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

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.

• Authors: Giao Q Phan, James C Yang, Richard M Sherry, Patrick Hwu, Suzanne L Topalian, Douglas J Schwartzentruber, Nicholas P Restifo, Leah R Haworth, Claudia A Seipp, Linda J Freezer, Kathleen E Morton, Sharon A Mavroukakis, Paul H Duray, Seth M Steinberg, James P Allison, Thomas A Davis, Steven A Rosenberg
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 14 Pg. 8372-7 (Jul 08 2003) ISSN: 0027-8424 [Print] United States
• PMID: 12826605 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neoplasm
• Antigens, CD
• Antigens, Differentiation
• Antigens, Neoplasm
• CTLA-4 Antigen
• CTLA4 protein, human
• HLA-A2 Antigen
• Membrane Glycoproteins
• Neoplasm Proteins
• PMEL protein, human
• Peptide Fragments
• Peptides
• gp100 Melanoma Antigen
• gp100(280-288) melanoma antigen peptide

Topics

• Adult
• Antibodies, Monoclonal (adverse effects, immunology, therapeutic use)
• Antibodies, Neoplasm (adverse effects, immunology, therapeutic use)
• Antigens, CD
• Antigens, Differentiation (immunology, physiology)
• Antigens, Neoplasm (administration & dosage, immunology)
• Autoimmune Diseases (etiology, immunology, pathology)
• CTLA-4 Antigen
• Colitis (etiology, immunology, pathology)
• Dermatitis (etiology, immunology, pathology)
• Female
• HLA-A2 Antigen (immunology)
• Hepatitis, Autoimmune (etiology, immunology, pathology)
• Humans
• Immune Tolerance (immunology)
• Immunotherapy
• Injections, Intravenous
• Injections, Subcutaneous
• Lymphocyte Activation
• Male
• Melanoma (immunology, therapy)
• Membrane Glycoproteins (chemistry, immunology)
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Proteins (chemistry, immunology)
• Peptide Fragments (administration & dosage, immunology)
• Peptides
• Salvage Therapy
• T-Lymphocyte Subsets (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Vaccination
• Vitiligo (etiology, immunology, pathology)
• gp100 Melanoma Antigen