GPRC5D-Targeted CAR T Cells for Myeloma.
GPRC5D-Targeted CAR T Cells for Myeloma.
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DOI：
10.1056/nejmoa2209900
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发表时间：
2022-09-29
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B细胞成熟抗原（BCMA）导向的嵌合抗原受体（CAR）T细胞疗法已在晚期骨髓瘤患者中产生应答，但复发很常见。G蛋白偶联受体，C类，5组，D成员（GPRC 5D）已被确定为多发性骨髓瘤的免疫靶点。临床前研究已经显示了GPRC 5D靶向CAR T细胞的功效，包括在BCMA抗原逃逸模型中的活性。在这项1期剂量递增研究中，我们以四种剂量水平对接受过大量预治疗的多发性骨髓瘤患者（包括BCMA CAR T细胞治疗后复发的患者）进行了GPRC 5D靶向CAR T细胞治疗（MCARH 109）。共有17名患者入组并接受了MCARH 109治疗。最大耐受剂量确定为150×106个CAR T细胞。在450×106 CAR T细胞剂量下，1例患者出现4级细胞因子释放综合征和免疫效应细胞相关神经毒性综合征（ICANS），2例患者出现3级病因不明的小脑疾病。在接受25×106至150×106个细胞剂量的12名患者中，没有发生小脑疾病、任何级别的ICANS或3级或更高级别的细胞因子释放综合征。在整个队列中，71%的患者报告了缓解，在接受25×106至150×106个细胞剂量的患者中，58%的患者报告了缓解。出现缓解的患者包括既往接受过BCMA治疗的患者;在整个队列的10例此类患者中有7例观察到缓解，在接受25×106至150×106个细胞的6例此类患者中有3例观察到缓解。这项GPRC 5D靶向CAR T细胞疗法（MCARH 109）的研究结果证实，GPRC 5D是多发性骨髓瘤的主动免疫靶点。（由Juno Therapeutics/布里斯托Myers Squibb资助; ClinicalTrials.gov编号，NCT 0455551。）
B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein–coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.)