A Clinical Study Of Fourth-generation CD19-CAR T-cells In The Threapy Of Relapsed/Refractory Adult Acute B Lymphocytic Leukemia

Background:Under traditional standard treatment,the 5-year survival rate of adult B-ALL patients is 30%-40%.Disease relapse and chemotherapy tolerance are key factors affecting its prognosis.There is currently no standard salvage treatment for relapsed/refractory adult B-ALL.Chimeric antigen receptor(CAR)targeting CD 19 T-cell therapy has been reported to induce high response rate in patients with relapsed/refractory B-cell acute lymphoblastic leukaemia(B-ALL).However,the CAR T-cell manufacturing process is time consuming and expensive,and most of the existing CAR T clinical studies have ex vivo culture time of 9-14 days.Up to 18.5%of patients cannot receive CAR T-cells infusion because of tumor progression before infusion or insufficient dose of cultured CAR T-cells,which is a threshold for promoting the widespread application.Additionally,severe adverse reactions including cytokine release syndrome(CRS)and CAR T-cell-related encephalopathy syndrome(CRES),were significant challenges to executing this strategy.Preclinical studies recently demonstrated that reducing ex vivo culture of CAR T-cell also exhibited potent anti-leukaemia effects.However,clinical data is lacking.Therefore,our center intends to explore the clinical feasibility of the fourth-generation CAR T-cells to treat relapsed/refractory adult B-ALL patients.Methods:We conducted a clinical trial using the fourth-generation CAR T cells with intracellular signaling components of CD28/CD27/CD3z-iCasp9 to explore the safety and feasibility of fourth-generation CAR T-cell in adult patients with relapsed/refractory B-cell ALL.In addition,we also conducted a statistical analysis of related factors that may affect its safety and efficacy.Results:Reducing ex vivo culture of fourth-generation CAR T-cell resulted in a limited differentiation,with a higher percentage of native and central memory CAR T-cell.From May 23,2016 to February 15 2021,33 relapsed/refractory adult B-ALL enrolled patients all successfully received CD 19-CAR T cell infusion.Under a median CAR T-cell dose of 1 × 106/kg,the objective response rate was 94%,and 85%of patients obtained minimal residual disease(MRD)-negative complete remission(CR).Patients with lower disease burden have more opportunity to achieve MRD-negative remission.In the clinical trial,a total of 19 patients(58%)experienced CRS and 2 patients(6%)developed CRES.Patients with higher than 1×106/kg of CAR T-cell infusion had a higher incidence of CRS than patients infused with lower doses.Serious adverse reactions occurred in 2 patients,one with grade 3 CRS combined with grade 1 CRES,and 1 case with grade 3 CRES combined with grade 1 CRS,but they were all reversed after tocilizumab and dexamethasone therapy.As of the last follow-up time,the patient’s median follow-up time was 859 days,the median OS was 384 days,and the median DFS was 257 days.Conclusions:Our clinical study showed that the fourth-generation CAR T-cell is a promising therapy strategy,which maintaining low toxicity while remains potent anti-leukaemia efficacy in vivo.