Cancer immunotherapy: The beginning of the end of cancer?

BMC Medicine

Volumn 14, Issue 1, 2016, Pages

  Farkona, Sofia ^a,b   Diamandis, Eleftherios P ^a,b,c   Blasutig, Ivan M ^a,c,d  

^a UNIVERSITY OF TORONTO   (Canada)

^b MOUNT SINAI HOSPITAL   (Canada)

^c UNIVERSITY HEALTH NETWORK   (Canada)

^d TORONTO GENERAL HOSPITAL   (Canada)

Author keywords

Adoptive cellular therapy; Cancer; Cytotoxic T lymphocyte associated protein 4; Immune checkpoint blockade; Immunotherapy; Programmed cell death protein 1; T cells

Indexed keywords

ATEZOLIZUMAB; B RAF KINASE; BEVACIZUMAB; CANCER VACCINE; CD134 ANTIGEN; CETUXIMAB; CHIMERIC ANTIGEN RECEPTOR; CYCLOPHOSPHAMIDE; CYTOKINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DABRAFENIB; DACARBAZINE; FLUOROURACIL; IMMUNOLOGIC AGENT; IPILIMUMAB; MONOCLONAL ANTIBODY; NIVOLUMAB; ONCOLYTIC VIRUS; PACLITAXEL; PEMBROLIZUMAB; PLACEBO; PROGRAMMED DEATH 1 RECEPTOR; RECOMBINANT PROTEIN; TRAMETINIB; TRASTUZUMAB; URELUMAB; VEMURAFENIB; VESENCUMAB; TUMOR MARKER;

ADOPTIVE TRANSFER; ADVANCED CANCER; ANTIGEN PRESENTING CELL; CANCER IMMUNIZATION; CANCER IMMUNOTHERAPY; CANCER PREVENTION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; COLON CANCER; CYTOKINE RELEASE; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; DRUG TOLERABILITY; EX VIVO STUDY; GIANT CELL ARTERITIS; HEAD AND NECK CANCER; HEPATITIS; HUMAN; HUMAN CELL; IMMUNOSTIMULATION; KIDNEY CARCINOMA; LIVER TOXICITY; LUNG CANCER; MELANOMA; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; MOUSE; NATURAL KILLER CELL; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; ONCOLYTIC VIROTHERAPY; OVERALL SURVIVAL; PERIPHERAL BLOOD MONONUCLEAR CELL; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PROTEIN STRUCTURE; REVIEW; SOLID TUMOR; STOMACH CANCER; T LYMPHOCYTE; UVEITIS; ANTAGONISTS AND INHIBITORS; IMMUNOLOGY; IMMUNOTHERAPY; MULTIMODALITY CANCER THERAPY; NEOPLASMS; PROCEDURES;

ANTIBODIES, MONOCLONAL; BIOMARKERS, TUMOR; CANCER VACCINES; COMBINED MODALITY THERAPY; CTLA-4 ANTIGEN; HUMANS; IMMUNOTHERAPY; NEOPLASMS;

EID: 84965032167     PISSN: None     EISSN: 17417015     Source Type: Journal    
DOI: 10.1186/s12916-016-0623-5     Document Type: Review

References (161)

1. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805-12.
2. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14:561-84.
3. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29:4828-36.
4. Sharma P, Allison JP. Immune checkpoint targeting in Cancer Therapy: toward combination strategies with curative potential. Cell. 2015;161:205-14.
5. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-9.
6. Yaddanapudi K, Mitchell RA, Eaton JW. Cancer vaccines. Oncoimmunology. 2013;2(3):e23403.
7. Pardoll DM, Topalian SL. The role of CD4+ T cell responses in antitumor immunity. Curr Opin Immunol. 1998;10:588-94.
8. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy. Moving beyond current vaccines. Nat Med. 2004;10:909-15.
9. Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity. 2013;39:38-48.
10. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265-77.
11. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity Cycle. Immunity. 2013;39:1-10.
12. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119-27.
13. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.
14. Vansteenkiste J, Zilelinski M, Linder A, Dahabre J, Esteban E, Malinowski W, et al. Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC). J Clin Oncol. 2007;25:abstract 7554.
15. Copier J, Dalgleish A. Whole-cell vaccines: A failure or a success waiting to happen? Curr Opin Mol Ther. 2010;12:14-20.
16. Schuler G. Dendritic cells in cancer immunotherapy. Eur J Immunol. 2010;40:2123-30.
17. Sabado RL, Bhardwaj N. Dendritic cell immunotherapy. Ann N Y Acad of Sci. 2013;1284:31-45.
18. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670-9.
19. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.
20. Fenoglio D, Traverso P, Parodi A, Kalli F, Zanetti M, Filaci G. Generation of more effective cancer vaccines. Hum Vaccin Immunother. 2013;9:2543-7.
21. Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, et al. The prioritization of cancer antigens. A national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15:5323-37.
22. zur Hausen H. Papillomaviruses in the causation of human cancers: a brief historical account. Virology. 2009;384:260-5.
23. Greiner J, Bullinger L, Guinn BA, Dohner H, Schmitt M. Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells. Clin Cancer Res. 2008;14:7161-6.
24. Thomas AM, Santarsiero LM, Lutz ER, Armstrong TD, Chen Y-C, Huang L-Q, et al. Mesothelin-specific CD8+ T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med. 2004;200:297-306.
25. Kasuga K. Comprehensive analysis of MHC ligands in clinical material by immunoaffinity-mass spectrometry. Methods Mol Biol. 2013;1023:203-18.
26. Rammensee H-G, Weinschenk T, Gouttefangeas C, Stevanovi Eq S. Towards patient-specific tumor antigen selection for vaccination. Immunol Rev. 2002;188:164-76.
27. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008;68:889-92.
28. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642-62.
29. Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy. Nat Rev Cancer. 2014;14(8):559-67.
30. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.
31. Dharmadhikari N, Mehnert JM, Kaufman HL. Oncolytic virus immunotherapy for melanoma. Curr Treat Options Oncol. 2015;16:1-15.
32. DeWeese TL, van der Poel H, Li S, Mikhak B, Drew R, Goemann M, et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation Therapy. Cancer Res. 2001;61:7464-72.
33. Brown SM, MacLean AR, McKie EA, Harland J. The herpes simplex virus virulence factor ICP34.5 and the cellular protein MyD116 complex with proliferating cell nuclear antigen through the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34. J Virol. 1997;71:9442-9.
34. Liu BL, Robinson M, Han ZQ, Branston RH, English C, Reay P, et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 2003;10:292-303.
35. Toda M, Martuza RL, Rabkin SD. Tumor growth inhibition by intratumoral inoculation of defective herpes simplex virus vectors expressing granulocyte-macrophage colony-stimulating factor. Mol Ther. 2000;2:324-29.
36. Hu JCC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, et al. A phase I study of oncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12:6737-47.
37. Choi IK, Lee JS, Zhang SN, Park J, Lee KM, Sonn CH, et al. Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12R[beta]2 or IL-18R[alpha]. Gene Ther. 2011;18:898-909.
38. Lee Y-S, Kim J-H, Choi K-J, Choi I-K, Kim H, Cho S, et al. Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model. Clin Cancer Res. 2006;12:5859-68.
39. DeRubertis BG, Stiles BM, Bhargava A, Gusani NJ, Hezel M, D'Angelica M, et al. Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms. Cancer Gene Ther. 2007;14:590-7.
40. Varghese S, Rabkin SD, Liu R, Nielsen PG, Ipe T, Martuza RL. Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther. 2005;13:253-65.
