Glioblastoma immunotherapy through re-activation of virus-specific memory T cells
Introduction: The immune-suppressive glioblastoma microenvironment remains a major challenge in therapeutic development.
Objective: We explore reactivation of virus-specific memory T cell as a strategy to overcome this therapeutic challenge.
Methods: Standard laboratory techniques
Results: Viral infections are a fact of life for the typical human experience. After an initial anti-viral response, the host retains anti-viral memory CD8+ T cells that are located throughout the body and persistently survey for the presence of viral peptides indicative of re-infection. Upon encounter of the peptides that they were primed against, these memory T-cells induce killing of the cells harboring these peptides and promote potent local immune activation. These responses occurs within hours of viral peptide exposure.
Here, we show that virus-specific memory T cells extend their surveillance to mouse and human glioblastomas. Intra-tumoral injection of viral peptide into glioblastomas mimics viral reinfection event to anti-viral memory CD8-T cells, resulting in the recruitment of these T-cells into the tumor microenvironment. The viral peptides further re-activate the recruited antiviral T-cells, potently inducing activation of both innate and adaptive immune system against the tumor, arrest tumor growth, and synergize with PD-LA checkpoint blockage to eliminate glioblastomas that are otherwise refractory to chemotherapy and ionizing radiation. Anti-viral memory T cells are detected in freshly resected human glioblastoma specimens. Moreover, immune activation was observed in these specimens treated ex vivo with viral-derived peptides.
Conclusions: Our results suggest that pre-existing viral immunity can be repurposed as a anti-glioblastoma immunotherapy. Efforts are underway for a “first-in-man” trial as proof-of-principle for this therapeutic paradigm.