T cell lymphomas acquire mutations that endow them with advantages to endure the immunosuppressive tumor microenvironment. Researchers have now found a way to turn the tables on cancer by using these mutations to develop more effective chimeric antigen receptor (CAR) T cell therapies. In a study published in Nature, the authors created a barcoded library of mutant genes from T cell malignancies and screened CAR T cells in vivo for improved persistence in solid tumors. These data were paired with an in vitro screen of T cell signaling. One of the strongest hits was a gene fusion of CARD11–PIK3R3 that enhances CARD11–BCL10–MALT1 signaling. CARD11–PIK3R3-expressing CAR T cells (and engineered T cell receptor (TCR) T cells) were tested in several tumor models and even relatively low cell numbers were effective against tumors in mice, including some that are ordinarily refractory to immunotherapy. Whether these CAR T cells might be used in humans is dependent on planned clinical trials, but perhaps the bigger advance here is in the strategy applied, one which might lead to further CAR T cell designs tailored for specific cancers.

Original reference: Nature 626, 626–634 (2024)

T 细胞淋巴瘤获得的突变赋予它们耐受免疫抑制肿瘤微环境的优势。研究人员现已找到一种扭转癌症局面的方法，即利用这些突变开发更有效的嵌合抗原受体 (CAR) T 细胞疗法。在《自然》杂志上发表的一项研究中，作者创建了 T 细胞恶性肿瘤突变基因的条形码文库，并在体内筛选 CAR T 细胞，以提高在实体瘤中的持久性。这些数据与 T 细胞信号传导的体外筛选相匹配。其中最引人注目的成果之一是CARD11-PIK3R3的基因融合，它增强了 CARD11-BCL10-MALT1 信号传导。表达 CARD11-PIK3R3 的 CAR T 细胞（和工程化 T 细胞受体 (TCR) T 细胞）在多种肿瘤模型中进行了测试，即使相对较低的细胞数量也能有效对抗小鼠肿瘤，包括一些通常对免疫疗法耐药的肿瘤。这些 CAR T 细胞是否可以用于人类取决于计划的临床试验，但也许这里更大的进步在于所应用的策略，这可能会导致针对特定癌症的进一步 CAR T 细胞设计。

原始参考文献： Nature 626, 626–634 (2024)