41. Shin EJ, Wanna GB, Choi B, Aguila D, Ebert O, Genden EM, et al. Interleukin-12 expression enhances Vesicular stomatitis virus oncolytic therapy in murine squamous cell carcinoma. Laryngoscope. 2007;117:210-4.
42. Gaston DC, Odom CI, Li L, Markert JM, Roth JC, Cassady KA, et al. Production of bioactive soluble interleukin-15 in complex with interleukin-15 receptor alpha from a conditionally-replicating oncolytic HSV-1. PLoS One. 2013;8:e81768.
43. Stephenson KB, Barra NG, Davies E, Ashkar AA, Lichty BD. Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity. Cancer Gene Ther. 2012;19:238-46.
44. van Rikxoort M, Michaelis M, Wolschek M, Muster T, Egorov A, Seipelt J, et al. Oncolytic effects of a novel influenza A virus expressing interleukin-15 from the NS reading frame. PLoS One. 2012;7:e36506.
45. Fukuhara H, Ino Y, Kuroda T, Martuza RL, Todo T. Triple gene-deleted oncolytic herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed by bacterial artificial chromosome-mediated system. Cancer Res. 2005;65:10663-8.
46. Huang J-H, Zhang S-N, Choi K-J, Choi I-K, Kim J-H, Lee M, et al. Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL. Mol Ther. 2009;18:264-74.
47. Kim HS, Kim-Schulze S, Kim DW, Kaufman HL. Host lymphodepletion enhances the therapeutic activity of an oncolytic vaccinia virus expressing 4-1BB ligand. Cancer Res. 2009;69:8516-25.
48. Galivo F, Diaz RM, Diaz RM, Thanarajasingam U, Jevremovic D, Wongthida P, Thompson J, et al. Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. Human Gene Ther. 2010;21:439-50.
49. Tesfay MZ, Kirk AC, Hadac EM, Griesmann GE, Federspiel MJ, Barber GN, et al. PEGylation of vesicular stomatitis virus extends virus persistence in blood circulation of passively immunized mice. J Virol. 2013;87:3752-9.
50. Morrison J, Briggs SS, Green N, Fisher K, Subr V, Ulbrich K, et al. Virotherapy of ovarian cancer with polymer-cloaked adenovirus retargeted to the epidermal growth factor receptor. Mol Ther. 2007;16:244-51.
51. Berger C, Xuereb S, Johnson DC, Watanabe KS, Kiem H-P, Greenberg PD, et al. Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8+ cytotoxic T lymphocytes. J Virol. 2000;74:4465-73.
52. Fulci G, Breymann L, Gianni D, Kurozomi K, Rhee SS, Yu J, et al. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12873-8.
53. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2:295-300.
54. Ledford H. Cancer-fighting viruses win approval. Nature. 2015;526:622-3.
55. Hersey P, Gallagher S. Intralesional immunotherapy for melanoma. J Surg Oncol. 2014;109:320-6.
56. Hercus TR, Thomas D, Guthridge MA, Ekert PG, King-Scott J, Parker MW, et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood. 2009;11:1289-98.
57. Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, et al. Phase II clinical trial of a ganulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27:5763-71.
58. Kaufman HL, Kim DW, DeRaffele G, Mitcham J, Coffin RS, Kim-Schulze S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. 2009;17:718-30.
59. Kaufman HL, Bines SD. OPTIM trial: a phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 2010;6:941-9.
60. Shi H, Qi X, Ma B, Cao Y, Wang L, Sun L, et al. The status, limitation and improvement of adoptive cellular immunotherapy in advanced urologic malignancies. Chin J Cancer Res. 2015;27:128-37.
61. Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. 2014;257:56-71.
62. Gilham DE, Anderson J, Bridgeman JS, Hawkins RE, Exley MA, Stauss H, et al. Adoptive T-cell therapy for cancer in the United Kingdom: a review of activity for the British Society of Gene and Cell Therapy annual meeting 2015. Hum Gene Ther. 2015;26:276-85.
63. Kazemi T, Younesi V, Jadidi-Niaragh F, Yousefi M. Immunotherapeutic approaches for cancer therapy: an updated review. Artif Cells Nanomed Biotechnol. 2015;24:1-11.
64. Yee C. Adoptive T-cell therapy for cancer: boutique therapy or treatment modality? Clin Cancer Res. 2013;19:4550-2.
65. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850-4.
66. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299-308.
67. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907-12.
68. Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci U S A. 2004;101:1969-74.
69. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550-7.
70. Qian X, Wang X, Jin H. Cell transfer therapy for cancer: past, present, and future. J Immunol Res. 2014;2014:525913. doi: 10.1155/2014/525913.
71. Morgan RA, Dudley ME, Rosenberg SA. Adoptive cell therapy: genetic modification to redirect effector cell specificity. Cancer J. 2010;16:336-41.
72. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86:10024-8.
73. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51-81.
74. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734-6.
75. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;74:561-9.
76. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100:8372-7.
77. Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med. 2015;373:1490-2.
78. Grosso JF, Jure-Kunkel MN, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 2013;13:5.
79. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain J-F, Testori A, Grob J-J, et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N Engl J Med. 2011;364(26):2517-26.
80. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985-8.
81. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887-95.
82. Mary EK, Manish JB, Gordon JF, Arlene HS. PD-1 and Its Ligands in Tolerance and Immunity. Annu Rev Immunol. 2008;26(1):677-704.
83. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14(12):1212-8.
84. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-9.
85. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261-8.
86. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-54.
87. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020-30.
88. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173:945-54.
89. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25:9543-53.
90. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-65.
91. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393-405.
92. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207:2187-94.
93. Sierro S, Romero P, Speiser DE. The CD4-like molecule LAG-3, biology and therapeutic applications. Expert Opin Ther Targets. 2011;15:91-101.
94. Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;5:6225-31.
95. Brignone C, Gutierrez M, Mefti F, Brain E, Jarcau R, Cvitkovic F, et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med. 2010;8:71. doi: 10.1186/1479-5876-8-71.
96. Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol. 2003;4:1093-101.
97. Melero I, Berman DM, Aznar MA, Korman AJ, Gracia JLP, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15:457-72.
98. Curran MA, Montalvo W, Yagita H, Allison JP. 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 U S A. 2010;107:4275-80.
99. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-33.
100. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:1270-1.
101. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51-72.
102. Melero I, Rouzaut A, Motz GT, Coukos G. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discovery. 2015;4:522-6.
103. 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. 2008;57:1579-87.
104. Moschella F, Proietti E, Capone I, Belardelli F. Combination strategies for enhancing the efficacy of immunotherapy in cancer patients. Ann NY Acad Sci. 2010;1194:169-78.
105. Le DT, Jaffee EM. Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res. 2012;72:3439-44.
106. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T Cell-dependent antitumor immunity. Cancer Res. 2010;70(8):3052-61.
107. Sevko A, Michels T, Vrohlings M, Umansky L, Beckhove P, Kato M, et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J Immunol. 2013;190:2464-71.
108. Alagkiozidis I, Facciabene A, Tsiatas M, Carpenito C, Benencia F, Adams S, et al. Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy. J Transl Med. 2011;9:77. doi: 10.1186/1479-5876-9-77.
109. Machiels J-PH, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized Mice. Cancer Res. 2001;61:3689-97.
110. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-16.
111. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J of Med. 2013;368:1365-6.
112. Ribas A BM, Butler M, Lutzky J, Lawrence DP, Robert C, Miller W, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol. 2015;33 (Suppl; abstr 3003).
113. Minor DR, Puzanov I, Callahan MK, Hug BA, Hoos A. Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab. Pigment Cell Melanoma Res. 2015;28:611-2.
114. Comin-Anduix B, Chodon T, Sazegar H, Matsunaga D, Mock S, Jalil J, 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. 2010;16:6040-8.
115. Amin A, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, et al. Nivolumab (anti-PD1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients 9pts0 with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32:5s. Suppl; abstr 5010.
116. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632-42.
117. Chaudhary B, Khaled Y, Ammori B, Elkord E. Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother. 2014;63:81-99.
118. Papatriantafyllou M. T cells: neuropilin 1 distinguishing Treg cell subsets. Nat Rev Immunol. 2012;12:746-47.
119. Grandclement C, Borg C. Neuropilins: a new target for cancer therapy. Cancers (Basel). 2011;3:1899-928.
120. Weekes CD, Beeram M, Tolcher AW, Papadopoulos KP, Gore L, Hegde P, et al. A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors. Invest New Drugs. 2014;32:653-60.
