BiTE Gene Therapy to Augment Oncolytic Virotherapy
Abstract
Cancer remains the number one cause of death from disease in children, and a significant burden to adults including those who serve in the military. Advances in gene therapy and immunotherapy have now advanced to the point where we can leverage these disciplines to devise novel treatments for cancer. One of the exciting new immune-based therapies for cancers are small proteins called BiTEs, which stands for Bispecific T cell Engagers. BiTEs serve to bind a highly destructive T cell of the immune system to a cancer cell. By bringing the two cells together, the T cell destroys the cancer cell. This technology is already Food and Drug Administration (FDA) approved for certain types of leukemia, which speaks to both its safety and its success, and is in development for many types of solid cancers including neuroblastoma, one of the childhood cancers targeted by the CDMRP. The problem with BiTEs is that they only last 2 hours in the bloodstream after they are given intravenously. They require a constant pump during treatment, which can last 6 months or more, and they must be replenished multiple times each week. For pediatric patients, carrying a pump for such a duration and having to change it frequently is highly burdensome. BiTEs are also expense, with a 6 month treatment costing over half a million United States dollars. In this new idea application, we propose to use a gene therapy approach to solve all of these problems with BiTEs. We will express the gene encoding a secreted BiTE using an adeno-associated virus to deliver the gene to liver and other normal organs, effectively turning them into BiTE factories. The result will be sustained, high levels of BiTEs after a one-time infusion, thus eliminating the need for a pump and for frequent pump replenishments. In a separate project beyond the scope of this award, we will also devise a method to turn expression of the BiTE on and off, in the event there are any side effects. In addition to testing the gene-based BiTE on its own, we will leverage this new technology to complement the oncolytic virotherapy approach we have been studying in my research laboratory and in clinical trials Ive conducted. Briefly, live viruses such as the recently FDA-approved T-VEC, derived from the cold sore virus, can infect and kill tumor cells. In addition, there is mounting evidence that viruses can induce or increase an immune response against cancer cells, resulting in long-lasting immunity that prevents cancer recurrence. Viruses arent likely to be curative by themselves; however, particularly since cancers often develop a number of ways to suppress immunity. One of the biggest changes in a tumor after virus injection is the influx of T cells recruited to eliminate the virus infection. We thus propose to combine the AAVBiTE therapy with oncolytic virotherapy. We think that T cells stimulated by the virus will be redirected by BiTEs to attack tumor cells, thus resulting in much better cancer control than either therapy alone. This project is a completely new and exciting avenue of research for me, making it ideal for the Idea Award. If the proposed experiments are successful, we will seek to develop the technology further and translate it into clinical trials. Our collaborator, Dr. Jerry Mendell, has already led many AAV-based gene therapy trials in humans using vectors produced in our institutions Good Manufacturing Procedures facility. With his involvement, we have a team that is knowledgeable regarding all of the steps required to ultimately benefit patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910371
Entities
People
- Timothy Cripe
Organizations
- The Research Institute at Nationwide Children's Hospital
- United States Army