New Investigator Grant Awarded to Ernest Moles

Diffuse Midline Gliomas(DMGs) are highly aggressive and incurable pediatric brain tumors with <1-year overall survival. Radiotherapy remains the only treatment available for DMG, extending survival by only a few months. While immunotherapies like CAR-T cell therapy have shown transformative success in other cancers, they have yet to demonstrate meaningful survival benefits in DMGs. It is therefore imperative to advance new and more effective treatments against DMGs. Tumor-associated macrophages and microglia (TAMs) have come to the forefront of the cancer immunotherapy field due to their central role in regulating immune responses and eliminating tumor cells. In an anti-tumor state, TAMs engulf tumor cells, produce tumoricidal molecules and induce anti-tumor immune responses. However, in most solid tumors, TAMs remain immunosuppressive, resulting in a cold microenvironment that promotes tumor growth and inactivates the immune system; and this is particularly exacerbated in DMGs. Reprogramming TAMs from immunosuppressive into anti-tumoral represents a promising strategy to reconstitute anti-tumor immunity and drive tumor regression. PI Moles has developed an innovative approach using mRNA nanoparticles to re-educate the immune system to fight DMG. This is achieved through nanoparticle-driven expression of specialized tumor-targeting molecules in the immune cells, called Chimeric Antigen Receptors, which reprogram the immune cells to acquire anti-tumor functions and specifically attack the DMG cells. This project will explore the therapeutic value of our mRNA technology in reprogramming TAMs directly in the tumor microenvironment to combat DMG, offering a potentially more effective approach to restore anti-tumor immunity and suppress DMG growth. An additional Aim of this proposal will be to investigate the potential benefits of our approach in boosting the tumor infiltration and efficacy of CAR-T cell therapy. Our novel approach has the potential to change the treatment paradigm for DMG to ultimately improve outcomes and survival of patients. This project integrates a team of internationally recognized investigators who are experts in nanomedicine (Moles), DMG (Dun,Ziegler) and macrophage biology (Hampton, Pimanda), immunocompetent DMG models (Phoenix) and CAR-T cell therapy (Brown,Gargett). Our team provides a network of established scientific and clinical collaborative structures, being uniquely positioned to carry out this study and translate its findings.