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科学家完成CAR T细胞双靶向CD19和CD22治疗复发性或难治性B细胞恶性肿瘤成年患者的1期试验
作者:小柯机器人 发布时间:2021/7/31 22:02:23

美国斯坦福大学David B. Miklos、Crystal L. Mackall等研究人员合作完成CAR T细胞双靶向CD19和CD22治疗复发性或难治性B细胞恶性肿瘤成年患者的1期试验。这一研究成果于2021年7月26日在线发表在国际学术期刊《自然—医学》上。

研究人员表示,尽管取得了令人印象深刻的进展,但超过50%的患者在接受CD19靶向嵌合抗原受体T细胞(CAR19)治疗时出现了进展性疾病。16名在CAR19治疗后出现进展性疾病的大B细胞淋巴瘤(LBCL)患者中,有10名患者的CD19缺失或偏低。治疗前较低的表面CD19密度与进展性疾病有关。

为了防止CD19-或CD19lo疾病的复发,研究人员在一项针对复发/难治性B细胞急性淋巴细胞白血病(B-ALL)和LBCL成人的I期临床试验(NCT03233854)中测试了一种针对CD19和/或CD22的双特异性CAR(CD19-22.BB.z-CAR)。主要终点是生产可行性和安全性,次要终点是疗效。

主要终点已经达到;97%的产品达到了方案规定的剂量,在剂量升级过程中没有出现剂量限制性毒性。在B-ALL(n=17)中,100%的患者有反应,88%的最小残留疾病阴性完全缓解(CR);在LBCL(n=21)中,62%的患者有反应,29%CR。50%的B-ALL患者(10人中有5人)和29%的LBCL患者(14人中有4人)出现CD19-/lo复发,但与CD22-/lo疾病没有关系。CD19/22-CAR产品在受到CD22相对于CD19的刺激时表现出细胞因子的产生减少。

这些结果进一步暗示抗原丢失是CAR T细胞耐药性的主要原因,从而突出了工程化多特异性CAR T细胞在不同靶点上具有同等效力的难题,并确定了细胞因子产生是CAR T细胞效力的一个重要质量指标。

附:英文原文

Title: CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial

Author: Jay Y. Spiegel, Shabnum Patel, Lori Muffly, Nasheed M. Hossain, Jean Oak, John H. Baird, Matthew J. Frank, Parveen Shiraz, Bita Sahaf, Juliana Craig, Maria Iglesias, Sheren Younes, Yasodha Natkunam, Michael G. Ozawa, Eric Yang, John Tamaresis, Harshini Chinnasamy, Zach Ehlinger, Warren Reynolds, Rachel Lynn, Maria Caterina Rotiroti, Nikolaos Gkitsas, Sally Arai, Laura Johnston, Robert Lowsky, Robbie G. Majzner, Everett Meyer, Robert S. Negrin, Andrew R. Rezvani, Surbhi Sidana, Judith Shizuru, Wen-Kai Weng, Chelsea Mullins, Allison Jacob, Ilan Kirsch, Magali Bazzano, Jing Zhou, Sean Mackay, Scott J. Bornheimer, Liora Schultz, Sneha Ramakrishna, Kara L. Davis, Katherine A. Kong, Nirali N. Shah, Haiying Qin, Terry Fry, Steven Feldman, Crystal L. Mackall, David B. Miklos

Issue&Volume: 2021-07-26

Abstract: Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19 or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n=17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n=21), 62% of patients responded with 29% CR. Relapses were CD19/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

DOI: 10.1038/s41591-021-01436-0

Source: https://www.nature.com/articles/s41591-021-01436-0

期刊信息

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:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex