Phase II year
2016
(last award dollars: 2017)
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 Burkitt's lymphomas, T/NK lymphomas, and post-transplant lymphoproliferative disorders (LPD), as well as some T- and B-cell lymphomas, and half of Hodgkin'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 "latent" 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 26% of patients, and good partial responses (PRs) in an additional 40% within one treatment cycle (total tumor response rate of 67%). 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: 1.) Optimize lead compound - Refine this EBV/KSHV-targeted therapeutic regimen in animal models; 2.) Expand application of this therapeutic approach into other herpesvirus-associated malignancies; 3.) Complete pre-clinical development; 4.) 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 γ-herpesviruses; iii.) Complete pre-clinical development of lead compound; iv.) Filing of IND for phase II clinical trial.
Public Health Relevance Statement: 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 Hodgkin'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.
Project Terms: Acquired Immunodeficiency Syndrome; Adverse event; African Burkitt's lymphoma; AIDS-Related Hodgkin's Lymphoma; Animal Model; Antiviral Agents; antiviral nucleoside analog; B-Cell Lymphomas; Breast; Breast Carcinoma; Burkitt Lymphoma; Cells; chemotherapy; Clinical; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; Data; Databases; design; Development; Drug Exposure; EBV-associated malignancy; Electronics; Enzymes; Family; gammaherpesvirus; Ganciclovir; Gene Expression; Goals; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Institutional Review Boards; Killings; Lead; Lymphoma; Lymphoproliferative Disorders; Malignant lymphoid neoplasm; Malignant Neoplasms; Measurable; meetings; member; Nasopharynx Carcinoma; Neoplasms; neoplastic cell; Normal Cell; nucleoside analog; oncology; Oral; Outcome; Outpatients; partial response; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Play; Population; pre-clinical; Prodrugs; Protein Kinase; Protocols documentation; prototype; public health relevance; Radiation; Radiation therapy; Refractory; Regimen; research clinical testing; Research Personnel; Resistance; response; Role; Safety; sarcoma; Site; Small Business Innovation Research Grant; Staging; Stomach Carcinoma; System; targeted treatment; Testing; Therapeutic; Thymidine Kinase; TK Gene; Toxicology; Transplantation; Treatment Protocols; tumor; Validation; Viral; Viral Drug Resistance; Viral Genome; Virus; virus development