121. Patnaik A, LoRusso P, Messersmith W, Papadopoulos K, Gore L, Beeram M, et al. A phase Ib study evaluating MNRP1685A, a fully human anti-NRP1 monoclonal antibody, in combination with bevacizumab and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;73:951-60.
122. Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellstrom KE, et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3:682-5.
123. Vinay DS, Kwon BS. Immunotherapy of cancer with 4-1BB. Mol Canc Ther. 2012;11:1062-70.
124. Ascierto PA, Simeone E, Sznol M, Fu Y-X, Melero I. Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin Oncol. 2010;37:508-16.
125. Kohrt HE, Colevas AD, Houot R, Weiskopf K, Goldstein MJ, Lund P, et al. Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest. 2014;124:2668-82.
126. Takeda K, Kojima Y, Uno T, Hayakawa Y, Teng MWL, Yoshizawa H, et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J Immunol. 2010;184:5493-501.
127. Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One. 2011;6:e19499.
128. Youlin K, Li Z, Xiaodong W, Xiuheng L, Hengchen Z. Combination immunotherapy with 4-1BBL and CTLA-4 blockade for the treatment of prostate cancer. Clin Dev Immunol. 2012;2012:439235. doi: 10.1155/439235.
129. Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012;72:3163-74.
130. Schaer DA, Hirschhorn-Cymerman D, Wolchok JD. Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy. J Immunother Cancer. 2014;2:7. doi: 10.1186/2051-1426-2-7.
131. Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, et al. OX40 Is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73:7189-98.
132. Weinberg AD, Morris NP, Kovacsovics-Bankowski M, Urba WJ, Curti BD. Science gone translational: the OX40 agonist story. Immunol Rev. 2011;244:218-31.
133. Jensen SM, Maston LD, Gough MJ, Ruby CE, Redmond WL, Crittenden M, et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;37:524-32.
134. Bulliard Y, Jolicoeur R, Zhang J, Dranoff G, Wilson NS, Brogdon JL. OX40 engagement depletes intratumoral Tregs via activating Fc[gamma]Rs, leading to antitumor efficacy. Immunol Cell Biol. 2014;92:475-80.
135. Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Curr Opin Immunol. 2012;24:217-24.
136. Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010;5:e10436.
137. Cai G, Freeman GJ. The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev. 2009;229:244-58.
138. Pasero C, Olive D. Interfering with coinhibitory molecules: BTLA/HVEM as new targets to enhance anti-tumor immunity. Immunol Letters. 2013;51:71-5.
139. Pasero C, Speiser DE, Derre L, Olive D. The HVEM network: new directions in targeting novel costimulatory/co-inhibitory molecules for cancer therapy. Curr Opin Pharmacol. 2012;12:478-85.
140. Derre L, Rivals JP, Jandus C, Pastor S, Rimoldi D, Romero P, et al. BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest. 2010;120:157-67.
141. Fourcade J, Sun Z, Pagliano O, Guillaume P, Luescher IF, Sander C, 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. 2012;72:887-96.
142. Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. 2014;11:509-24.
143. Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6:226ra32.
144. Puzanov I, Milhem MM, Andtbacka RHI, Minor DR, Hamid O, Li A, et al. Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. J Clin Oncol. 2015;33(suppl; abstr 9063).
145. Johnson DB, Puzanov I, Kelley MC. Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. Immunotherapy. 2015;7:611-9.
146. Sznol M, Kluger HM, Callahan MK, Postow MA, Gordon RA, Segal NH, 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). J Clin Oncol. 2014;32:5s. suppl; abstr LBA9003^.
147. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-17.
148. Hodi F, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312(17):1744-53.
149. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJM, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-12.
150. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, 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. 2014;30:2046-54.
151. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, 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. 2013;24:75-83.
152. Cully M. Trial watch: combinations with checkpoint inhibitors at wavefront of cancer immunotherapy. Nat Rev Drug Discov. 2015;14:374-5.
153. Schumacher TN, Kesmir C, van Buuren MM. Biomarkers in cancer immunotherapy. Cancer Cell. 2015;27(1):12-4.
154. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214-8.
155. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-21.
156. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207-11.
157. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43-51.
158. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-8. doi: 10.1126/science.aaa1348.
159. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A. 2004;101:17174-9.
160. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56-61.
161. Woo S-R, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917-27.