Concepedia

Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

Giao Q. Phan, James Chih‐Hsin Yang, Richard M. Sherry, Patrick Hwu, Suzanne L. Topalian, Douglas J. Schwartzentruber, Nicholas P. Restifo, Leah Haworth, Claudia A. Seipp, Linda J. Freezer,

Proceedings of the National Academy of Sciences · 2003 · 1.6K citations · 35 references

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TL;DR

CTLA‑4, expressed on activated T cells and a subset of regulatory T cells, down‑regulates T‑cell activation and its blockade has been shown in animal models to enhance cancer immunotherapy. Fourteen metastatic melanoma patients received serial intravenous MDX‑010, a fully human anti‑CTLA‑4 antibody, together with subcutaneous vaccination using two gp100‑derived HLA‑A*0201‑restricted peptides. CTLA‑4 blockade induced grade III/IV autoimmune toxicity in 43 % of patients and produced objective tumor regression in 21 % (two complete and one partial responses), demonstrating that CTLA‑4 regulates tolerance to self and can be targeted to break tolerance to cancer antigens.

Abstract

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A * 0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209–217(210M) and gp100:280–288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to “self” antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.