Anti-CD19/CD22 CAR-T(Stanford University)

Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease–negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854.