Zhang Yu, Li Saisai, Wang Ying, Lu Yang, Xu Yingxi, Rao Qing, Wang Huijun, Xing Haiyan, Tian Zheng, Tang Kejing, Lv Lulu, Wang Min, Wang Jianxiang
State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
Exp Hematol Oncol. 2022 Mar 22;11(1):15. doi: 10.1186/s40164-022-00270-5.
CD19 chimeric antigen receptor (CAR) therapy has achieved impressive success in relapsed or refractory (R/R) B-cell malignancies, but relapse due to antigen escape is increasingly appearing reported. As the expression profile of CD22 is similar to that of CD19, CD22 has become a candidate target when CD19 CAR-T therapy fails.
A novel CD22 CAR incorporating scFv derived from an HIB22 hybridoma which bound the first and second Ig-like extracellular domains of CD22 antigen was constructed. Preclinical investigation of the CD22 CAR-T therapy against B-cell malignancies was evaluated by coculturing CD22 CAR-T cells with tumor cell lines or primary blasts from patients in vitro and using a xenograft mouse model in vivo. Further clinical study of CD22/CD19 CAR-T sequential therapy was conducted in 4 R/R adult B-cell acute lymphoblastic leukemia (B-ALL) patients.
The novel CD22 CAR-T treatment had specific cytotoxicity to CD22 + target cells, and the survival time of mice in the CD22 CAR-T treatment group was significantly prolonged. Furthermore, it's validated that sequential CD22/CD19 CAR-T therapy was significantly superior than single CD19 or CD22 CAR-T treatment in a relapse xenograft model. All 4 patients achieved complete remission (CR) with negative minimal residual disease (MRD), including 3 patients who had received prior CD19-related immunotherapy. The proliferation of CD19 and CD22 CAR-T cells was observed respectively in vivo, and 3 of the 4 patients experienced cytokine release syndrome (CRS); 2 of these patients had grade 1 CRS and 1 had grade 3 CRS. Long term follow-up showed that 3 of the 4 (75%) patients had sustained CR for up to 1 year. Analysis of antigen expression in the relapsed patients demonstrated that loss or diminution of CD19 and CD22 expression might cause antigen escape from CAR-T surveillance.
In summary, the novel CD22 CAR-T therapy was validated with antitumor effects both in vitro and in vivo. Furthermore, our study demonstrated the safety and robust efficacy of sequential CD22/CD19 CAR-T therapy in xenograft models and clinical trials, especially as the salvage treatment for R/R B-ALL patients with antigen loss or in whom anti-CD19 related immunotherapy failure failed.
Chinese Clinical Trial Registry (ChiCTR): ChiCTR1900025419, Supplementarily registered 26 August, 2019.
CD19嵌合抗原受体（CAR）疗法在复发或难治性（R/R）B细胞恶性肿瘤中取得了令人瞩目的成功，但因抗原逃逸导致的复发报道日益增多。由于CD22的表达谱与CD19相似，当CD19 CAR-T疗法失败时，CD22已成为一个候选靶点。
构建了一种新型CD22 CAR，其包含源自HIB22杂交瘤的scFv，该scFv可结合CD22抗原的第一个和第二个Ig样细胞外结构域。通过在体外将CD22 CAR-T细胞与肿瘤细胞系或患者的原代母细胞共培养，并在体内使用异种移植小鼠模型，评估了CD22 CAR-T疗法针对B细胞恶性肿瘤的临床前研究。对4例R/R成人B细胞急性淋巴细胞白血病（B-ALL）患者进行了CD22/CD19 CAR-T序贯疗法的进一步临床研究。
新型CD22 CAR-T治疗对CD22 +靶细胞具有特异性细胞毒性，CD22 CAR-T治疗组小鼠的生存时间显著延长。此外，在复发异种移植模型中验证了序贯CD22/CD19 CAR-T疗法显著优于单一CD19或CD22 CAR-T治疗。所有4例患者均实现完全缓解（CR），微小残留病（MRD）为阴性，其中3例患者曾接受过与CD19相关的免疫治疗。在体内分别观察到CD19和CD22 CAR-T细胞的增殖，4例患者中有3例出现细胞因子释放综合征（CRS）；其中2例患者为1级CRS，1例为3级CRS。长期随访显示，4例患者中有3例（75%）持续CR长达1年。对复发患者抗原表达的分析表明，CD19和CD22表达的缺失或减少可能导致抗原逃避CAR-T的监测。
总之，新型CD22 CAR-T疗法在体外和体内均验证了抗肿瘤作用。此外，我们的研究证明了序贯CD22/CD19 CAR-T疗法在异种移植模型和临床试验中的安全性和强大疗效，特别是作为对有抗原缺失或抗CD19相关免疫治疗失败的R/R B-ALL患者的挽救治疗。
中国临床试验注册中心（ChiCTR）：ChiCTR1900025419，于2019年8月26日补充注册。
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