Realizing the Potential of
The immunogenicity of tumors varies across different malignancies
Current evidence supports
Immuno-Oncology (I-O) research across a broad range of tumors
Both solid tumors and hematologic malignancies can induce an immune response that regulates their initial growth. This ability is known as tumor immunogenicity and may occur at any of the key stages of presentation, infiltration, and elimination.1,2
Evidence of tumor immunogenicity across a wide range of solid tumors and hematologic malignancies provides the rationale for the breadth of I-O research across tumor types.22
*List of tumor types represents common tumor types, butis not exhaustive.
Research suggests that targeting immune pathways, alone or in combination, may help in eliminating tumor cells
Robust evidence supports that the body’s own immune system has the ability to induce an antitumor response against cancer.20 Research on this subject is actively under way, as evidence suggests that targeting immune pathways may help in eliminating tumor cells.21
PresentationTumors produce neoantigens that may be recognized by the immune system
A broad range of tumors are defined by a high rate of mutations, including melanoma and non-small cell lung cancer (NSCLC).3 These mutations create neoantigens that can be recognized by the immune system, activating an antitumor immune response.4
InfiltrationImmune cells infiltrate the tumor microenvironment
Numerous studies have demonstrated the presence of immune cells within the tumor microenvironment, indicating their capacity to identify and migrate to tumor cells.5-18
EliminationImmune cells can remove foreign threats
Studies have shown certain tumors reducing in size without any intervention, suggesting that the immune system can recognize and eliminate some tumor cells.19 Targeting the immune system may engage or enhance immune cell tumor elimination.
The immune system’s ability to detect and destroy tumor cells is the foundation of I-O research.22
Bristol-Myers Squibb continues to investigate the expanding field of I-O research, driven by the many patients with cancer who await the offer of renewed hope and the potential of a longer life.
References–Potential of I-O research
1. Warrington R, Watson W, Kim HL, Antonetti FR. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S1. doi:10.1186/1710-1492-7-S1-S1. 2. Van Parijs L, Abbas AK. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science. 1998;280(5361):243-248. 3. Mapara MY, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol. 2004;22(6):1136-1151. 4. Leung J, Suh W-K. The CD28-B7 family in anti-tumor immunity: emerging concepts in cancer immunotherapy. Immune Netw. 2014;14(6):265-276. 5. Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013;10(3):230-252. 6. Lu Y-C, Robbins PF. Cancer immunotherapy targeting neoantigens. Semin Immunol. 2016;28(1):22-27. 7. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004;4(1):11-22. 8. Bryceson YT, Ljunggren H-G, Long EO. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood. 2009;114(13):2657-2666. 9. Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132(2):315-325. 10. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15:243-254. 11. Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331(6013):44-49. 12. Gismondi A, Stabile H, Nisti P, Santoni A. Effector functions of natural killer cell subsets in the control of hematological malignancies. Front Immunol. 2015;6:567. doi:10.3389/fimmu.2015.00567. 13. Lau LL, Jamieson BD, Somasundaram T, Ahmed R. Cytotoxic T-cell memory without antigen. Nature. 1994;369(6482):648-652. 14. Ghiringhelli F, Apetoh L, Tesniere A, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med. 2009;15(10):1170-1178. 15. Liu C, Lou Y, Lizée G, et al. Plasmacytoid dendritic cells induce NK cell–dependent, tumor antigen–specific T cell cross-priming and tumor regression in mice. J Clin Invest. 2008;118(3):1165-1175. 16. Zhang Q, Zhu B, Li Y. Resolution of cancer-promoting inflammation: a new approach for anticancer therapy. Front Immunol. 2017;8:71. doi:10.3389/fimmu.2017.00071. 17. Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G. Type I interferons in anticancer immunity. Nat Rev Immunol. 2015;15(7):405-414. 18. Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830-842. 19. He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012-1021. 20. Shao B-Z, Xu Z-Q, Han B-Z, Su D-F, Liu C. NLRP3 inflammasome and its inhibitors: a review. Front Pharmacol. 2015;6:262. doi:10.3389/fphar.2015.00262. 21. Dhodapkar MV, Dhodapkar KM, Palucka AK. Interactions of tumor cells with dendritic cells: balancing immunity and tolerance. Cell Death Differ. 2008;15(1):39-50. 22. Storni T, Lechner F, Erdmann I, et al. Critical role for activation of antigen-presenting cells in priming of cytotoxic T cell responses after vaccination with virus-like particles. J Immunol. 2002;168(6):2880-2886. 23. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. 24. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34. doi:10.1186/s13073-017-0424-2. 25. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719-724. 26. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-421. 27. Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124-128. 28. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. 29. Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;15(4):857-865. 30. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. doi:10.1016/j.immuni.2013.07.012. 31. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013;31:227-258. 32. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 33. Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782-795. 34. Chen F, Zhuang X, Lin L, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015;13:45. doi:10.1186/s12916-015-0278-7. 35. Spranger S, Gajewski TF. Tumor-intrinsic oncogene pathways mediating immune avoidance. Oncoimmunology. 2016;5(3):e1086862. doi:10.1080/2162402X.2015.1086862. 36. Salmon H, Donnadieu E. Within tumors, interactions between T cells and tumor cells are impeded by the extracellular matrix. Oncoimmunology. 2012;1(6):992-994. 37. Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22(8):1865-1874. 38. Chen DS, Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature. 2017;541(7637):321-330. 39. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signaling prevents anti-tumour immunity. Nature. 2015;523(7559):231-235. 40. Harlin H, Meng Y, Peterson AC, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077-3085. 41. Taube JM, Klein A, Brahmer JR, 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. 2014;20(19):5064-5074. 42. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med. 2013;5:200. doi:10.1126/scitranslmed.3006504. 43. Gajewski TF, Woo S-R, Zha Y, et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol. 2013;25(2):268-276. 44. Lam M, Tie J, Lee B, Desai J, Gibbs P, Tran B. Systemic inflammation – impact on tumor biology and outcomes in colorectal cancer. J Clin Cell Immunol. 2015;6:377. doi:10.4172/2155-9899.1000377. 45. Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 2016;9:47. doi:10.1186/s13045-016-0277-y. 46. Gajewski TF. The next hurdle in cancer immunotherapy: overcoming the non–T-cell–inflamed tumor microenvironment. Semin Oncol. 2015;42(4):663-671. 47. Zhang T, Somasundaram R, Berencsi K, et al. CXC chemokine ligand 12 (stromal cell-derived factor 1 α) and CXCR4-dependent migration of CTLs toward melanoma cells in organotypic culture. J Immunol. 2005;174:5856-5863. 48. Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 2010;16(4):399-403. 49. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-1544. 50. Zhu H, Bengsch F, Svoronos N, et al. BET bromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression. Cell Rep. 2016;16(11):2829-2837. 51. Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, et al. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Res. 2013;73(20):6264-6276. 52. Pastori C, Daniel M, Penas C, et al. BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics. 2014;9(4):611-620. 53. Fisk B, Blevins TL, Wharton JT, Ioannides CG. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med. 1995;181(6):2109-2117. 54. Brezicka F-T, Olling S, Nilsson O, et al. Immunohistological detection of fucosyl-Gm1 ganglioside in human lung cancer and normal tissues with monoclonal antibodies. Cancer Res. 1989;49(5):1300-1305. 55. Brezicka F-T, Holmgren J, Kalies I, Lindholm L. Tumor-cell killing by MAbs against fucosyl GM1, a ganglioside antigen associated with small-cell lung carcinoma. Int J Cancer. 1991;49(6):911-918. 56. Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol. 2003;170(10):4905-4913. 57. Anyaegbu CC, Lake RA, Heel K, Robinson BW, Fisher SA. Chemotherapy enhances cross-presentation of nuclear tumor antigens. PLoS ONE. 2014;9(9):e107894. doi:10.1371/journal.pone.0107894. 58. Kaur P, Asea A. Radiation-induced effects and the immune system in cancer. Front Oncol. 2012;2:191. doi:10.3389/fonc.2012.00191. 59. Adkins I, Fucikova J, Garg AD, Agostinis P, Špíšek R. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology. 2014;3(12):e968434. doi:10.4161/21624011.2014.968434. 60. Liao Y-P, Wang C-C, Butterfield LH, et al. Ionizing radiation affects human MART-1 melanoma antigen processing and presentation by dendritic cells. J Immunol. 2004;173(4):2462-2469. 61. Aurelian L. Oncolytic viruses as immunotherapy: progress and remaining challenges. Onco Targets Ther. 2016;9:2627-2637. 62. Diaconu I, Cerullo V, Hirvinen MLM, et al. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res. 2012;72(9):2327-2338. 63. Steinman RM, Dhodapkar M. Active immunization against cancer with dendritic cells: the near future. Int J Cancer. 2001;94(4):459-473. 64. Castle JC, Kreiter S, Diekmann J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72(5):1081-1091. 65. Fuertes MB, Kacha AK, Kline J, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J Exp Med. 2011;208(10):2005-2016.
66. Demaria O, De Gassart A, Coso S, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408-15413. 67. Weiss JM, Guérin MV, Regnier F, et al. The STING agonist DMXAA triggers a cooperation between T lymphocytes and myeloid cells that leads to tumor regression. Oncoimmunology. 2017;6(10):e1346765. doi:10.1080/2162402X.2017.1346765. 68. Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res. 2002;62(5):1462-1470.