A PEG-conjugated IL-15R agonist (NKTR-255) was combined with CD19/22 CAR T therapy in 9 adults with r/r B-ALL and was well tolerated, although grade 3/4 neutropenia occurred in 2/2 patients at the highest dose. 89% of the patients achieved MRD-negativity, and 12-month PFS was 67%, compared to 38% in a historical CD19/22 CAR T cohort. IFNγ, IL-10, IL-6, and chemokines (CXCL9/10) were elevated. While both CAR T and total lymphocyte counts declined in the periphery following NKTR-255 infusion, CAR T levels in cerebrospinal fluid increased 10-fold in patients with CNS disease, indicative of tissue trafficking.
Contributed by Morgan Janes
ABSTRACT: While chimeric antigen receptor 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, nine 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 eight out of nine 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 blood and ten-fold increases in CSF 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 (NCT03233854).
Author Info: (1) Stanford University, Stanford, California, United States. (2) UT Southwestern, Dallas, Texas, United States. (3) Stanford University, Stanford, California, United States. (4) S
Author Info: (1) Stanford University, Stanford, California, United States. (2) UT Southwestern, Dallas, Texas, United States. (3) Stanford University, Stanford, California, United States. (4) Stanford University, Stanford, California, United States. (5) Stanford University, Stanford, California, United States. (6) Stanford University School of Medicine, Palo Alto, California, United States. (7) Stanford University School of Medicine, Palo Alto, California, United States. (8) Stanford Unviersity, Hacienda Heights, California, United States. (9) Center for Cell Therapy, Stanford, California, United States. (10) Center for Cell Therapy, Stanford, California, United States. (11) Stanford University School of Medicine, Stanford, California, United States. (12) Stanford University, Stanford, California, United States. (13) Stanford University, Stanford, California, United States. (14) Stanford University, Palo Alto, California, United States. (15) Stanford University School of Medicine, Palo Alto, California, United States. (16) Stanford University, Stanford, California, United States. (17) Stanford University, Palo Alto, California, United States. (18) Stanford University, Stanford, California, United States. (19) Stanford University. (20) Stanford University, Stanford, California, United States. (21) Stanford University School of Medicine, Stanford (CA), Stanford, California, United States. (22) Stanford University School of Medicine, Palo Alto, California, United States. (23) Stanford University Medical Center, Stanford, California, United States. (24) Stanford University, Stanford, California, United States. (25) Stanford University, Palo Alto, California, United States. (26) Stanford University Medical Center, Stanford, California, United States. (27) Stanford University, Stanford, California, United States. (28) Stanford University School of Medicine, Palo Alto, California, United States. (29) Stanford School of Medicine, Palo Alto, California, United States. (30) Stanford University, Stanford, California, United States. (31) Nektar Therapeutics, San Francisco, California, United States. (32) Nektar Therapeutics, San Francisco, California, United States. (33) Nektar Therapeutics, San Francisco, California, United States. (34) Stanford University Medical School, Stanford, California, United States. (35) Stanford University, Stanford, California, United States. (36) Stanford University, Stanford, California, United States.
