/MeetingAbstracts/S82 (2007)
103. Curran, M. A., Montalvo, W., Yagita, H. &Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275-4280 (2010)
104. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. &Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591-3603 (2013)
105. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543-9553 (2005)
106. Walker, L. S. &Sansom, D. M. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat. Rev. Immunol. 11, 852-863 (2011)
107. Kvistborg, P. et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci. Transl. Med. 6, 254ra128 (2014)
108. Bulliard, Y. et al. Activating Fc? receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685-1693 (2013)
109. Quezada, S. A., Peggs, K. S., Curran, M. A. &Allison, J. P. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935-1945 (2006)
110. Hammers, H. et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). American Society of Clinical Oncology [online] http://meetinglibrary.asco.org/content/129458-144 (2014)
111. Antonia, S. J. et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: interim Phase I results. American Society of Clinical Oncology [online] http://meetinglibrary.asco.org/content/125736-144 (2014)
112. Fourcade, J. et al. CD8+ T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 72, 887-896 (2012)
113. Tirapu, I. et al. Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal, and get ready to face autoimmunity. Arch. Immunol. Ther. Exp. 50, 13-18 (2002)
114. Menard, C., Martin, F., Apetoh, L., Bouyer, F. &Ghiringhelli, F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol. Immunother. 57, 1579-1587 (2008)
115. Moschella, F., Proietti, E., Capone, I. &Belardelli, F. Combination strategies for enhancing the efficacy of immunotherapy in cancer patients. Ann. NY Acad. Sci. 1194, 169-178 (2010)
116. Hannani, D. et al. Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy. Cancer J. 17, 351-358 (2011)
117. Formenti, S. C. &Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Nat. Cancer Inst. 105, 256-265 (2013)
118. Patel, S. P. et al. Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma. American Society of Clinical Oncology [online] http://meetinglibrary. asco.org/content/93186-114 (2012)
119. Ribas, A., Hodi, F. S., Callahan, M., Konto, C. &Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368, 1365-1366 (2013)
120. Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225-1231 (2013)
121. Wilmott, J. S. et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18, 1386-1394 (2012)
122. Comin-Anduix, B. et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin. Cancer Res. 16, 6040-6048 (2010)
123. Harding, J. J., Pulitzer, M. &Chapman, P. B. Vemurafenib sensitivity skin reaction after ipilimumab. N. Engl. J. Med. 366, 866-868 (2012)
124. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925-931 (2012
125. Grimaldi, A. M. et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 3, e28780 (2014)
126. Victor, C. T. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373-377 (2015)
127. Weber, J. S., Dummer, R., de Pril, V., Lebbe, C. &Hodi, F. S. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a Phase 3 trial in patients with advanced melanoma. Cancer 119, 1675-1682 (2013)
128. Kahler, K. C. &Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691-2697 (2012)
129. Voskens, C. J. et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS ONE 8, e53745 (2013)
130. Berman, D. et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 10, 11 (2010)
131. Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra45 (2014)
132. Takeda, K. et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J. Immunol. 184, 5493-5501 (2010)
133. Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400-404 (2013)
134. Prieto, P. A. et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin. Cancer Res. 18, 2039-2047 (2012)
135. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020-1030 (2014)
136. Lipson, E. J. et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin. Cancer Res. 19, 462-468 (2013)
137. Ascierto, P. A., Kalos, M., Schaer, D. A., Callahan, M. K. &Wolchok, J. D. Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumor types. Clin. Cancer Res. 19, 1009-1020 (2013)
138. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568-571 (2014)
139. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064-5074 (2014)
140. Tarhini, A. A. et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS ONE 9, e87705 (2014)
141. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883-892 (2012)
142. Balch, C. M. et al. A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III). J. Clin. Oncol. 1, 126-134 (1983)
143. Hino, R. et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116, 1757-1766 (2010)
144. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439-e442 (2013)
145. Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015)
146. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. http://dx.doi. org/10.1056/NEJMoa1500596 (2015)
147. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 349, 203-213 (2003)
148. Fridman, W. H. et al. Immune infiltration in human cancer: prognostic significance and disease control. Curr. Top. Microbiol. Immunol. 344, 1-24 (2011)
149. Gooden, M. J., de Bock, G. H., Leffers, N., Daeman, T. &Nijman, H. W. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-Analysis. Br. J. Cancer 105, 93-103 (2011)
150. Erdag, G. et al. Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. Cancer Res. 72, 1070-1080 (2012)
151. Adams, S. et al. Prognostic value of tumour-infiltrating lymphocytes in triple-negative breast cancers from two Phase III randomized Adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J. Clin. Oncol. 32, 2959-2967 (2014)
152. Spranger, S. et al. Up-regulation of PD-L1, IDO, and TRegs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013)
153. Taube, J. M. et al. Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012)
154. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2, 3-dioxygenase. Nat. Med. 9, 1269-1274 (2003)
155. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558-562 (2014)
156. Hamid, O. et al. A prospective Phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9, 204 (2011)
157. Ji, R. R. et al. An immune-Active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 6, 1019-1031 (2012)
158. Ribas, A. et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2, 3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin. Cancer Res. 15, 390-399 (2009)
159. Frankel, T. L. et al. Identification and characterization of a tumor infiltrating CD56+/CD16-NK cell subset with specificity for pancreatic and prostate cancer cell lines. Cancer Immunol. Immunother. 59, 1757-1769 (2010)
160. Hodi, F. S. et al. Biologic activity of cytotoxic T lymphocyte-Associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl Acad. Sci. USA 100, 4712-4717 (2003)
161. Choueiri, T. K. et al. Immunomodulatory activity of nivolumab in previously treated and untreated metastatic renal cell carcinoma (mRCC): biomarker-based results from a randomized clinical trial. American Society of Clinical Oncology [online] http://meetinglibrary.asco.org/content/125914-144 (2014)
162. Huang, R. R. et al. CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin. Cancer Res. 17, 4101-4109 (2011)
163. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1504627 (2015)
164. Melief, C. J. Selective activation of oxygen-deprived tumor-infiltrating lymphocytes through local intratumoral delivery of CD137 monoclonal antibodies. Cancer Discov. 2, 586-587 (2012)
165. Dai, M., Yip, Y. Y., Hellstrom, I. &Hellstrom, K. E. Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies. Clin. Cancer Res. 21, 1127-1138 (2015)
166. Soliman, H. H. et al. A first in man Phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget 5, 8136-8146 (2014)
167. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641-645 (2014)
168. Lu, Y. C. et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20, 3401-3410 (2014)
169. Marabelle, A., Kohrt, H., Caux, C. &Levy, R. Intratumoral immunization: a new paradigm for cancer therapy. Clin. Cancer Res. 20, 1747-1756 (2014)
170. Ruocco, M. G. et al. Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects. J. Clin. Invest. 122, 3718-3730 (2012)
171. Llosa, N. J. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43-51 (2015)
172. Fourcade, J. et al. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8+ T cells induced by melanoma vaccines. Cancer Res. 74, 1045-1055 (2014)
173. Kocak, E. et al. Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res. 66, 7276-7284 (2006)
174. Morales-Kastresana, A. et al. Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model. Clin. Cancer Res. 19, 6151-6162 (2013)
175. Brody, J. D. et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a Phase I/II study. J. Clin. Oncol. 28, 4324-4332 (2010)
176. Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra32 (2014)
177. Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747-752 (2013)
178. Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-Antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81-85 (2015)
179. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189-2199 (2014)
180. Jenkins, M. K., Chu, H. H., McLachlan, J. B. &Moon, J. J. On the composition of the preimmune repertoire of T cells specific for peptide-major histocompatibility complex ligands. Annu. Rev. Immunol. 28, 275-294 (2010)
181. Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577-581 (2014)
182. Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572-576 (2014)
183. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692-696 (2015