Cited by 1,006Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients

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Hodi, F. Stephen, Mihm, Martin C., Soiffer, Robert J., Haluska, Frank G., Butler, Marcus, Seiden, Michael V., Davis, Thomas, Henry-Spires, Rochele +9 more·2003·Proceedings of the National Academy of Sciences

Abstract

A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.

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Crossref · 10.1073/pnas.0830997100

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Authors
Hodi, F. S., Mihm, M. C., Soiffer, R. J., Haluska, F. G., Butler, M., Seiden, M. V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M. T., Shankar, S., Chen, T. C., Korman, A., Allison, J. P., & Dranoff, G.
Affiliations
  • Brigham and Women's Hospital (US)
  • Department of Adult Oncology, Dana–Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Departments of Pathology and Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Medarex, Inc., Annandale, NJ 08801; Departments of Pathology and Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Department of Radiology, Dana–Farber Cancer Institute and Harvard Medical...
Venue
Proceedings of the National Academy of Sciences
Published
2003-04-07
Volume
100
Issue
8
Pages
4712-4717
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2143467222
Cited by
1,006
References
58
Citations by year
2026: 11 · 2025: 12 · 2024: 24 · 2023: 27 · 2022: 37 · 2021: 41 · 2020: 46 · 2019: 51 · 2018: 45 · 2017: 45 · 2016: 44 · 2015: 56 · 2014: 47 · 2013: 51 · 2012: 36
FWCI
23.13
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Cancer Research Institute
  • Leukemia and Lymphoma Society
  • Partridge Foundation
  • National Institutes of Health (5k08ca078880-02)
  • National Cancer Institute (CA 74886, CA 78880, CA 39542, R01CA074886, P01CA039542)
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, metastatic melanoma, ovarian carcinoma, cancer immunotherapy, cancer vaccines, tumor immunogenicity, T cell tolerance, CA125, tumor necrosis, GM-CSF, autologous tumor cells, tumor antigens
MeSH terms
Abatacept, Adult, Aged, Animals, Antibodies, Monoclonal, Antigens, Differentiation, Female, Humans, Male, Melanoma, Middle Aged, Necrosis, Ovarian Neoplasms, Antigens, CD, Antigen Presentation, CD8-Positive T-Lymphocytes, Immunoconjugates, Antibodies, Blocking, Cancer Vaccines, Mice, CTLA-4 Antigen

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