MEDB-56. POx NPs mediated delivery of (TLR7/8) agonist resiquimod improves treatment outcomes in SHH medulloblastoma by targeting tumor associated macrophages

Abstract

Cancer immunotherapy, the utilization of the patients’ own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. Recent clinical data has demonstrated immunotherapy to be effective in a wide range of cancers, including lung, bladder, renal cell, colorectal, gastro-esophageal, and head and neck cancers5-11. However, clinical reports of immune-based treatments for medulloblastomas are scarce and preliminary. Therefore, there is a need in developing strategies to improve medulloblastoma immunotherapy. Our recent studies have confirmed that SHH medulloblastomas are enriched in Tumor Associated Macrophages (TAMs) and unlike other tumors, TAMs are associated with positive outcomes and play a positive role by impairing tumor growth. Overall, analysis of TME in medulloblastomas reveals TAMs as a potential therapeutic target. Resiquimod is a synthetic small molecule agonist of Toll-like receptors 7 and 8 (TLR7/8) that modulates innate immune cells. We have loaded resiquimod into ultra-high-capacity polyoxazoline (POx) block copolymers forming small, homogeneous nanoparticles (POx-resiquimod). Our recent study shows that loading into POx nanoparticles improves drug delivery to tumors and treatment with 3 injections of POx-res as the single-agent treatment results in a profound anti-tumor effect G-Smo mice while treatment with free drug shows no therapeutic benefit. Our data also shows that that the tumors of G-Smo mice are enriched with the mixed populations of anti-inflammatory and pro-inflammatory macrophages and the treatment with POx-resiquimod have enhanced infiltration of macrophages into the tumors, enhanced the repolarization of macrophages to M1 subtype and decreased tumor cells viability. These studies show for the first time that targeting the medulloblastoma TME with POx-resiquimod can produce a significant anti-tumor effect. Furthermore, combination of POx-resiquimod with radiation resulted in long term survivals, showing potential therapeutic combination. The expression of TLR7/8 on TAMs in patient-derived medulloblastoma samples suggests that resiquimod may produce similar anti-medulloblastoma effects in humans.