The development of an effective vaccine against human cancers is of tremendous importance. Glioblastoma multiforme (GBM) is the most malignant form of brain tumor with extremely poor survival. The human cytomegalovirus (HCMV) is involved in GBM pathogenesis suggesting that viral proteins might provide therapeutic targets. We propose a vaccination strategy against GBM based on a genetically modified HCMV that could target HCMV, as well as tumor specific antigens. The proposal builds on the successful implementation of the ERC-AdG StAdvInn, which investigates a murine cytomegalovirus (MCMV) expressing the NKG2D ligand RAE-1γ (RAE-1γMCMV), which has tremendous potential for strengthening the CD8 T cell response to a vectored antigen (Trsan et al, PNAS 2013). We have shown the strong potential of such vector to act as a CD8 T cell-based vaccine against malignant tumors (Trsan et al, Eur J Immunol 2017). Moreover, the efficiency of this vector can be enhanced by blocking immune checkpoints. We have constructed HCMV expressing the human NKG2D ligand ULBP2 (HCMV/ULBP2) and confirmed its efficacy in vitro and in humanized mice (Tomic et al, PLoS Pathog 2016). Here we propose to determine the capacity of the HCMV/ULBP2 vector in the immune control of GBM. In short, immune cells from GBM patients will be transferred to NSG mice that will be grafted with GBM from the same patients. Mice will be vaccinated with HCMV/ULBP2 vector expressing GBM associated neoantigens. Based on results with the RAE-1γMCMV in the melanoma model and with HCMV/ULBP2 in NSG humanized mice, we expect a strong effector CD8 T cell response to be generated in these mice resulting in the control of tumor in the NSG host. The proposed project activities include: development and validity testing of the prototype of the integrated vaccine vector, implementation of IPR protection and exploitation strategy. The results of this project will be used to establish the first in man trial in GBM bearing patients.
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