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Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography
Published on: February 17, 2022
Clinical Activity, Toxicity, Biomarkers, and Future Development of CTLA-4 Checkpoint Antagonists
Margaret K Callahan1, Jedd D Wolchok2
1Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; Weill Medical College of Cornell University, New York, NY.
Abstract:
Evidence that the immune system can recognize, and in some cases control or even eliminate tumors, is increasingly clear. Encouraging T-cell activation by blocking regulatory or "checkpoint" molecules is a potent way to amplify anti-tumor immune responses. Successfully exploiting this concept, a new class of anti-cancer therapies, "checkpoint-blocking" antibodies has emerged. The first checkpoint-blocking antibody to enter the clinic was ipilimumab, an antibody that blocks the co-inhibitory receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Herein we review the clinical development of CTLA-4 blocking antibodies, including preclinical studies, clinical activity, toxicities, the search for potential biomarkers, and early clinical experience with combinations.
Insights
Checkpoint-blocking antibodies, like ipilimumab targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), amplify anti-tumor immune responses. This review covers their clinical development, activity, toxicities, and biomarker research for cancer therapy.
Area of Science:
- Immunology and Oncology
- Cancer Immunotherapy
Background:
- The immune system possesses mechanisms to recognize and eliminate tumors.
- Modulating immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can enhance anti-tumor T-cell responses.
- Checkpoint-blocking antibodies represent a novel class of anti-cancer therapies.
Purpose of the Study:
- To review the clinical development of CTLA-4 blocking antibodies.
- To summarize preclinical findings, clinical activity, and toxicities associated with CTLA-4 blockade.
- To discuss the ongoing search for biomarkers and early combination therapy experiences.
Main Methods:
- Review of preclinical studies investigating CTLA-4 blockade.
- Analysis of clinical trial data on CTLA-4 blocking antibodies, including ipilimumab.
- Examination of safety profiles and toxicity data.
- Assessment of biomarker research efforts.
- Evaluation of early clinical experience with combination therapies.
Main Results:
- CTLA-4 blockade, exemplified by ipilimumab, has emerged as a potent anti-cancer strategy.
- Clinical activity has been demonstrated, alongside characteristic toxicities.
- Biomarker discovery is crucial for identifying patient populations likely to benefit.
- Early combination studies show potential for enhanced efficacy.
Conclusions:
- CTLA-4 blocking antibodies have significantly advanced cancer immunotherapy.
- Further research into biomarkers and combination strategies is essential for optimizing treatment outcomes.
- This therapeutic approach holds promise for improving anti-tumor immune responses in various cancers.
