Decoding the Mechanisms Behind Durable Immunotherapy Responses in Glioblastoma

About This Grant

Project Summary Despite glioblastoma's reputation as an "immunologically cold" tumor, some glioblastoma patients who received autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccine have shown remarkable tumor control. While standard of care yields a 5.7% five-year survival rate, the rate for those treated with ATL-DC rises to 13%. In the subset of patients whose tumor exhibit hypermethylation of the MGMT gene, the fraction of patients surviving past 5-year mark nearly doubles to 25%, with their median survival extended from 21 to 33 months after ATLDC therapy. Our team hypothesizes that these long-term survivors harbor more antigen specific, progenitor-exhausted TCF7+ PD1+ CD8 T cells in their tumors. These specialized T cells, maintaining their stemness phenotype, persist longer in the tumor microenvironment and kill more tumor cells throughout their lifetime. We further posit that these CD8 T cells are supported by a T-cell-supportive microenvironment, which is marked by reduced levels of immunosuppressive macrophages commonly found in the brain microenvironment. We propose utilizing spatial transcriptomics and high-plex immunofluorescence to map the immune architecture within tumors from these exceptional responders, comparing them to short-term survivors. In parallel, we will analyze the blood samples of the long-term responders to track systemic immune activation and T cell repertoire dynamics, using single cell sequencing to characterize clonally expanded T cells. Finally, we plan to use two different murine models of glioblastoma, one with a more immune rich tumor microenvironment and one with an immunosuppressive microenvironment, to test any nominated mechanisms from our omics analysis. The use of murine glioblastoma models is necessary to observe the effects of ATL-DC therapy not only in the tumor microenvironment but also in the systemic immunity. Immune system level changes in response to a cellular vaccine therapy such as ATL-DC have not been modeled previously using in vitro models. Through this comprehensive approach, our team aims to uncover the mechanisms behind durable antitumor responses after ATL-DC-based immunotherapy in glioblastoma. If successful, our findings could guide new strategies to extend these benefits more broadly, potentially transforming outcomes for a disease that typically claims lives within two years of its diagnosis.