多功能 CD19-CAR T 细胞工程改造分泌抗 CD47 单链可变片段增强肿瘤免疫治疗。
Enhanced tumor immunotherapy by polyfunctional CD19-CAR T cells engineered to secrete anti-CD47 single-chain variable fragment.
机构信息
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510280, P. R. China.
Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, 510005, P. R. China.
出版信息
Int J Biol Sci. 2023 Sep 18;19(15):4948-4966. doi: 10.7150/ijbs.86632. eCollection 2023.
A high recurrence rate of non-Hodgkin's lymphoma (NHL) following chimeric antigen receptor T (CAR T) cell treatment remains a bottleneck, and immunosuppressive tumor microenvironment (TME) compromising CAR T cell efficacy in NHL is the primary cause of relapse. Accordingly, modifying the structure of CAR T cells to attenuate the inhibitory effect of TME thus reducing recurrence rate is a valuable research topic. CD47 has been proved to be a promising therapeutic target and is crucial in regulating macrophage function. Herein, we engineered CD19-CAR T cells to secrete an anti-CD47 single-chain variable fragment (scFv) and validated their function in enhancing antitumor efficacy, regulating T cells differentiation, modifying phagocytosis and polarization of macrophages by and researches. The efficacy was analogous or preferable to the combination of CAR T cells and CD47 antibody. Of note, anti-CD47 scFv secreting CAR T cells exert a more potent immune response following specific antigen stimulation compared with parental CAR T cells, characterized by more efficient degranulation and cytokine production with polyfunctionality. Furthermore, locally delivering anti-CD47 by CAR T cells potentially limits toxicities relevant to systemic antibody treatment. Collectively, our research provides a more effective and safer CAR T cell transformation method for enhancing tumor immunotherapy.
嵌合抗原受体 T (CAR T)细胞治疗后非霍奇金淋巴瘤(NHL)的高复发率仍然是一个瓶颈,而抑制性肿瘤微环境(TME)影响 CAR T 细胞在 NHL 中的疗效是复发的主要原因。因此,修饰 CAR T 细胞的结构以减弱 TME 的抑制作用,从而降低复发率是一个有价值的研究课题。CD47 已被证明是一个很有前途的治疗靶点,对调节巨噬细胞功能至关重要。在此,我们构建了分泌抗 CD47 单链可变片段(scFv)的 CD19-CAR T 细胞,并通过 和 研究验证了其增强抗肿瘤疗效、调节 T 细胞分化、修饰巨噬细胞吞噬和极化的功能。其疗效与 CAR T 细胞与 CD47 抗体的联合治疗相当或更优。值得注意的是,与亲本 CAR T 细胞相比,抗 CD47 scFv 分泌的 CAR T 细胞在特异性抗原刺激下产生更强的免疫反应,其特点是具有更高的脱颗粒和细胞因子产生效率以及多功能性。此外,CAR T 细胞局部递送抗 CD47 可能会限制与全身抗体治疗相关的毒性。总之,我们的研究为增强肿瘤免疫治疗提供了一种更有效、更安全的 CAR T 细胞转化方法。