Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Clinic I for Internal Medicine, University Hospital Cologne, Cologne, Germany.
Immunol Rev. 2014 Jan;257(1):83-90. doi: 10.1111/imr.12125.
Adoptive T-cell therapy recently achieved impressive efficacy in early phase trials, in particular in hematologic malignancies, strongly supporting the notion that the immune system can control cancer. A current strategy of favor is based on ex vivo-engineered patient T cells, which are redirected by a chimeric antigen receptor (CAR) and recognize a predefined target by an antibody-derived binding domain. Such CAR T cells can substantially reduce the tumor burden as long as the targeted antigen is present on the cancer cells. However, given the tremendous phenotypic diversity in solid tumor lesions, a reasonable number of cancer cells are not recognized by a given CAR, considerably reducing the therapeutic success. This article reviews a recently described strategy for overcoming this shortcoming of the CAR T-cell therapy by modulating the tumor stroma by a CAR T-cell-secreted transgenic cytokine like interleukin-12 (IL-12). The basic process is that CAR T cells, when activated by their CAR, deposit IL-12 in the targeted tumor lesion, which in turn attracts an innate immune cell response toward those cancer cells that are invisible to CAR T cells. Such TRUCKs, T cells redirected for universal cytokine-mediated killing, exhibited remarkable efficacy against solid tumors with diverse cancer cell phenotypes, suggesting their evaluation in clinical trials.
过继性 T 细胞疗法最近在早期临床试验中取得了令人瞩目的疗效，特别是在血液恶性肿瘤方面，这有力地支持了免疫系统可以控制癌症的观点。目前的一种优选策略基于体外工程化的患者 T 细胞，这些 T 细胞通过嵌合抗原受体 (CAR) 重新定向，并通过抗体衍生的结合域识别预定的靶标。只要靶抗原存在于癌细胞上，这种 CAR T 细胞就可以显著减少肿瘤负担。然而，鉴于实体瘤病变中存在巨大的表型多样性，相当数量的癌细胞不能被特定的 CAR 识别，这大大降低了治疗的成功率。本文综述了一种最近描述的策略，通过 CAR T 细胞分泌的转化生长因子如白细胞介素-12 (IL-12) 来调节肿瘤基质，从而克服 CAR T 细胞疗法的这一缺陷。基本过程是，CAR T 细胞被其 CAR 激活后，在靶向肿瘤病变部位沉积 IL-12，这反过来又吸引先天免疫细胞对 CAR T 细胞无法识别的癌细胞产生反应。这种 TRUCKs（通过通用细胞因子介导杀伤重定向的 T 细胞）对具有不同癌细胞表型的实体瘤表现出显著的疗效，提示它们在临床试验中的评估。
