The cancer vaccine activates tumor-specific T cells by providing immunogenicity in tumors with low immunogenicity. Conferring to immunogenicity to cancer using personalized neoantigens has limitation in application to large number of patients because of the inter-/intra-tumor heterogeneity. To overcome these limitations, I am intended to convert cancer cells into targets of virus-specific T cell by delivering virus-derived antigens commonly infected to many people.
To this end, viral antigen containing T cell epitope was fused to tumor-specific cytosol penetrating cytotransmab to deliver antigen to cytosol of tumor cells. I selected the cytomegalovirus (CMV) that infected with a population of 60-80% worldwide, and the 495-503 sequence of the CMV pp65 antigen is the highly immunogenic epitope which binds to HLA-A*02:01 subtype of MHC-I. To efficiently produce peptide/MHC-I complex on the cell surface, I constructed various format: only T cell epitope, N-terminally extended, C-terminally extended and both extended fragments-fused cytotransmabs.
Because N-terminally-extended fragment of the T cell epitope fused cytotransmab showed cell surface MHC-I binding, both terminally-extended fragment formed peptide/MHC-I only through intracellular processing in cytosol without no surface MHC-I binding ability.
I showed that CMV pp65-specific CD8 T cells isolated from healthy donors efficiently kill HLA-A*02:01 positive cancer cells, after the extracellular treatment with CMV pp65-derived T cell epitope fragment-fused cytotransmab.
Lastly, since the CMV pp65-derived T cell epitope fragment-fused cytotransmab located in the cytosol is degraded by proteasome to generate T cell epitope precursor, I confirmed that the activity of CMV pp65-specific CD8 T cells is reduced through proteasome inhibitor treatment.
These data demonstrate the viral antigen-derived T cell epitope-fused cytotransmab can be used to treat cancer with reduced immunogenicity as a new cancer vaccine platform. In addition, by fusing other viral antigen which infected in many people besides CMV to cytotransmab will be provide the possibility of expanding the technology.
