【ASH2020】北恒生物公布通用型CAR-T产品CTA101治疗复发性或难治性B细胞急性淋巴细胞白血病研究数据

CTA101是北恒生物第一代通用CAR-T技术平台开发的基于CRISPR基因编辑技术、“现货供应型”、抗CD19/CD22的双靶点通用CAR-T细胞疗法。浙江大学医学院附属第一医院院长、血液骨髓移植中心学科带头人黄河教授以口头报告的形式在第62届美国血液年会上详述了这项单臂、开放标签、剂量递增研究者发起的临床研究的结果。 

截至2020年8月31日，共筛选 8例成人患者，纳入6例。6例患者分别接受2个剂量水平的CTA101单次输注，其中3例患者接受了1×10⁶ CAR+T 细胞/kg，另外3例患者接受3×10⁶ CAR+T 细胞/kg。入组到输注等待时间不超过8天。6名患者的既往中位治疗管线数为5，3名患者在入组前存在高白细胞血症，1名患者存在自体T细胞计数过低。

5例（83%）患者获得CR/CRi，且均为MRD-，其中1例患者在D60缓解状态下接受了allo-HSCT治疗。中位随访时间4.3个月，5例获得CR/CRi患者中3例患者仍维持MRD-，1例患者在输注后D47 MRD+且在D74确认为CD19+CD22^dim复发。截至数据截至日，最长的缓解状态已持续超过8个月。

未发生剂量限制性毒性（DLTs）、移植物抗宿主病（GvHD）以及神经毒性事件。6例患者均经历了细胞因子释放综合征（CRS）。其中5例（83%）发生了1-2级CRS，经支持性治疗缓解。1例（17%）发生了3级CRS，经托珠单抗及糖皮质激素治疗后，在7天内缓解。未检测到可复制的慢病毒（RCL）及CRISPR/Cas9基因组编辑相关的AEs。

该项临床研究的主要研究者（PI）黄河教授表示：“CTA101表现的特征，如小于8天的输注等待时间、100%的输注成功率、针对自体CAR-T制备困难人群的适用性、强效的抗肿瘤作用以及良好的耐受性结果令人鼓舞。此外也初步验证了CRISPR基因编辑在通用型CAR-T应用的可行性。期待有更多的通用型CAR-T进入临床，为解决未满足的临床需求提供更多选择。”

北恒生物首席执行官贺小宏博士表示：“CTA101是我们基于CRISPR基因编辑技术的第一代通用型CAR-T产品。我们的数据提示了其良好的耐受性以及强效的抗肿瘤作用。通用型CAR-T很大程度克服由于单采或制备失败，以及回输前疾病进展等导致病人失去治疗机会的问题。未来，北恒生物将会加速推进通用型细胞治疗产品的开发，并及时分享最新进展。”

CTA101, a CRISPR/Cas9-engineered off-the-shelf CD19/CD22 dual-targeted CAR-T cell product, was evaluated in an open-label dose-escalation phase I study, which presented  at the 62nd Annual Meeting of the American Society of Hematology (ASH) by He Huang, MD, PhD, Professor of Hematology, President of The First Affiliated Hospital, Zhejiang University School of Medicine.

As of the August 31st, 2020 data cutoff, 8 adult patients were screened, and 6 adult patients all enrolled received CTA101 infusion at two dose levels (DL1 = 1×10⁶/kg cells, DL2 =3×10⁶/kg cells), with less than 8 days between enrollment and infusion. The median number of prior lines of therapy was 5, and three patients had hyperleukocytosis and one had CD3+ T lymphocytopenia prior to enrollment.

Across both cohorts, 5 patients (83.3%) achieved complete response (CR) or complete response with incomplete hematologic recovery (CR/CRi). Minimal residual disease (MRD) assessment was completed in five patients with a CR/CRi response and all achieved an MRD negative status. With a median follow-up of 4.3 months, three out of the five patients who achieved CR/CRi remained MRD negative. The longest sustained remission has been observed for more than 8 months to date.

No dose limiting toxicity (DLT), graft-vs-host disease (GvHD) or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were observed. Cytokine release syndrome (CRS) was identified in all patients, and the majority of CRS was mild and manageable with supportive therapies. Only one patient experienced grade 3 CRS and required tocilizumab and glucocorticoids treatment. No CRISPR/Cas9 genome editing associated adverse events occurred.

“We are encouraged by CTA101’s manageable safety profile and potent anti-leukemia ability, which illustrate the potential feasibility of CRISPR/Cas9-engineered universal CAR-T,” said the PI of this study, Prof. Huang. “All patients enrolled successfully received infusions within 8 days. Three patients with leukocytosis and one patient with lymphopenia prior to enrollment, for whom autologous CAR-T therapy was not suitable, received CTA101 therapy successfully in this study. These data suggest that CTA101 may offer an alternative therapy for patients with r/r ALL. I hope more and more universal CAR-T therapies can be developed to address unmet medical needs in the future.”

“We are excited to demonstrate for the first time that a CRISPR-engineered allogeneic CAR-T therapy directed at CD19/CD22 can achieve deep clinical responses,” said Xiaohong He, PhD, CEO of Bioheng. “We believe these initial results support that we are on the right track to bring the benefits of an off-the-shelf therapy to cancer patients.”