Immunotherapy + Immunotherapy

Immunotherapy + Immunotherapy

NON-REDUNDANT PATHWAYS

Simultaneously inhibiting the CTLA-4 and PD-L1 non-redundant pathways has potential for synergistic immune effects4-7*

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 cells10

CTLA-4

CTLA-4 pathway inhibition enhances T-cell activation, amplifies T-cell proliferation, and promotes differentiation into memory T cells7-9,11-13

Learn more about how CTLA-4 pathway inhibition enhances antitumor response

PD-L1

PD-L1 pathway inhibition reverses T-cell exhaustion and reinvigorates antitumor activity11,15,17-20

PD-L1 blockade also increases the availability of ligands for the co-stimulatory pathway (CD80, CD86) in the lymph node, thereby enhancing T-cell activation and proliferation.

Learn more about PD-L1 pathway inhibition

SYNERGISTIC EFFECTS

CTLA-4 and PD-L1 both bind to CD80 (B7.1): Simultaneous inhibition of both pathways may lead to synergistic effects on antitumor activity4,5,19,21

TAKE A DEEPER LOOKat the science of combination immuno-oncology therapy

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

PD-L1=programmed cell death ligand-1; CTLA-4=cytotoxic T-lymphocyte–associated antigen 4.

References

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 2. Dizon DS. Krilov L, Cohen E, et al. Clinical cancer advances 2016; annual report on progress against cancer from the American Society of Clinical Oncology [published online ahead of print February 4, 2016]. J Clin Oncol. 2016;34(9):987-1011. doi:10.1200/JCO.2015.65.8427. 3. McDermott DF, Atkin MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013;2:662-673. 4. Melero I, Berman DM, Aznar A, et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15:457-472. 5. Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23:viii41-viii46. 6. 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. 7. 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. 8. 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. 9. 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. 10. Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt's Essential Immunology. 13th ed. Chichester, West Sussex, UK: Wiley-Blackwell; 2017. 11. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227-242. 12. 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. 13. Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunotherapy for melanoma. J Clin Oncol. 2008;26:3445-3455. 14. Lee SJ, Jang BC, Lee SW, et al. Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-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. 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. 17. 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. 18. Ibrahim R, Stewart R, Shalabi A. PD-L1 blockade for cancer treatment: MEDI4736. Semin Oncol. 2015;42:474-483. 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. 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. 21. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98-106.

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