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

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