肿瘤细胞治疗研究
英文原题：Antigen-binding affinity is a key determinant of the durable antitumor activity of CD5 CAR-T cells.
我们的结果表明，与高亲和力对应物如标准 H65 和 A2 克隆相比，使用低亲和力单克隆抗体工程化的 CD5 CAR-T 细胞在输注产品中表现出显著降低的自相残杀和减轻的 T 细胞耗竭，这被认为与改善的长期抗肿瘤反应相关。
靶向T细胞抗原的嵌合抗原受体（CAR）-T细胞疗法中的T细胞自相残杀仍然是实现最佳抗肿瘤疗效的关键障碍。为应对这一挑战，我们探索了调节抗原结合亲和力作为一种简单而有效的策略来减轻自相残杀。为此，我们旨在开发低亲和力CD5特异性CAR-T细胞，并验证以下假设：低亲和力CD5 CAR-T细胞能够逃避T细胞自相残杀，从而减轻T细胞耗竭并增强持续性抗肿瘤活性。我们的结果表明，与高亲和力对应物如标准H65和A2克隆相比，用低亲和力单克隆抗体改造的CD5 CAR-T细胞在输注产品中表现出显著减少的自相残杀和减轻的T细胞耗竭，这被认为与改善的长期抗肿瘤反应相关。这些发现确立了抗原结合亲和力调节作为广泛基因编辑方法的一种有前景的替代方案，可能简化CD5 CAR-T细胞制造，同时改善治疗结果。
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.
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