Simultaneously Inhibiting the CTLA-4 and PD-L1 Non-Redundant Pathways has Potential for Synergistic Immune Effects1-4

Immunotherapy + Immunotherapy Combination Therapy Immunotherapy + Immunotherapy Combination Therapy

The major histocompatibility complex (MHC) on tumor cells must also present antigens to T-cell receptors to activate T cells.7

CTLA-4 pathway inhibition enhances T-cell activation, amplifies T-cell proliferation, and promotes differentiation into memory T cells4-6,8-10

  • As part of an adaptive immune response, CTLA-4 inhibition may lead to PD-L1 upregulation in the tumor microenvironment3,4,11-15

PD-L1 pathway inhibition reverses T-cell exhaustion and reinvigorates antitumor activity8,15-20

Some activated T cells differentiate into memory T cells, which are trained to recognize tumors, persist in the body, and provide long-term immune memory6,7,21

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CTLA-4 and PD-L1 Both Bind to CD80 (B7.1): Simultaneous Inhibition of Both Pathways May Lead to Synergistic Effects on Antitumor Activity1,2,19,22

Prevented T-cell activation
  • Both CTLA-4 and PD-L1 may bind to and reduce availability of CD80 (B7.1), preventing it from activating T cells via CD2819,22

T-Cell Activation Restored
  • CTLA-4 and PD-L1 inhibition increase the availability of ligands for the co-stimulatory pathway (CD80, CD86), thereby increasing T-cell activation and proliferation9,16-19,21,22

Combination strategies are a key area of clinical research because they have the potential to simultaneously inhibit complementary immunosuppressive pathways.1-4

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References: 1. Melero I, Berman DM, Aznar A, et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15:457-472. 2. Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23:viii41-viii46. 3. Das R, Verma R, Sznol M, et al. Combination therapy with anti–CTLA-4 and anti–PD-1 leads to distinct immunologic changes in vivo. J Immunol. 2015;194:950-959. 4. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94:25-39. 5. Robert C, Ghiringhelli F. What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? Oncologist. 2009;14:848-861. 6. Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose of anti–CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci USA. 2011;108:268-271. 7. Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt's Essential Immunology. 12th ed. Chichester, West Sussex, UK: Wiley-Blackwell; 2011. 8. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227-242. 9. Ménard C, Ghiringhelli F, Roux S, et al. CTLA-4 blockade confers lymphocyte resistance to regulatory T-cells in advanced melanoma: surrogate marker of efficacy of tremelimumab? Clin Cancer Res. 2008;14:5242-5249. 10. Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunotherapy for melanoma. J Clin Oncol. 2008;26:3445-3455. 11. 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;107:4275-4280. 12. Lussier DM, Johnson JL, Hingorani P, Blattman JN. Combination immunotherapy with a-CTLA-4 and a-PD-L1 antibody blockade prevents immune escape and leads to complete control of metastatic osteosarcoma. J Immunother Cancer. 2015;3:21. 13. Ostrand-Rosenberg S, Horn LA, Haile ST. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol. 2014;193:3835-3841. 14. Lee SJ, Jang BC, Lee SW, et al. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-?-induced upregulation of B7-H1 (CD274). FEBS Letters. 2006;580:755-762. 15. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021-1034. 16. Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti–PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3:1052-1062. 17. Ibrahim R, Stewart R, Shalabi A. PD-L1 blockade for cancer treatment: MEDI4736. Semin Oncol. 2015;42:474-483. 18. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. 19. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111-122. 20. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373-377. 21. Kalia V, Penny LA, Yuzefpolskiy Y, Baumann FM, Sarkar S. Quiescence of memory CD8+ T cells is mediated by regulatory T cells through inhibitory receptor CTLA-4. Immunity. 2015;42:1116-1129. 22. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibitionAm J Clin Oncol. 2016;39:98-106.