Cited by 1,575Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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

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Phan, Giao Q., Yang, James C., Sherry, Richard M., Hwu, Patrick, Topalian, Suzanne L., Schwartzentruber, Douglas J., Restifo, Nicholas P., Haworth, Leah R., Seipp, Claudia A., Freezer, Linda J., Morton, Kathleen E., Mavroukakis, Sharon A., Duray, Paul H., Steinberg, Seth M., Allison, James P., Davis, Thomas A., Rosenberg, Steven A.·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1533209100PMC PMC166236

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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.

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Authors: Phan, G. Q., Yang, J. C., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Freezer, L. J., Morton, K. E., Mavroukakis, S. A., Duray, P. H., Steinberg, S. M., Allison, J. P., Davis, T. A., & Rosenberg, S. A.
Affiliations: National Institutes of Health (US)
Surgery Branch, Laboratory of Pathology, and Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; and Medarex, Inc., Princeton, NJ 08540
ORCID: Phan, Giao Q.
Yang, James C.
Sherry, Richard M.
Hwu, Patrick
Topalian, Suzanne L.
Restifo, Nicholas P.
Mavroukakis, Sharon A.
Steinberg, Seth M.
Allison, James P.
Davis, Thomas A.
Rosenberg, Steven A.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-06-25
Volume: 100
Issue: 14
Pages: 8372-8377
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1533209100
PMC: PMC166236
OpenAlex: W2134638467
Cited by: 1,575
References: 38
Citations by year: 2026: 10 · 2025: 11 · 2024: 26 · 2023: 41 · 2022: 48 · 2021: 52 · 2020: 58 · 2019: 56 · 2018: 68 · 2017: 82 · 2016: 58 · 2015: 72 · 2014: 70 · 2013: 78 · 2012: 72
FWCI: 46.70
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (Z99 CA999999)
National Cancer Institute (Z01BC010763)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: CTLA-4 blockade, metastatic melanoma, autoimmunity, tumor regression, anti-CTLA-4 antibody, HLA-A*0201, cancer immunotherapy, self-tolerance, regulatory T cells, T cell activation, enterocolitis, hypophysitis, hepatitis, skin inflammation
MeSH terms: Adult, Antibodies, Monoclonal, Antibodies, Neoplasm, Antigens, Differentiation, Antigens, Neoplasm, Autoimmune Diseases, Colitis, Dermatitis, Female, Humans, Immune Tolerance, Immunotherapy, Injections, Intravenous, Injections, Subcutaneous, Lymphocyte Activation, Male, Melanoma, Membrane Glycoproteins, Middle Aged, Neoplasm Metastasis, Neoplasm Proteins, Peptide Fragments, Peptides, T-Lymphocytes, Cytotoxic, Vaccination, Vitiligo, Antigens, CD, HLA-A2 Antigen, T-Lymphocyte Subsets, Salvage Therapy, Hepatitis, Autoimmune, gp100 Melanoma Antigen, CTLA-4 Antigen

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

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