Department of Internal Medicine V, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
J Hematol Oncol. 2023 Jul 22;16(1):79. doi: 10.1186/s13045-023-01470-0.
Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).
Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10 and 50 × 10 CARTs/m. Leukapheresis, manufacturing and administration of CARTs were performed in-house.
For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response.
In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.
gov as NCT03676504.
第三代嵌合抗原受体（CAR）修饰的 T 细胞（CART）可能改善 B 细胞恶性肿瘤患者的临床结局。这是首例报告关于第三代 CART 剂量递增、1/2 期研究者发起的临床试验，旨在治疗成人难治性和/或复发（r/r）急性淋巴细胞白血病（ALL）患者。
13 例患者接受了 1×10 至 50×10 CARTs/m 的递增剂量的 CD19 靶向 CART 治疗。CART 的白细胞分离、制造和给药均在内部进行。
对于所有患者，CART 制造都是可行的。没有患者出现任何等级的免疫效应细胞相关神经毒性综合征（ICANS）或更高级别的（≥等级 III）细胞因子释放综合征（CRS）。可评估患者的外周血（PB）中可观察到 CART 的扩增和长期 CART 的持续存在。在 CART 输注后第 90 天的研究结束时，10 例患者可评估疗效：8 例患者（80%）达到完全缓解（CR），其中 5 例患者（50%）为微小残留病灶（MRD）阴性 CR。反应和结局与给予的 CART 剂量有关。在 1 年随访时，中位总生存期未达到，无进展生存期（PFS）为 38%。中位 PFS 在第 120 天达到。与非应答者的 CART 产品相比，应答者的记忆样 T 细胞上缺乏 CD39 表达更为常见。在 CART 给药后，PB 中 CD8+和γδ-T 细胞频率较高、免疫细胞的生理模式以及单核细胞计数较低与反应相关。
总之，第三代 CART 与有前景的临床疗效和显著降低的特定于程序的毒性相关，为 r/r ALL 患者开辟了新的治疗前景。
该试验在 www.clinicaltrials.gov 上注册为 NCT03676504。
