英国伦敦大学学院Martin Pule等研究人员完成CAR T细胞双靶向CD19和CD22治疗复发或难治性B细胞急性淋巴细胞白血病的儿童和年轻成人患者的1期临床试验。2021年10月12日，《自然—医学》杂志在线发表了这项成果。

据研究人员介绍，靶向CD19或CD22的嵌合抗原受体（CAR）T细胞在B细胞急性淋巴细胞白血病（B-ALL）中显示出显著的活性。治疗失败的主要原因是抗原下调或丧失。双重抗原靶向有可能防止这种情况，但同时靶向CD19和CD22的CAR T细胞的临床安全性和疗效仍不清楚。

研究人员在复发或难治性B-ALL的儿童和年轻成人患者（n=15）中进行了一项1期试验，测试AUTO3，即表达抗CD19和抗CD22 CAR的自体转导T细胞（AMELIA试验，EUDRA CT 2016-004680-39）。主要终点是剂量限制性毒性期的3-5级毒性发生率和剂量限制性毒性的频率。次要终点包括形态学缓解率（完全反应或完全反应伴有不完全骨髓恢复）与最小残留疾病阴性反应，以及不良事件的频率和严重程度、AUTO3的扩展和持续性、B细胞增生的持续时间，以及总生存期和无事件生存期。该研究的终点已经达到。AUTO3显示出良好的安全性，没有剂量限制性毒性或AUTO3相关的严重细胞因子释放综合症或神经毒性病例的报道。

治疗后1个月，缓解率（即完全反应或完全反应但骨髓不完全恢复）为86%（15名患者中有13名）。1年的总生存率和无事件生存率分别为60%和32%。复发可能是由于AUTO3长期持久性有限。为了充分实现双靶向CAR T细胞疗法在B-ALL中的潜力，需要采取改善CAR T细胞持久性的策略。

附：英文原文

Title: CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Author: Cordoba, Shaun, Onuoha, Shimobi, Thomas, Simon, Pignataro, Daniela Soriano, Hough, Rachael, Ghorashian, Sara, Vora, Ajay, Bonney, Denise, Veys, Paul, Rao, Kanchan, Lucchini, Giovanna, Chiesa, Robert, Chu, Jan, Clark, Liz, Fung, Mei Mei, Smith, Koval, Peticone, Carlotta, Al-Hajj, Muhammad, Baldan, Vania, Ferrari, Mathieu, Srivastava, Saket, Jha, Ram, Arce Vargas, Frederick, Duffy, Kevin, Day, William, Virgo, Paul, Wheeler, Lucy, Hancock, Jeremy, Farzaneh, Farzin, Domning, Sabine, Zhang, Yiyun, Khokhar, Nushmia Z., Peddareddigari, Vijay G. R., Wynn, Robert, Pule, Martin, Amrolia, Persis J.

Issue&Volume: 2021-10-12

Abstract: Chimeric antigen receptor (CAR) Tcells targeting CD19 or CD22 have shown remarkable activity in Bcell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR Tcells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n=15) to test AUTO3, autologous transduced Tcells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of Bcell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR Tcell persistence are needed to fully realize the potential of dual targeting CAR Tcell therapy in B-ALL.

DOI: 10.1038/s41591-021-01497-1

Source: https://www.nature.com/articles/s41591-021-01497-1