A Feasibility and Safety Study of CD19 and CD22 Chimeric Antigen Receptors-Modified T Cell Cocktail for Therapy of B Cell Acute Lymphoblastic Leukemia

摘要: Introduction: Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has recently demonstrated high success but also shown limitations regarding their toxicity and development of CD19negative variants. Here we reported results from a phase I study designed to determine the safety CAR-T CD22 cocktail feasibility making enough quantities treat patients with CD19+CD22+ relapsed/refractory B acute lymphoblastic leukemia (B-ALL). Patients Methods: From July 2017 2018, total 15 B-ALL were treated, including 5 children 10 adults (Table 1). All received fludarabine 30mg/m2/d´3d cyclophosphamide 250mg/m2/d´2d before infusion cells, followed by median number 2 (0.9-5)´105 CAR+ cells/kg 0.5 (0.4-12)´105 cells/kg. The lentiviral backbone containing constructs CAR are in Figure 1. includes truncated EGFR sequence which can be used identify select cells. single chain variable fragment (ScFv) derived monoclonal antibody against human PD-L1 attempts reduce exhaustion cells blocking PD-1/PD-L1. Real-time quantitative PCR using primers specificity for ScFv detect vivo persistence either CAR. Sequential transduction was performed days after activation sorted stimulated CD3 CD28 antibodies. Percentages determined flow cytometry through staining an fusion protein CD22-Fc, respectively, expression anti-PDL1 intracellular PD-L1-Fc protein. primary end points this evaluate toxicity, secondary included disease response persistent engraftment infused cell. Results: observation period 133 (24-392 days). percentage pre-treatment bone marrow blasts 21.5%(0.11-74.1%). On day 20-30 infusion, 15/15 (100%) cases achieved complete remission (CR) or incomplete CR(CRi), 14/15 (93.3%) had negative minimal residual (MRD). Patient P098 (0.58%) BM at 30 post-infusion thereafter MRD re-infusion 11/17 bridged into allo-HSCT have remained state follow up (97-214) days. 2/5 without bridging relapsed on 240 105 post-infusion, respectively. Notably, both Despite achievement very CR rate, low treatment-related observed trial. Only 1 experienced grade 3 cytokine release syndrome (CRS) another patient (6.7%) developed central nervous system (CNS) toxicity; all other CRS Conclusion: This demonstrates technical feasibility, efficacy toxicities treating B-ALL. Both CD19+ suggests treatment may risk relapse. Low relate small CAR-T, involvement is co-expressed construct cannot excluded. Therefore, related mechanisms currently being investigated lab. Disclosures No relevant conflicts interest declare.