异基因靶向CD19嵌合抗原受体修饰的T细胞联合造血干细胞输注的免疫学演变及抗白血病机制研究

复发难治急性B淋巴细胞白血病（B-ALL）预后差，自体嵌合抗原受体修饰的T细胞（CART）仍存在复发、培养失败等问题，未经基因编辑的异基因CART是否诱发移植物抗宿主病（GVHD）以及体内存活仍不明确。化疗联合HLA不全相合造血干细胞输注（微移植）明显改善了老年白血病疗效，输注大量异基因T细胞并未增加严重GVHD；在此基础上我们利用异基因CART联合微移植治疗复发难治B-ALL，明显提高了缓解率，并检测到CART及供体不同比例嵌合长期存在，但其免疫学演变过程及抗白血病机制仍不明确。我们拟采用人源化CD19+白血病小鼠，同时输注供者来源CART及造血干细胞，以阐明异基因CART在不同比例供者嵌合状态下的免疫学演变规律及对白血病细胞的影响；另一方面，通过临床研究探讨异基因CART存活及扩增、嵌合状态持续时间、细胞因子变化对白血病残留、生存及复发的影响，为复发难治B-ALL开辟新的治疗手段。

Relapsed and refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) has poor prognosis. Although autologous chimeric antigen receptor-modified T cells (CART) improved remission rate, problems such as relapse and culture failure still exist. Whether non-gene-edited allogeneic CART (allo-CART) induce severe graft-versus-host disease (GVHD) or experience survival difficulty is uncertain. Previously we successfully used chemotherapy combined with mobilized HLA-mismatched donor stem cell infusion (microtransplantation) to treat elderly acute leukemia. Although abundant allogeneic T cells was infused, the risk of severe GVHD did not increase. Based on this, we utilized non-gene-edited allo-CART combining microtransplantation to treat r/r B-ALL. Remission rate was significantly improved, and long-term existence of CART and donor chimerism was detected. However, the immunological evolution pattern and anti-leukemic mechanism are unknown. We aim to utilize the humanized CD19+ leukemia mouse model, and co-infuse with donor-derived CART and hematopoietic stem cells, to elucidate immunological evolution pattern and impact on leukemic cells of allo-CART in the context of varied donor chimeric status. We also carry out clinical research to explore the influence of allo-CART survival and expansion, chimeric status and cytokine changes on minimal residual leukemia, patient survival and relapse. We believe our research will bring an alternative strategy for r/r B-ALL.