CTLA-4

The Role of CTLA-4 Pathway Inhibition in Immunotherapy

CTLA-4 INHIBITION

CTLA-4 pathway

Immune checkpoint pathways regulate activation of T cells at various stages of immune response.5

CTLA-4 and PD-L1 both play crucial roles in T cell regulation but have distinct differences. The CTLA-4 pathway is believed to regulate T-cell proliferation at the early stage of naive T-cell activation, principally in the lymph nodes. Activation of the CTLA-4 pathway downregulates the immune response by binding to CD80 (B7.1) or CD86 (B7.2).5

Inhibiting the CTLA-4 pathway1,6-10:

CTLA-4 is a co-inhibitory receptor CTLA-4: cytotoxic T-lymphocyte– associated antigen 4; CD80: cluster of differentiation 80; CD86: cluster of differentiation 86; CD28: cluster of differentiation 28

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TREMELIMUMAB

Tremelimumab (anti–CTLA-4 antibody)

Tremelimumab11,12:

Tremelimumab, when used in combination with an anti–PD-L1 agent, such as durvalumab (MEDI4736), may have the potential to augment the biological and clinical effect of PD-L1 inhibition. These therapies combined may have enhanced activity compared with each one being used alone and may provide the unique benefits of immunotherapy to a broader population of cancer patients.11-13

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CTLA-4=cytotoxic T-lymphocyte–associated antigen 4; IgG2=immunoglobulin G2; mAb=monoclonal antibody; PD-L1=programmed cell death ligand-1.

References

1. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25-39. 2. Gardner D, Jeffery LE, Sansom DM. Understanding the CD28/CTLA-4 (CD152) pathway and its implications for costimulatory blockade. Am J Transplant. 2014;14(9):1985-1991. 3. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol. 2002;3(7):611-618. 4. Ribas A, Hanson DC, Noe DA, et al. Tremelimumab (CP-675,206), a cytotoxic T lymphocyte–associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. The Oncologist. 2007;12:873-883. 5. 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. 6. 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. 7. 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(1):266-271. 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(20):3445-3455. 11. Tarhini AA. Tremelimumab: a review of development to date in solid tumors. Immunotherapy. 2013;5(3):215-229. 12. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 13. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299-308.