A phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia

Abstract

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.

Graphical abstract

Figure 1.

Clinical Outcomes. (A) Swimmer plot for patients who received CAR19-22 and NKTR-255; 3 patients received NKTR-255 dose-level 1 (1.5 μg/kg, green), 4 patients received dose-level 2 (3.0 μg/kg, orange), and 2 patients received dose-level 3 (6.0 μg/kg, blue). Circles represent doses of NKTR-255, squares represent allogeneic stem cell transplant, and X’s represent relapse. (B) PFS for patients who received NKTR-255 (n = 9) with events as death or relapse and without censoring for allogeneic HCT. (C) PFS considering allogeneic HCT as censoring event.

Figure 2.

Cytokine profiling. (A) IL15 during the first month after CAR19-22 infusion. Shown are medians and interquartile ranges for MFIs of IL15 for control patients (red) and those treated with NKTR-255 (blue). NKTR-255 administration is denoted by the red dashed line. The number of observations at each time point is shown below the graph. “PLD” indicates time points before lymphodepleting chemotherapy. Control patients did not have samples at day +15 or +16 available for analysis. Cytokine levels before and after NKTR-255 administration for patients with both samples available for analysis. (B) Comparison of day +14 preinfusion with postinfusion values (n = 8); (C) comparison day +14 preinfusion with day +15 values (n = 6). P values were calculated with the paired Mann-Whitney U test. Cytokines were grouped according to common γ-chain cytokines (top), interferon-γ–related (middle), and proinflammatory cytokines (bottom).

Figure 3.

CAR19-22 expansion and persistence. Shown are CAR19-22 levels (medians with interquartile ranges) in the peripheral blood in the first month after CAR infusion as measured by (A) quantitative PCR and (B) CARFACS. NKTR-255 administration is denoted by the red dashed line. The number of observations at each time point is shown below the graph. (C) CD4 and (D) CD8 CAR subsets assessed by CARFACS. (E) CD4:CD8 CAR⁺ ratio during the first month after CAR19-22. (F) ALC (circles) and total CD3⁺ T cells by CARFACS (triangles).

Figure 4.

CAR trafficking. CAR dynamics for patients with CNS leukemia. Shown are (A) peripheral blood ALC, (B) CD8⁺ CAR-Ts, and (C) CSF absolute white blood cell count (WBC; circles) and CAR19-22⁺ cells (triangles) for patients treated with NKTR-255 with CNS disease (n = 2). (D) WBC count (circles) and CAR⁺ cells in the CSF on day +28 evaluated by flow cytometry for the same patients treated with NKTR-255 (blue, n = 2) and the historical control patient with evaluable CSF (red, n = 1).