Chimeric Antigen Receptor Modified T Cells For B-cell Acute Lymphoblastic Leukemia:Basic And Clinical Study

Background:The engineering of T lymphocytes to express chimeric antigen receptors (CARs) aims to establish T cell-mediated tumor immunity rapidly. In this study, we report the findings from the first nine relapsed or chemotherapy-refractory B-cell lineage acute lymphocytic leukemia (B-ALL) adult patients we have enrolled for treatment with autologous or donor-derived T cells genetically modified to express a CAR targeting the B-cell antigen CD 19 harboring 4-1BB and the CD3zeta moiety. Method:We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CART-19) lentiviral vector in patients with relapsed or refractory ALL at doses of 3×106 to 12.7×106 CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CART-19 T cells. Results:Of the nine patients, six had definite extramedullary involvement. One of the two patients who received conditioning chemotherapy achieved a three-month durable complete response with partial regression of extramedullary lesions. Four of 7 patients who did not receive conditioning chemotherapy achieved dramatic regression or a mixed response in the hematopoietic system and extramedullary tissues for two- to nine-months. Grade 2-3 graft-versus-host disease (GVHD) was observed in two patients who received substantial donor-derived anti-CD 19 CART cells three to four weeks after cell infusions. Conclusions:These results show for the first time that donor-derived anti-CD 19 CART cells can cause GVHD and regression of extramedullary B-ALL. CART-19 cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur...