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

作者：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, Kathleen E. Morton, Sharon Mavroukakis, Paul H. Duray, Seth M. Steinberg, James P. Allison, Thomas A. Davis, Steven A. Rosenberg · 发表于：Proceedings of the National Academy of Sciences · 年份：2003 · DOI：10.1073/pnas.1533209100 · 被引用次数：1579 · 研究领域：T-cell and B-cell Immunology、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

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.