A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR-T cell immunotherapy.

Chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapies targeting CD19 represent a new treatment for patients with relapsed/refractory (R/R) B-cell malignancies. However, CAR-T therapy fails to elicit durable responses in a significant fraction of patients. Limited in vivo proliferation and survival of infused CAR-T are key causes of failure. In a phase I/II clinical trial of CD19 CAR-T for B-cell malignancies (NCT01865617), low serum interleukin-15 (IL-15) concentration after CAR-T infusion was associated with inferior CAR-T kinetics. IL-15 supports T cell proliferation and survival, and therefore supplementation of IL-15 may enhance CAR-T therapy. However, clinical use of native IL-15 is challenging due to its unfavorable pharmacokinetics and toxicity. NKTR-255 is a polymer-conjugated IL-15 that engages the entire IL-15 receptor complex (IL-15R/IL-2Rβɣ) and exhibits reduced clearance, providing sustained pharmacodynamic responses. We investigated pharmacokinetics and immune cell pharmacodynamics in non-human primates treated with NKTR-255 and found that NKTR-255 enhanced in vivo proliferation of T and NK cells. In vitro, NKTR-255 induced dose-dependent proliferation and accumulation of human CD19 CAR-T, especially at low target cell abundance. In vivo studies in lymphoma-bearing immunodeficient mice demonstrated enhanced antitumor efficacy of human CD19 CAR-T. In contrast to mice treated with CAR-T alone, those that received CAR-T and NKTR-255 had markedly higher CAR-T counts in blood and marrow that were sustained after tumor clearance, without evidence of persistent proliferation or ongoing activation/exhaustion assessed by Ki-67 and inhibitory receptor co-expression. These data support an ongoing phase I clinical trial of combined CD19 CAR-T and NKTR-255 for R/R B-cell malignancies. This trial is registered at www.clinicaltrials.gov as NCT01865617.