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

TLDR

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.