抗体技术联合T细胞免疫治疗B细胞肿瘤的研究

基于抗体技术利用T细胞免疫治疗是近年来B细胞恶性肿瘤治疗的有效手段。治疗策略主要包括嵌合抗原受体T细胞(CAR-T)和双特异性T细胞衔接器(BiTE)靶向免疫治疗。目前存在如下问题:1)靶细胞抗原缺失2)T细胞激活后耗竭导致疾病复发；3)BiTE对T细胞激活不足导致治疗失败。在以往B细胞恶性肿瘤免疫治疗的基础上，拟研究:1)在BiTE中引入共刺激因子，制备三特异性T细胞衔接器(TriTE)，以增强对T细胞的激活；2)制备表达PD-1单链抗体和IL15的CAR-T细胞，以抑制T细胞耗竭，促进T细胞存活；3)联合应用TriTE和CAR-T，以增强治疗疗效；4)使用RNA-seq和10×Genomics技术，探讨T细胞激活、耗竭等机制。藉此研究，希望证实TriTE功能，提高CAR-T活性，联合应用多靶点TriTE和CAR-T技术为临床治疗提供多种组合，为患者个体化治疗提供更多临床方案。

Antibody based T cells immunotherapies are the dramatic strategy for B cell malignancies. Therapeutic strategies mainly contain chimeric antigen receptor T cells (CAR-T) and bispecific T cell engager (BiTE). But, there exist several problems: 1) the deletion of antigen on target cells, 2) the exhaustion of T cells after activation led to relapse; 3) insufficient activation of T cells by BiTE led to treatment failure. Based on the experiences of immunotherapy to B cell malignancies, we will investigate: 1) to construct TriTE by adding the co-stimulator into the structure of BiTE, to enhance the activation of T cells; 2) to construct CAR-T cells expressing PD-1 single-chain antibody or IL15, to inhibit exhaust of T cells, and to increase the survival of T cells; 3) to use TriTE and CAR-T at the same time, to facilitate the treatment efficiency; 4) to use RNA-seq and 10×Genomics to investigate the mechanism of T cells’ activation and exhaustion. We hope to confirm the function of TriTE, heighten the activation of CAR-T, combine TriTE and CAR-T with multiple targets to provide multiple combinations for clinical therapy, and offer more treatment strategies for individualized treatment.