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Published on: August 16, 2019
Antigen-binding affinity is a key determinant of the durable antitumor activity of CD5 CAR-T cells
Jeong-Hoon Jeong1, Yu Ri Seo1, Seung Rok Yu1
1Curocell Inc., Daejeon 34002, Republic of Korea.
Abstract:
T cell fratricide in T cell antigen-targeted chimeric antigen receptor (CAR)-T cell therapies remains a critical barrier to achieving optimal antitumor efficacy. To address this challenge, we explored modulation of antigen-binding affinity as a simple yet effective strategy to mitigate fratricide. To this end, we aimed to develop low-affinity CD5-specific CAR-T cells and to test the hypothesis that low-affinity CD5 CAR-T cells can evade T cell fratricide, thereby alleviating T cell exhaustion and enhancing sustained antitumor activity. Our results demonstrate that CD5 CAR-T cells engineered with low-affinity monoclonal antibodies exhibit significantly reduced fratricide and diminished T cell exhaustion in the infusion product compared to high-affinity counterparts such as the standard H65 and A2 clones, which is assumed to correlate with improved long-term antitumor responses. These findings establish antigen-binding affinity modulation as a promising alternative to extensive gene editing approaches, potentially simplifying CD5 CAR-T cell manufacturing while improving therapeutic outcomes.
Insights
Modulating antigen-binding affinity in chimeric antigen receptor (CAR)-T cell therapy reduces T cell fratricide and exhaustion. Low-affinity CD5 CAR-T cells show promise for improved antitumor activity and simplified manufacturing.
Area of Science:
- Immunotherapy
- Cellular Therapy
- Oncology
Background:
- T cell fratricide is a major limitation in chimeric antigen receptor (CAR)-T cell therapies, hindering optimal antitumor efficacy.
- Existing strategies to overcome T cell fratricide often involve complex gene editing techniques.
Purpose of the Study:
- To investigate antigen-binding affinity modulation as a strategy to mitigate T cell fratricide.
- To develop and evaluate low-affinity CD5-specific CAR-T cells for reduced fratricide and T cell exhaustion.
Main Methods:
- Engineering CD5-specific CAR-T cells with varying antigen-binding affinities using monoclonal antibodies.
- Comparing the fratricide and T cell exhaustion levels of low-affinity CAR-T cells against high-affinity counterparts.
Main Results:
- Low-affinity CD5 CAR-T cells demonstrated significantly reduced T cell fratricide compared to high-affinity versions.
- Diminished T cell exhaustion was observed in the low-affinity CAR-T cell infusion product.
- These outcomes suggest a correlation with improved long-term antitumor responses.
Conclusions:
- Antigen-binding affinity modulation is an effective strategy to mitigate T cell fratricide in CAR-T cell therapy.
- This approach offers a simpler alternative to gene editing for CAR-T cell manufacturing.
- Optimizing affinity may enhance therapeutic outcomes and simplify the production of CD5 CAR-T cells.
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