T cell therapies are still hindered by poor T cell persistence and function, making them largely ineffective against solid tumors. Human cancerous T cells acquire mutations that increase their fitness and evade immune challenges in similar situations to those faced by therapeutic T cells. Writing in Nature, Garcia and colleagues exploit the fitness-enhancing abilities of these cancer mutations by incorporating them into engineered therapeutic T cells for improved performance.

The authors screened 71 cancerous T cells mutations for their potential effect on therapeutic T cell function. Among these candidates, they identified a gene fusion, CARD11–PIK3R3, that significantly improved anti-tumor activity of T cell therapies in mouse models bearing various cancers, including melanoma. CARD11–PIK3R3 improved the efficacy of both T cell receptor (TCR) and chimeric antigen receptor (CAR)-T cell therapy by amplifying signaling through CBM, a complex that is essential for T cell activation and function in response to antigens. The mutated T cells also improved general treatment conditions, requiring lower dosing and eliminating the need for lymphodepletion chemotherapy — a procedure that is often used to improve T cell therapy effectiveness but is associated with substantial toxicities.

T 细胞疗法仍然受到 T 细胞持久性和功能不佳的阻碍，使其对实体瘤基本上无效。人类癌性 T 细胞会发生突变，从而增强其适应性，并在与治疗性 T 细胞面临的类似情况下逃避免疫挑战。Garcia 及其同事在《自然》杂志上撰文，通过将这些癌症突变整合到工程治疗性 T 细胞中来提高性能，从而利用这些癌症突变的健康增强能力。

作者筛选了 71 种癌性 T 细胞突变，以确定它们对治疗性 T 细胞功能的潜在影响。在这些候选者中，他们发现了一种基因融合体CARD11 – PIK3R3，该融合体显着提高了患有多种癌症（包括黑色素瘤）的小鼠模型中 T 细胞疗法的抗肿瘤活性。CARD11 – PIK3R3通过放大 CBM 信号传导来提高 T 细胞受体 (TCR) 和嵌合抗原受体 (CAR)-T 细胞疗法的功效，CBM 是 T 细胞激活和响应抗原的功能所必需的复合物。突变的 T 细胞还改善了一般治疗条件，需要较低的剂量并消除了淋巴细胞清除化疗的需要——这种手术通常用于提高 T 细胞治疗的效果，但与大量的毒性相关。