Enhancement of Antitumor Immunity by CTLA-4 Blockade
Abstract
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
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Overcoming checkpoints through therapeutic antibodies targeting CTLA-4, PD-1, or PD-L1 promotes anti-tumor T cell responses in mice and cancer patients.
“Overcoming such checkpoints through the use of therapeutic antibodies targeting the CTLA-4, PD-1, or PD-L1 cell-surface receptors was shown to be instrumental in promoting anti-tumor T cell responses in mice and in cancer patients”
From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Leach et al., 1996
In murine colon carcinoma and fibrosarcoma models, co-administration of anti-CTLA-4 antibodies with tumor lysate-loaded dendritic cells can reduce Tregs, increase CD8+ lymphocytes, inhibit metastatic growth, and prolong survival.
“Additionally, studies by Allison et al. using murine colon carcinoma and fibrosarcoma models demonstrated that co-administration of anti-CTLA-4 antibodies with tumor lysate-loaded dendritic cells can reduce Tregs, increase CD8+ lymphocytes, inhibit metastatic growth, and prolong survival [121].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [121]
CTLA-4 is expressed on CD4+ Treg and activated CD8+ T cells, restrains T cell costimulation, and serves as an immune checkpoint.
“CTLA-4, another inhibitory receptor that is expressed on CD4+ Treg and activated CD8+ T cells, restrains costimulation of T cells and thus also serves as immune checkpoint357,358.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [358]
Immune checkpoint therapy can produce durable clinical responses and improve overall survival in some patients with cancer.
“Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival.”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [1]
In early studies, anti-CTLA4 antibody prevented CTLA4 from engaging B7, prolonging T-cell responses and eradicating cancer cells.
“In early studies, an anti-CTLA4 antibody prevented CTLA4 from engaging B7, leading to prolonged T-cell responses and eradication of cancer cells (1).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [1]
In vivo administration of anti-CTLA4 enhanced the antitumor effect of tumor-infiltrating T cells, causing regression of established tumors and long-lived immunity in tumor models.
“Similarly, the in vivo administration of anti-CTLA4 antibodies enhanced the antitumor effect of tumor-infiltrating T cells, leading to regression of established tumors and long-lived immunity in tumor models (1).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [1]
In preclinical studies, antibody blockade of CTLA-4 enhanced long-lasting anti-tumor immune responses and caused regression of immunogenic tumors.
“Initial preclinical studies demonstrated that blockade of CTLA-4 with an antibody led to an enhanced and a long-lasting anti-tumor immune response and regression of immunogenic tumors (Leach et al., 1996; van Elsas et al., 1999).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Leach et al., 1996
CTLA-4 blockade did not produce substantial autoimmunity in preclinical models, unlike complete absence of CTLA-4.
“CTLA-4 blockade did not demonstrate substantial autoimmunity (Leach et al., 1996; Rowshanravan et al., 2018).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Leach et al., 1996
Immune checkpoint blockade in preclinical models did not cause overwhelming autoimmune pathology.
“ICB treatment in pre-clinical models did not lead to overwhelming autoimmune pathology”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Leach et al., 1996
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- Authors
- Leach, D. R., Krummel, M. F., & Allison, J. P.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Allison, James P.
- Venue
- Science
- Published
- 1996-03-22
- Volume
- 271
- Issue
- 5256
- Pages
- 1734-1736
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2094366129
- Cited by
- 3,955
- References
- 3
- Citations by year
- 2026: 114 · 2025: 210 · 2024: 248 · 2023: 271 · 2022: 254 · 2021: 327 · 2020: 331 · 2019: 317 · 2018: 243 · 2017: 216 · 2016: 204 · 2015: 188 · 2014: 88 · 2013: 113 · 2012: 87
- FWCI
- 20.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA40041, CA 09179, R01CA057986, T32CA009179, CA57986)
- 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, CTLA-4 blockade, antitumor immunity, tumor immunogenicity, CD28 costimulation, B7 costimulatory molecules, T cell activation, tumor rejection, anti-CTLA-4 antibody
- MeSH terms
- Abatacept, Animals, Antibodies, Antigens, Differentiation, Female, Graft Rejection, Immunologic Memory, Lymphocyte Activation, Mice, Inbred A, Mice, Inbred BALB C, Neoplasm Transplantation, Neoplasms, Experimental, T-Lymphocytes, Transfection, Tumor Cells, Cultured, Antigens, CD, CD28 Antigens, B7-1 Antigen, Immunoconjugates, Mice, CTLA-4 Antigen
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