Abstract CT051: Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL
Abstract CT051: Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL
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摘要 CT051：CD19/CD22 CAR T 细胞治疗儿童和年轻人复发/难治性 ALL 的安全性和有效性
作者：
Haneen Shalabi;B. Yates;Shilpa A. Shahani;Haiying Qin;S. Highfill;S. Panch;Minh Tran;D. Stroncek;L. Hoffman;Lauren Little;Katherine Graap;M. Stetler;C. Yuan;Hao;T. Fry;N. Shah
背景资料：基于双重抗原靶向策略可以防止抗原阴性逃逸的假设，我们在复发性/难治性B ALL患者中测试了新型人源化双特异性CD 19/CD 22 CAR T细胞构建体。基于我们对有效的CD 19（NCT 01593696）和CD 22（NCT 02315612）CAR T细胞构建体的经验，我们报告了我们的初步发现。设计：这是一项1期剂量递增研究，以3x 105个转导的CAR T细胞/kg开始。CD 19/CD 22构建体由具有4-1BB共刺激结构域的FMC 63（CD 19 scFv）和m971（CD 22 scFv）组成（NCT：03448393）。主要目的是安全性和毒性;次要目的包括疗效、CAR持久性和细胞因子谱。使用封闭系统装置（CliniMACS Prodigy®）现场制造CAR T细胞。ASTCT共识指南用于细胞因子释放综合征（CRS）分级。先前的CAR T细胞不是排他性的。结果：11例受试者（中位年龄21岁）接受了3个剂量水平的输注。4例发生轻度、可逆CRS，无神经毒性（表）。8例受试者达到客观缓解（MRD阴性CR，n=4;部分缓解，n=4），2例继续接受移植。完全应答者是CAR初始的并且接受> 1 X IO 6个CAR T细胞/kg。CAR扩增在中位数13天（范围，6-20）达到峰值，并且在输注后中位数54天（范围：25-110天）通过流式细胞术可检测到。具有较高疾病负担的患者倾向于具有较高的CRS、CAR扩增和细胞因子升高。2例患者复发（1例BMT后），患有CD 19 +/CD 22+疾病。结论：在我们的初步经验中，CD 19/22 CAR在CAR初治患者中耐受良好且有效，4/6例患者达到MRD阴性CR。复发是抗原阳性的，可能是由于有限的CAR持续性。未来的计划包括探索额外的剂量水平，加强对既往CAR患者的淋巴细胞清除，以及评估CAR T细胞产品特性和结果。引文格式：Haneen Shalabi，Bonnie Yates，Shilpa Shahani，Haiying Qin，Steven L. Highfill、Sandhya Panch、Minh Tran、大卫Stroncek、Leah霍夫曼、Lauren Little、凯瑟琳Graap、Maryalice Stetler-Stevenson、Constance Yuan、Hao-Wei Wang、Terry J. Fry、Nirali N. Shah. CD 19/CD 22 CAR T细胞在儿童和年轻成人复发/难治性ALL中的安全性和有效性[摘要]。在：2020年美国癌症研究协会年会论文集; 2020年4月27日至28日和6月22日至24日。Philadelphia（PA）：AACR; Cancer Res 2020;80（16 Suppl）：Abstract nr CT051.
Background: With the hypothesis that dual antigen targeting strategies may prevent antigen negative escape, we tested a novel humanized bispecific CD19/CD22 CAR T cell construct in patients with relapsed/refractory B ALL. Building upon our experience with effective CD19 (NCT01593696) and CD22 (NCT02315612) CAR T cell constructs, we report our initial findings. Design: This was a phase 1 dose escalation study which started at 3 x 105 transduced CAR T-cell/kg. The CD19/CD22 construct was comprised of FMC63 (CD19 scFv) and m971 (CD22 scFv) with a 4-1BB costimulatory domain (NCT: 03448393). The primary objective was safety and toxicity; secondary objectives included efficacy, CAR persistence and cytokine profiling. CAR T cells were manufactured onsite utilizing a closed system device (CliniMACS Prodigy®). ASTCT consensus guidelines were used for cytokine release syndrome (CRS) grading. Prior CAR T cells were not exclusionary. Results: Eleven subjects (median age 21) were infused at 3 dose levels. Four experienced mild, reversible CRS without neurotoxicity (Table). Eight subjects had an objective response (MRD negative CR, n=4; partial response, n=4), and 2 proceeded to transplant. Complete responders were CAR naive and received > 1 x 106 CAR T-cells/kg. CAR expansion peaked at a median of 13 days (range, 6-20) and were detectable by flow cytometry to a median of 54 days (range: 25-110 days) post infusion. Patients with higher disease burden trended towards having higher CRS, CAR expansion, and cytokine elevation. Two patients have relapsed (1 post BMT) with CD19+/CD22+ disease. Conclusion: In our preliminary experience, CD19/22 CAR was well tolerated and effective in CAR naive patients, with 4/6 patients achieving MRD negative CR. Relapses were antigen positive likely due to limited CAR persistence. Future plans include exploring an additional dose level, intensifying lymphodepletion for prior CAR patients, and evaluating CAR T-cell product characteristics with outcomes. Citation Format: Haneen Shalabi, Bonnie Yates, Shilpa Shahani, Haiying Qin, Steven L. HIghfill, Sandhya Panch, Minh Tran, David Stroncek, Leah Hoffman, Lauren Little, Katherine Graap, Maryalice Stetler-Stevenson, Constance Yuan, Hao-Wei Wang, Terry J. Fry, Nirali N. Shah. Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT051.