Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Engineering Medicine, Beihang University, Beijing, China.
Department of Hematology and Lymphoma Research Center, Beijing Gobroad Boren Hospital, Beijing, China.
Clin Cancer Res. 2023 Apr 14;29(8):1484-1495. doi: 10.1158/1078-0432.CCR-22-2924.
CD7 chimeric antigen receptor T (CAR-T) therapy has potent antitumor activity against relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), however, immune reconstitution after CAR-T remains largely unknown.
An open-label phase I clinical trial (ChiCTR2200058969) was initiated to evaluate safety and efficacy of donor-derived CD7 CAR-T cells in 7 R/R T-ALL/LBL patients. CAR-T cells were detected by flow cytometry and PCR. Cytokine levels were quantified by cytometric bead arrays. Single-cell RNA sequencing (scRNA-seq) was adopted to profile immune reconstitution.
Optimal complete remission (CR) was 100% on day 28, and median followed-up time was 4 months. Leukopenia, thrombocytopenia, and neutropenia were observed in 6 patients, and infections occurred in 5 patients. Two patients died of serious infection and one died of a brain hemorrhage. CAR-T cells expanded efficiently in all patients. CD7+ T cells were eliminated in peripheral blood on day 11 after infusion, and CD7- T cells dramatically expanded in all patients. scRNA-seq suggested that immunologic activities of CD7- T cells were stronger than those of T cells before infusion due to higher expression levels of T-cell function-related pathways, and major characters of such CD7- T cells were activation of autoimmune-related pathways. Monocyte loss was found in 2 patients who died of serious infections, indicating the main cause of the infections after infusion. S100A8 and S100A9 were identified as potential relapse markers due to their notable upregulation in leukocyte lineage in relapsed patients versus non-relapse controls.
Our data revealed cellular level dynamics of immune homeostasis of CD7 CAR-T therapy, which is valuable for optimizing the treatment of R/R T-ALL/LBL.
嵌合抗原受体 T（CAR-T）疗法对复发/难治性（R/R）T 细胞急性淋巴细胞白血病/淋巴瘤（T-ALL/LBL）具有强大的抗肿瘤活性，然而，CAR-T 后的免疫重建在很大程度上仍不清楚。
一项开放标签的 I 期临床试验（ChiCTR2200058969）启动，以评估 7 例 R/R T-ALL/LBL 患者供体来源的 CD7 CAR-T 细胞的安全性和疗效。通过流式细胞术和 PCR 检测 CAR-T 细胞。采用单细胞 RNA 测序（scRNA-seq）对免疫重建进行分析。
28 天的最佳完全缓解（CR）率为 100%，中位随访时间为 4 个月。6 例患者出现白细胞减少、血小板减少和中性粒细胞减少，5 例患者发生感染。2 例患者因严重感染死亡，1 例患者因脑出血死亡。所有患者的 CAR-T 细胞均有效扩增。输注后第 11 天，外周血中 CD7+T 细胞被清除，所有患者的 CD7-T 细胞显著扩增。scRNA-seq 表明，由于 T 细胞功能相关途径的高表达，输注后 CD7-T 细胞的免疫活性强于输注前的 T 细胞，且此类 CD7-T 细胞的主要特征是自身免疫相关途径的激活。2 例死于严重感染的患者出现单核细胞丢失，表明输注后感染的主要原因。由于 S100A8 和 S100A9 在复发患者的白细胞谱系中显著上调，因此被确定为潜在的复发标志物。
我们的数据揭示了 CD7 CAR-T 治疗的免疫稳态的细胞水平动态，这对于优化 R/R T-ALL/LBL 的治疗具有重要价值。
