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Immunotherapy of sarcomas with modified T cells
Preethika Mahalingam1, Maximilian Julve2, Paul Huang3
1Sarcoma Unit, The Royal Marsden Hospital.
Purpose Of Review:
To summarize the development of modified T-cell therapies in sarcomas and discuss relevant published and ongoing clinical trials to date.
Recent Findings:
Numerous clinical trials are underway evaluating tumor-specific chimeric antigen receptor T cells and high affinity T-cell receptor (TCR)-transduced T cells in sarcomas. Notably, translocation-dependent synovial sarcoma and myxoid/round cell liposarcoma are the subject of several phase II trials evaluating TCRs targeting cancer testis antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen-A4 (MAGE A4), and response rates of up to 60% have been observed for NY-ESO-1 directed, modified T cells in synovial sarcoma. Challenges posed by modified T-cell therapy include limitations conferred by HLA-restriction, non-immunogenic tumor microenvironments (TME), aggressive lymphodepletion and immune-mediated toxicities restricting coinfusion of cytokines.
Summary:
Cellular therapy to augment the adaptive immune response through delivery of modified T cells is an area of novel therapeutic development in sarcomas where a reliably expressed, ubiquitous target antigen can be identified. Therapeutic tools to improve the specificity, signaling, proliferation and persistence of modified TCRs and augment clinical responses through safe manipulation of the sarcoma TME will be necessary to harness the full potential of this approach.
Insights
Modified T-cell therapies show promise for sarcomas, with ongoing trials targeting specific antigens like NY-ESO-1. Challenges include HLA-restriction and tumor microenvironments, requiring further therapeutic advancements.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Sarcomas are a diverse group of cancers.
- Modified T-cell therapy is an emerging treatment strategy for sarcomas.
Purpose of the Study:
- To review the development of modified T-cell therapies in sarcomas.
- To discuss current and planned clinical trials for these therapies.
Main Methods:
- Review of published and ongoing clinical trials.
- Evaluation of T-cell receptor (TCR) and chimeric antigen receptor (CAR) T-cell therapies targeting sarcoma antigens.
Main Results:
- Several phase II trials are evaluating TCRs targeting NY-ESO-1 and MAGE A4 in specific sarcoma subtypes.
- Response rates up to 60% observed with NY-ESO-1 directed T cells in synovial sarcoma.
- Identified challenges include HLA-restriction, tumor microenvironments, lymphodepletion, and toxicities.
Conclusions:
- Modified T-cell therapy is a promising area for sarcoma treatment.
- Further development of therapeutic tools is needed to enhance specificity, persistence, and safety.
- Overcoming challenges in T-cell function and tumor microenvironment manipulation is crucial for maximizing therapeutic potential.
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