PS1208 EFFECTS OF NKTR‐255, A POLYMER CONJUGATED HUMAN IL‐15, ON EFFICACY OF CD19 CAR T CELL IMMUNOTHERAPY IN A PRECLINICAL LYMPHOMA MODEL

Background: Immunotherapy with CD19 CAR T cells achieves complete or partial remission in a fraction of patients with B cell malignancies, but disease progression remains common. IL‐15 promotes T cell proliferation and survival and may enhance CAR T cell efficacy. However, exploiting native IL‐15 is challenging due to its unfavorable pharmacokinetics and tolerability. In contrast, NKTR‐255 is a polymer‐conjugated IL‐15 that retains binding affinity to IL15Rα and exhibits reduced clearance, providing sustained pharmacodynamic responses. Aims: We investigated the effects of NKTR‐255 on human CD19 CAR T cells both in vitro and in an in vivo xenogeneic B cell lymphoma model. Methods: T cells expressing a CD19/4–1BB/CD3ζ CAR were generated from healthy donors. For in vitro studies, CAR T cells were incubated with NKTR‐255 (0–100 ng/mL) with and without CD19 antigen. STAT5 phosphorylation and CFSE dilution were assessed by flow cytometry. For in vivo studies, NSG mice received 5x10 5 Raji lymphoma cells IV on day (D)‐7 and a subtherapeutic dose (0.8x10 6 ) of CAR T cells (1:1 CD4:CD8) on D0. NKTR‐255 (0.03–0.3 mg/kg IV) was administered weekly starting on D‐1, 7, or 14. Tumor‐free mice were rechallenged with Raji cells. Tumors were assessed by bioluminescence imaging. Results: In vitro, NKTR‐255 led to dose‐dependent STAT5 phosphorylation and increased antigen‐dependent proliferation of CD8 CAR T cells. In vivo, infusion of NKTR‐255 starting at D‐1, 7 or 14 increased peak CAR T cell numbers in blood. Raji cells were eliminated from marrow by D14 in mice receiving CAR T cells and NKTR‐255 on D7, but not CAR T cells alone. There was superior NKTR‐255 dose‐dependent tumor control and survival in mice receiving CAR T cells with NKTR‐255 compared to CAR T cells or NKTR‐255 alone. The benefit of combination therapy with NKTR‐255 and CART T cells was greater when NKTR‐255 was started by D7. Residual CAR T cells in NKTR‐255‐treated mice rejected re‐challenge of Raji tumor cells administered beyond 5 weeks after CAR T cell infusion. Summary/Conclusion: NKTR‐255 administration improves the antitumor efficacy and kinetics of CD19 CAR T cells, supporting advancement into clinical trials of combination therapy with NKTR‐255 and approved CD19 CAR T cell products.