NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control

CAR-T cells have yet to show widespread efficacy in solid tumors due in part to their poor persistence and loss of function in the tumor microenvironment. Further, heterogenous expression of most CAR target antigens in solid tumors can lead to escape of antigen-null tumors that resist CAR-T killing. Strategies to cooperatively boost both CAR-T and endogenous anti-tumor immunity could curb tumor escape and may be critical for achieving durable efficacy in cancer patients. NKTR-255 is a polymer-conjugated IL-15 with extended half-life that can boost endogenous T and NK cells, as well as CD19 CAR-T activity in B cell malignancies. However, whether NKTR-255 is sufficient to overcome CAR-T dysfunction in the suppressive solid tumor microenvironment, and how NKTR-255 and CAR-Ts together re-shape endogenous anti-tumor immunity, is not known. Using an autochthonous mouse model of ROR1⁺ lung adenocarcinoma, we show that NKTR-255 significantly boosted accumulation, reduced exhaustion, and improved function of tumor-infiltrating CAR-T cells. Compared with NKTR-255 or CAR-T treatment alone, combination of NKTR-255 and CAR-T therapy synergistically increased tumor-infiltrating CD11b⁺ cytotoxic NK cells, activated dendritic cells, and endogenous tumor-specific T cells that preserved a PD-1⁺Tcf1⁺ stem-like phenotype. Consequently, NKTR-255 and CAR-T combination therapy induced complete elimination of ROR1⁺ tumor and significantly improved survival, with enhanced tumor control dependent on activity of both CAR-Ts and endogenous T cells. Altogether, our data suggest that combining NKTR-255 with CAR-T therapy is a promising strategy to enhance both CAR-T and endogenous anti-tumor immunity to promote coordinated control of aggressive tumors.