IMMU-62. INVIGORATING EFFECTOR IMMUNE CELLS WITH HIGHLY SELECTIVE IL-2R AGONISTS AND POTENTIAL SYNERGY WITH TUMOR TARGETING THERAPEUTICS FOR TREATMENT OF GLIOBLASTOMAS

Abstract Glioblastoma (GBM) is an aggressive brain tumor with a median overall survival (mOS) of 14 months. Treatment options are limited with no new approved therapies over the past 3 decades and no standard of care for a majority of patients (> 90%) who experience recurrence. GBM has a highly immune suppressive tumor microenvironment (TME) comprising of myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) that are capable of suppressing the activity of anti-cancer CD8+ T and NK cells. We have engineered highly selective IL-2 superkines (IL-2SK) that preferentially expand and activate CD8+ T and NK cells with limited effects on immune suppressive regulatory T cells (i.e., Tregs). MDNA11 is an IL-2SK -albumin fusion protein designed to increase half-life and promote tumor accumulation. MDNA223 is a bi-functional anti-PD1-IL-2SK designed to stimulate effector immune cells while preventing immune exhaustion. MDNA11 and MDNA223 extended survival of mice harboring orthotopic GBM tumors with accompanying increase in CD8+ T and NK cells within the TME. When patient-derived GBM tumor explants were treated with MDNA11 and MDNA223 ex vivo, there was clear evidence of activation among resident CD8+ T cells characterized by increased levels of intra-cellular Granzyme B responsible for tumor cell killing. There was also increased release of soluble Fas ligand and granulysin, consistent with an activated anti-tumor immune response within the TME. Ongoing studies include in depth immune profiling to further understand the mechanism of MDNA11 and MDNA223 in GBM as well as to test potential synergy with tumor targeting therapeutics and other treatment modalities capable of eliciting immunogenic cell death.