Virus targeted therapeutic for EBV Associated Malignancies

DESCRIPTION provided by applicant Epstein Barr virus EBV is associated with a number of human malignancies and likely plays a causal role in two endemic tumors African Burkitt lymphoma BL and nasopharyngeal carcinoma NPC Clonal EBV can be found in Burkittandapos s lymphomas T NK lymphomas and post transplant lymphoproliferative disorders LPD as well as some T and B cell lymphomas and half of Hodgkinandapos s lymphomas In addition EBV may be involved in the development of other neoplasias including AIDS related sarcomas and gastric carcinomas and certain breast carcinomas However we have demonstrated that merely the very presence of the virus in a tumor provides the opportunity for a targeted therapeutic strategy EBV persists in these tumors in a dormant or andquot latentandquot state Many Herpes family virus infected cells can be killed by nucleoside analog antiviral pro drugs like ganciclovir which targe the viral thymidine kinase TK enzyme EBV is resistant to these antiviral agents because latently infected tumor cells do not express the viral TK enzyme We have demonstrated that selected agents which induce the EBV TK gene expression in the tumor cells renders the tumor susceptible to standard anti viral agents This is a tumor targeted therapy in that only the tumor cells containing EBV are killed normal cells are spared We have conducted a successful Phase I II study of this virus targeted therapeutic approach in patients with EBV associated lymphoid malignancies all of which were resistant to conventional radiation and chemotherapy Our targeted therapy produced complete clinical responses CRs in of patients and good partial responses PRs in an additional within one treatment cycle total tumor response rate of This is an exceptionally high rate of response and the adverse event profile was favorable The overall goal of this SBIR proposal is to develop a more potent more selective and more patient accessible virus targeted therapeutic for testing in EBV malignancies In our Phase I period we have screened validated and selected a highly potent clinical stage lead inducing agent which is orally available and has significant human safety data for use in combination with an anti viral agent for EBV lymphomas In this Phase II proposal we will complete the preclinical development of the virus inducing agent for this specific indication generate data to expand its potential therapeutic application and value and prepare for a Phase II proof of concept clinical trial Our Specific Aims in this Phase II Proposal are Optimize lead compound Refine this EBV KSHV targeted therapeutic regimen in animal models Expand application of this therapeutic approach into other herpesvirus associated malignancies Complete pre clinical development Clinical trial planning and set up Measurable Outcomes and Deliverables i Optimization of treatment regimen ii Validation of this virus targeted approach in other malignancies associated with herpesviruses iii Complete pre clinical development of lead compound iv Filing of IND for phase II clinical trial PUBLIC HEALTH RELEVANCE Epstein Barr virus EBV is associated with a number of human malignancies including Burkitt lymphoma BL nasopharyngeal carcinoma NPC T NK lymphomas post transplant lymphoproliferative disorders LPD as well as some T and B cell lymphomas half of Hodgkinandapos s lymphomas AIDS related sarcomas and gastric carcinomas We have demonstrated pre clinically and in a multinational Phase I II clinical trial that selected agents which induce the EBV TK gene expression in the tumor cells renders the tumor susceptible to standard anti viral agents In this Phase II proposal we will complete the preclinical development of a new oral and highly potent virus inducing agent for this specific indication generate data to expand its potential therapeutic application and value and prepare for a Phase II proof of concept clinical trial