11. Michelle Hess, PhD

Glioblastoma multiforme (GBM) is an aggressive and incurable brain cancer with a median survival rate of less than 1.5 years. Although immune-harnessing therapies have achieved durable responses in many solid tumors, GBM has thus far proven refractory. Indeed, GBM poses several challenges for successful immunotherapy, including poor T cell infiltration, low antigenicity, and deficient anti-tumor T cell activation. To overcome these barriers we have: 1) Bioengineered a novel nanoparticle-based vaccine platform to increase the priming, activation, and effector differentiation of GBM-specific T cells, and 2) Identified that the Nectin family checkpoints PVRIG and TIGIT are more widely expressed on T cells than CTLA4 and PD1 in GBM through analysis of human data. Our novel nanoparticle vaccine is composed of oxidized phospholipid PGPC and DOPS liposomes encapsulating immune adjuvant LPS and the model antigen SIINFEKL. We found that PGPC liposomes enhance dendritic cell (DC) activation and antigen presentation in vitro compared to inert liposomes composed of DOPC and DOPS . In vivo, PGPC liposome vaccination of mice bearing orthotopic SB28-ova GBM increased survival compared to no treatment. Additionally, we found that PVRIG-deficient mice bearing orthotopic SB28 GBM exhibited enhanced survival, supporting the relevance of Nectin family checkpoints in suppressing immunity against GBM. As the PVRIG and TIGIT ligands, CD112 and CD155 are expressed on human and murine GBM tumor cells, we genetically engineered SB28 cells lacking CD155 expression and observed a trend towards increased survival in mice bearing CD155KO compared to WT SB28 cells. Finally, we performed neoantigen discovery in SB28 and identified several candidate neoantigens with validated immunogenicity. These antigens can now be incorporated into our PGPC liposomes for the generation of neoantigen vaccines. This work establishes a novel nanoparticle cancer vaccine platform and the relevance of the understudied Nectin pathway as new therapeutic alternatives for harnessing immunity in GBM.