Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients
Open accessAbstract
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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Ipilimumab was the first immune checkpoint inhibitor tested and approved for cancer treatment.
“The anti-CTLA-4 blocking antibody ipilimumab was the first immune checkpoint inhibitor to be tested and approved for the treatment of cancer patients (19, 20).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [19]
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“Seventyfive patients were treated in a phase 2, multicenter treatment protocol for expanded access of ipilimumab (BMS-734016) monotherapy in subjects with histologically confirmed unresectable stage III or stage IV melanoma, and 15 patients were treated in a phase 1 trial of AntiCytotoxic T-Lymphocyte-Associated Antig…”
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Overcoming immunological tolerance to melanoma: targeting CTLA-4
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Self-citationImmunotherapy Resistance in Glioblastoma
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Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response
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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...
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-04-07
- Volume
- 100
- Issue
- 8
- Pages
- 4712-4717
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC153621
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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