小柯机器人

美国宾夕法尼亚大学Marco Ruella、Nathan Singh等研究人员合作发现，抗原非依赖性激活可增强4-1BB共刺激的CD22 CAR T细胞功效。2021年4月22日，国际知名学术期刊《自然—医学》在线发表了这一成果。

研究人员表示，虽然CD19定向嵌合抗原受体（CAR）T细胞可以诱导B细胞急性淋巴细胞白血病（ALL）患者的缓解，但CD19^-疾病中却有很大一部分复发。像CD19一样，CD22在B谱系细胞中广泛表达，因此可作为ALL中的替代免疫治疗靶标。

研究人员报道了在患有复发性或难治性ALL的患者中，以4-1BB为基础，以CD22为靶向的CAR T细胞两项初步临床试验结果（NCT02588456和NCT02650414）。这些研究的主要终点是评估安全性，次要终点是抗白血病的功效。研究人员观察到出乎意料的低响应率，因此需要对负责的CAR生物学进行详细的研究。研究人员发现，缩短连接CAR抗原结合域可变重链和轻链的氨基酸接头能够驱动受体均二聚化和不依赖抗原的信号传导 。

与基于CD28的CAR相比，基于4-1BB自主信号的CAR表现出增强的免疫突触形成、促炎基因激活和优异的效应子功能。研究人员验证了几种CAR构造中自主信号与增强功能之间的这种联系，并基于这些观察结果设计了一种新的短接头CD22单链可变片段用于临床评估。这些发现表明，4-1BB信号传导对CAR功能有益，并证明了在CAR T细胞疗法的设计和实施中的临床转化潜能。 

附：英文原文

Title: Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells

Author: Nathan Singh, Noelle V. Frey, Boris Engels, David M. Barrett, Olga Shestova, Pranali Ravikumar, Katherine D. Cummins, Yong Gu Lee, Raymone Pajarillo, Inkook Chun, Amy Shyu, Steven L. Highfill, Andrew Price, Linlin Zhao, Liaomin Peng, Brian Granda, Melissa Ramones, Xueqing Maggie Lu, David A. Christian, Jessica Perazzelli, Simon F. Lacey, Nathan H. Roy, Janis K. Burkhardt, Florent Colomb, Mohammad Damra, Mohamed Abdel-Mohsen, Ting Liu, Dongfang Liu, Daron M. Standley, Regina M. Young, Jennifer L. Brogdon, Stephan A. Grupp, Carl H. June, Shannon L. Maude, Saar Gill, Marco Ruella

Issue&Volume: 2021-04-22

Abstract: While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19 disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials (NCT02588456 and NCT02650414) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.

DOI: 10.1038/s41591-021-01326-5

Source: https://www.nature.com/articles/s41591-021-01326-5

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex