Safety And Efficacy Of CAR-T In The Treatment Of Relapsed Or Refractory B-cell Hematologic Malignant Tumors: An Open-label,uncontrolled,single-center Clinical Study

[Background]Hematologic malignant tumors originate from hematopoietic and lymphoid tissues,which can be further divided into myeloid,lymphoid and histiocytic / dendritic cells according to cell types.Most of lymphoid tumors originate from B cells.The highest clinical incidence is B-cell acute lymphoblastic leukemia(B-ALL)and diffuse large B-cell lymphoma(DLBCL).The long-term survival of B-cell acute lymphoblastic leukemia(B-ALL)treated with traditional chemotherapy is poor.With the advent of new immune drugs such as anti-CD19/CD3 bispecific antibody and anti-CD22 monoclonal antibody,the response rate and survival time of patients have been improved,but the curative effect is still not satisfactory.The median survival time of patients is only 7.7months.However,the long-term remission rate of patients with diffuse large B-cell lymphoma after chemotherapy with R-CHOP regimen was only 60-70%.Although the combination of ibutenib,programmed death receptor(PD-1)inhibitor and lenalidomide may improve the progression-free survival rate(PFS)of some patients,there are still some patients who are insensitive to chemotherapy or have the risk of recurrence after treatment.Therefore,how to improve the prognosis of patients with B-cell malignant hematologic tumors through new treatments and new strategies is a major challenge in clinical work.In recent years,chimeric antigen receptor modified T cell therapy(CAR-T)has achieved remarkable efficacy in the treatment of malignant tumors.Clinical studies have shown that the remission rates of CAR-T targeting CD19 for B-ALL and DLBCL,can reach 70% and 54% respectively.CAR-T treatment provides a new choice for refractory / recurrent hematologic malignant tumors,but patients with remission after CAR-T treatment face a higher recurrence rate.Therefore,the purpose of this study is to explore whether CAR-T combined with hematopoietic stem cell transplantation in the treatment of refractory / recurrent B cell hematologic malignant tumors can reduce the recurrence rate after CAR-T treatment,and provide reference for CAR-T combined with stem cell transplantation in the treatment of B hematologic malignant tumors.[Methods] 55 patients with refractory / recurrent B-cell hematologic malignant tumors treated in the department of hematology of our hospital from January 1,2014 to May 30,2019 were statistically analyzed,including 38 cases of B-ALL and 17 cases of DLBCL.Of the 55 patients,25 patients received CAR-T therapy and 30 patients received donor lymphocyte infusion(DLI).The study was divided into two parts:(1)For patients with recurrent B-ALL after allogeneic transplantation,this study used CAR modified donor lymphocyte infusion(CAR-DLI)to explore the efficacy and safety of CAR-T in the treatment of recurrent B-ALL after allogeneic transplantation by comparing with traditional DLI therapy.(2)For refractory / recurrent DLBCL patients,autologous hematopoietic stem cell transplantation sequential CART was used to explore the efficacy and safety of CAR-T combined with autologous hematopoietic stem cell transplantation.[Results] A total of 8 patients with recurrent B-ALL after allo-HSCT were treated with CAR-DLI,7 patients(87.5%)received CR,30 patients were treated with DLI,and 16 patients(53.3%)received CR.The in vivo survival and amplification analyse of CAR-DLI showed that CAR-T cells were significantly expanded within 20 days after reinfusion,and CAR-T cells could still be detected in 2 patients on the 50 th day after CAR-T transfusion.The median PFS of CAR-DLI group was significantly longer than that of DLI group,which was 16 months and 3.3 months,respectively.Moreover,the OS of CAR-DLI group was significantly longer than that of traditional DLI group(P=0.0099).In addition,there was no a GVHD in the CAR-DLI group while the incidence of a GVHD grades I–II and grades III–IV were 2(7%)and 4(14.8%)in the DLI group,respectively.After CAR-DLI infusion,all patients developed CRS,but the symptoms were controllable.A total of 17 patients with relapsed refractory DLBCL received sequential CART after autologous hematopoietic stem cell transplantation.The in vivo survival and expansion analysis of CAR-T showed that CAR-T cells expanded within 15 days after reinfusion.CAR-T cells could still be detected in 1 patient on the 35 th day after CAR-T transfusion.The result of curative effect evaluation showed that the objective response rate of patients with recurrent / refractory lymphoma was 88.2%.Of these,10(58.8%)patients got CR,5(29.4%)and other patients got PR.During the follow-up,the mean PFS of DLBCL patients treated with CAR-DLI was 24.1 months.The mean OS of the patients receiving CAR-T treatment was 24.7 months.13 patients(76.5%)developed CRS,and improved immediately after symptomatic treatment.[Conclusion] CART treatment significantly improves the survival rate of patients with B hematologic malignant tumor,and the side effects such as CRS are relatively controllable.Compared with DLI,it may be a more effective scheme for the treatment of recurrent B-ALL,while autologous sequential CART therapy achieves an objective remission rate of 88.2%,which is beneficial to improve the long-term survival of patients.It is suggested that the combination of CART and stem cell transplantation is an important method for the treatment of recurrent refractory hematologic malignant tumors.