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ONCOLYTIC-HERPES - ONCOLYTIC HERPESVIRUSES RETARGETED TO CANCER- SPECIFIC RECEPTORS

3 - Good health and well-being; Research Projects; 2014; 2015; 2016; 2017; 2018; 2019; 2020

Cancer   remains a major health burden worldwide. The aggressive targeting of   metabolic pathways shared by normal and cancer cells results in prolonged   survival and cures, but at a tremendous cost to patient life quality. What is   missing is a therapeutic agent that clearly differentiates normal and cancer   cells. This proposal delineates a process for killing exclusively cancer   cells with no interference with normal cells. In the past two decades there   has been considerable effort to develop attenuated viruses for killing cancer   cells. Of the oncolytic viruses in clinical trials, attenuated herpes simplex   viruses (HSV) are among the most promising because of safety, affinity for   cancer cells, ability to treat patients multiple times without block by adaptive   immunity. The shortcoming is that they do not discriminate between normal and   cancer cells, are effective in a limited number of patients. The remarkable   accomplishment by my laboratory at the basis of the proposal is the genetic   engineering of HSVs that specifically infect and kill cancer cells and cannot   infect normal cells. The prototype retargeted HSV targets HER2, a receptor in   breast, ovary and other tumors. HER2-HSV ablates human breast and ovary   cancers, and glioblastoma after intratumoral or intraperitoneal   administration.
    
This proposal addresses basic research issues for the advancement of   retargeted oncolytic HSVs. It is organized in 5 AIMS:

  • Engineer a non-cancer cell line for virus production acceptable to Health Authorities   and re-engineer the retargeted-HSV accordingly. This will enable production   of clinical grade retargeted-HSVs for clinical tests (AIM1)
  • Engineer retargeted-HSVs suitable for systemic delivery and for boosting   anti-tumor immunity (AIM2-3)
  • Apply our platform to expand the repertoire of oncolytic HSVs that target   glioblastomas, prostate, head-and-neck, colon carcinomas (AIM4)
  • Determine the tumorigenic potential of cancer cells that escape killing by   retargeted HSVs (AIM5)
       

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