Bone marrow-derived engineered myeloid cells enhance the trafficking and activation of cytotoxic t cells in the glioma microenvironment.

Abstract INTRODUCTION Gliomas are the most prevalent type of brain tumors in the adolescent and young adult population (AYA) and one of the leading causes of cancer- related death. Two-third of glioma AYA patients are affected by low-grade gliomas (LGGs), but yet there are no specific treatments. Therefore, a significant percentage of LGG patients experience tumor recurrence and malignant progression to high-grade glioma (HGG) and the immune microenvironment plays a critical role in mediating mechanisms of tumor progression and treatment resistance. Specifically, tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been shown to restrict cytotoxic effector trafficking and activation. To that end, first-line immunotherapies have limited efficacy in improving outcomes for HGGs. HYPOTHESIS We investigated the preclinical efficacy of a novel immunotherapeutic approach for the treatment of LGGs in AYA mice to modulate and reprogram the immunosuppressive tumor microenvironment (TME) and enhance the trafficking of activated effector T cells. METHODS Immunocompetent RCAS n/tv-a LGG bearing animals were treated at day 28 with a single retroorbital dose of bone-marrow derived myeloid cells, engineered for the release of Interlekin-2 (GEMys-IL2). The treatment was well tolerated and no sign of toxicity was noted. RESULTS Our results demonstrated that GEMys-IL2 efficiently crossed the BBB, infiltrate the glioma microenvironment, and activate infiltrating immune cells while altering the TME underscored by an increased CD8+ T cell population. Of note, the RCAS/t-va immunocompetent LGG to HGG progression mouse model treated with a single dose of GEMys-IL2 demonstrated a transient arrest of tumor burden within 14 days post treatment, which was associated with a significant advantage in overall survival. CONCLUSIONS These results highlight the pre-clinical efficacy and anti-tumoral therapeutic activity of GEMYys-IL2 on CD8+ T cell trafficking and activation to the TME in low-grade glioma in vivo, thus supporting its potential as a novel cell-mediated innate immunotherapy.