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New approach to active immunotherapy of Hepatitis C related cancer (LIVE®VAC)

Project/agreement No.
lzp-2018/2-0308
Project funding
200 000.00 EUR
Project manager
Maria Issagouliantis
Project realization
01.12.2018. - 01.12.2020.

Aim

Project goal is to develop a prototype active immunotherapy to complement directly acting antiviral drugs in treatment of chronic hepatitis C, which would target and eliminate HCV-infected cells, specifically malignant (transformed) hepatocytes and lymphocytes. The immunotherapy will be based on a conserved HCV antigen nucleocapsid (Core) protein and tumor-associated antigen involved in the early events in hepatocarcinogenesis, human telomerase reverse transcriptase, presented by synthetic genes (HCV/TERT-DNA).

Description

Hepatitis C virus causes hepatocellular carcinomas/HCC and triggers Non-Hodgkin´s B-cell lymphomas/NHL affecting millions of people and presenting a devastating burden to health-care systems all over the world. Directly acting antiviral drugs cure HCV infection, but cannot reliably cure liver cancer, or lymphoid malignancies. Besides, they induce resistance, which would eventually limit their use. Recent clinical trials demonstrated possibility of active cancer immunotherapy. We will develop such therapy against HCC and NHL based on plasmid DNA. DNA-vaccine will target HCV core, and early tumor-associated antigen human telomerase reverse transcriptase/TERT. DNA-vaccine will be reinforced by Toll-Like Receptor 7/8 ligand and check-point inhibitors as PD-1/PD-L1. Their combination will be introduced intratumorally to enhance efficacy and reduce off-side toxicities. Combination will be tested for immunogenicity in two mouse strains. Effector response will be evaluated in the murine models of human cancer responsive and refractory to immunotherapy. Proof of concept will be to demonstrate the capacity of immune response to lyse HCV-, TERT- and HCV/TERT-expressing tumor cells, protect mice from tumor challenge and/or cure animals from HCV/TERT-(co)expressing tumors and their metastases. Project will integrate basic research with R&D of a prototype immunotherapeutical. This novel approach has direct relevance to immunotherapy of cancer caused by other tumorigenic human viruses.