肿瘤细胞治疗研究
英文原题：A phase 1/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed/refractory AML after allogeneic HCT.
15名患者根据疾病负荷分层，分布于两组的VCAR33治疗中：臂A组7名患者（骨髓原始细胞5%）接受剂量水平1（DL1；每公斤1×10^6 CAR+ T细胞），臂B组8名患者（骨髓原始细胞<5%）分别接受DL1（n=5）和DL2（每公斤3×10^6 CAR+ T细胞；n=3）治疗。
VCAR33是一种供者来源、靶向CD33的CAR-T 细胞产品，旨在降低异基因造血细胞移植（alloHCT）后高危急性髓系白血病（AML）或骨髓增生异常综合征（MDS）的复发风险。本文介绍了VCAR33构建体的临床前特征；该构建体基于杀伤和持续性实验进行了优化，以实现长期抗肿瘤监视。在用于alloHCT后维持治疗之前，研究者通过1/2期临床研究，评估VCAR33用于alloHCT后复发或微小残留病（MRD）阳性的CD33阳性AML/MDS成人患者的安全性和疗效。15例患者分为两个按疾病负荷分层的治疗组：A组7例（骨髓原始细胞5%），接受剂量水平1（DL1；每千克1×10^6个CAR阳性T细胞）；B组8例（骨髓原始细胞<5%），其中5例接受DL1，3例接受DL2（每千克3×10^6个CAR阳性T细胞）。研究因非安全性原因在剂量递增至DL3（每千克1×10^7个CAR阳性T细胞）前结束，因此未确定最大耐受剂量。最常见的治疗相关不良事件为细胞因子释放综合征（93.3%，均低于3级）。4例患者（26.7%）发生免疫细胞相关神经毒性综合征（其中1例3级）；1例（6.7%）在VCAR33输注后28天内发生3级急性移植物抗宿主病。14例患者（93.3%）出现短暂VCAR33扩增。总体缓解率为20%：A组2例达到伴血细胞计数未完全恢复的完全缓解，B组1例达到MRD清除。该异基因CAR-T产品显示出可接受的安全性及初步抗白血病活性。试验注册号：ClinicalTrials.gov NCT05984199。
VCAR33, a donor-derived CD33-directed chimeric antigen receptor T-cell (CAR T) product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe preclinical characterization of the VCAR33 construct, which was optimized for long-term antitumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in arm A (bone marrow blasts 5%) at dose level 1 (DL1; 1 106 CAR+ Ts per kg) and 8 patients in arm B (bone marrow blasts <5%) at DL1 (n = 5) and DL2 (3 106 CAR+ Ts per kg; n = 3). The study ended for nonsafety reasons before escalation to DL3 (1 107 CAR+ Ts per kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all <grade 3). Four patients (26.7%) experienced immune cell-associated neurotoxicity syndrome (1 grade 3) and 1 patient (6.7%) had grade 3 acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in arm A and 1 arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary antileukemic activity. This trial was registered at www.clinicaltrials.gov as #NCT05984199.
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