Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
Phan GQ,
Yang JC,
Sherry RM,
Hwu P,
Topalian SL,
Schwartzentruber DJ,
Restifo NP,
Haworth LR,
Seipp CA,
Freezer LJ,
Morton KE,
Mavroukakis SA,
Duray PH,
Steinberg SM,
Allison JP,
Davis TA,
Rosenberg SA.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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.
PMID: 12826605 [PubMed - indexed for MEDLINE]
PMCID: PMC166236