Novel anti-glioblastoma therapeutic vaccines based on optimal stimulation of tumor specific CD4+ T helper cells

Glioblastoma (GBM) is the most malignant tumor of the central nervous system. Current treatments based on surgery, chemotherapy, and radiotherapy, and more recently on immunological approaches, unfortunately produce dismal outcomes, and less than 2% of patients survive aver 5 years. Thus, there is an urgent need for new therapeutic strategies. The immune response against tumor starts with the cell-to-cell contact between professional antigen presenting cells (APC), and CD4+ T helper cells (TH). This is mainly attributable to the interaction between the T cell receptor (TCR), present on TH and the tumor-associated antigens (TAAs), expressed on MHC-II surface of APC. Considering the importance of TH cell activation in the adaptive immune response against tumor, in our laboratory has undertaken, an approach whereby tumor cells are genetically modified to express MHC-II molecules acting as surrogate APCs for self-antigen presentation. This is possible through the transfection in tumor cells of CIITA, the major controller of MHC-II gene expression. The efficacy of the CIITA-based vaccination strategy has been firstly demonstrated using the GL261 murine GBM model. Mice injected with GL261-CIITA cells exhibited tumor rejection, prolonged survival, and long-lasting protection against tumor challenges because of effective immune cell infiltration in the brain. These results indicated not only the acquisition of anti-tumor immune memory but also the capacity of immune T cells to migrate within the brain, overcoming the blood–brain barrier. The efficacy of this approach was confirmed through Overall Survival (OS) study and in vitro neurospheres model. The study also extended its findings to the CT-2A cell line, a versatile GBM murine model more similar to human GBM. Results confirmed the generality of the anti-tumor protection induced by CIITA-transfection. More significantly, upon challenge with CT-2A cells, animals vaccinated with GL261-CIITA displayed effective tumor rejection. These findings established for the first time the existence of shared immunogenic antigens between two distinct GBM cell lines, amenable to an identification by immunopeptidomics. Furthermore, the study explored the potential of oncolytic Herpes Simplex virus-1 (oHSV-1) in reducing tumor growth and inducing anti-tumor immune responses. Results from the GL261 GBM model indicated significant survival prolongation and complete tumor rejection upon oHSV-1 treatment, suggesting the liberation of immunogenic tumor antigens and subsequent activation of tumor-specific T cells. Overall, the research highlights promising avenues for GBM immunotherapy, including CIITA-based vaccination strategies and oHSV-1 treatment, which warrant further investigation into their underlying mechanisms and clinical applications. These findings offer hope for improved therapeutic outcomes in GBM patients.