Nature Medicine ( IF 58.7 ) Pub Date : 2024-09-03 , DOI: 10.1038/s41591-024-03228-8 Bernice L Z Oh 1, 2 , Noriko Shimasaki 2 , Elaine Coustan-Smith 2 , Esther Chan 3 , Limei Poon 3 , Shawn H R Lee 1, 2 , Frances Yeap 1, 2 , Lip Kun Tan 3 , Louis Y A Chai 4 , Nina Le Bert 5 , Nicole Tan 5 , Antonio Bertoletti 5 , Siew Peng Chen 2 , Francesca Del Bufalo 6 , Marco Becilli 6 , Franco Locatelli 6, 7 , Allen E J Yeoh 1, 2, 3, 8 , Dario Campana 2, 3, 8
T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7− T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.
中文翻译:
T-ALL 中的自相杀灭绝耐药 CD7-CAR T 细胞
T 细胞急性淋巴细胞白血病 (T-ALL) 在治疗后复发或对化疗耐药时难以治疗;复发或难治性 T-ALL 患者的预后通常较差。我们报告了 17 例此类患者的病例系列,这些患者接受了表达抗 CD7 CAR 和抗 CD7 蛋白表达阻滞剂 (PEBL) 的自体嵌合抗原受体 (CAR) T 细胞,从而防止了 CAR T 细胞自相残杀。尽管白血病负荷高且 CAR T 细胞剂量低,但 17 例患者中有 16 例在 1 个月内达到微小残留病阴性完全缓解。其余患者在输注前有 CD7− T-ALL 细胞,输注后持续存在。毒性较轻:10 例患者细胞因子释放综合征为 1 级,3 例患者为 2 级;2 例患者的免疫效应细胞相关神经毒性综合征 1 级。11 例患者保持无复发 (中位随访 15 个月),包括所有 9 例接受同种异体移植的患者。首例患者在输注后 55 个月处于缓解期,无需进一步化疗或移植;循环 CAR T 细胞可检测 2 年。淋巴细胞清除后再生的 T 细胞缺乏 CD7 表达,是多克隆的,对 SARS-CoV-2 疫苗接种有反应;CD7 + 免疫细胞与 CAR T 细胞消失同时重新出现。总之,自体抗 CD7 PEBL-CAR T 细胞具有强大的抗白血病活性,可能是治疗 T-ALL 的有效选择。