IMMU-34. NL-201, A DE NOVO ENGINEERED IL2 MIMETIC, SYNERGIZES WITH RADIOTHERAPY TO GENERATE POTENT ANTITUMOR ACTIVITY IN PRECLINICAL GLIOBLASTOMA MODELS

Combining radiotherapy (RT), a standard of care treatment for many cancer types, with immunotherapeutic agents has been gaining interest due to improved efficacy. One such approach is RT in combination with high-dose recombinant interleukin 2 (IL-2), which elicits anti-tumor immune responses by stimulating T-cell and NK cell populations. Although effective for some patients, the overall clinical benefit of recombinant IL-2 is limited by toxicity at high doses and the expansion of regulatory T cells (Tregs) at low doses, effects thought to be mediated by preferential binding to IL2Rα (i.e. CD25). In this study we examined RT in combination with NL-201, a highly potent and stable CD25-independent IL-2/IL-15 agonist with enhanced affinity for the IL-2Rβγ heterodimeric receptor. Single-agent NL-201 was well tolerated in mice, yielded tumoricidal activity, expanded peripheral T cells, and enhanced the infiltration of effector T cells and dendritic cells (DCs) into murine glioblastoma (GL261 and SB28). In combination with RT, NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, resulting in increased type I interferon (IFN) production in DCs and, consequently, greater tumor infiltration by T cells and more efficient priming of antigen-specific T cells by professional antigen presenting cells (APCs). The immune stimulatory mechanisms triggered by the NL-201 and RT combination resulted in superior tumor growth inhibition. We demonstrated that the CD25-independent IL-2 and IL-15 receptor agonist, NL-201, in combination with RT is well-tolerated and elicits robust anti-tumor activity through both innate and adaptive responses, including in checkpoint resistant tumors. Furthermore, we identify a unique mechanism in which NL-201 synergizes with RT. Taken together, the results provided herein support further preclinical and clinical investigation of this novel combination regimen.