Novel Ovarian Cancer Therapy
Abstract
Viruses can be engineered to selectively kill tumor cells. This new form of therapy is called "virotherapy". The advent of virotherapy has generated considerable excitement as these new agents embody the capacity to achieve therapy with a greatly reduced toxicity. In this context, virotherapy represents one of the emerging forms of "targeted" therapy for cancer. This term refers to the design of the agent to target specific vulnerabilities in the biology of the cancer cell. Owing to their exciting potential, virotherapy agents have been rapidly applied as experimental therapy for cancer of the ovary. Of note, these human trials have highlighted the safety of this approach. In some instances, there has been preliminary evidence of clinical responsiveness. These early indices of effectiveness have spurred the interest of scientists, and pharmacy companies, to advance the development of virotherapies to optimize their therapeutic possibilities. In addition to addressing safety and efficacy, these recent human trials have also defined the barriers to optimized virotherapy effectiveness. Specifically, these human trials have highlighted two key barriers limiting the full effectiveness of current virotherapy approaches for cancer of the ovary. First, pre-formed immunity to the virotherapy viral agent, in the form of antibodies, could neutralize the administered agent. This is highly relevant as many virotherapy agents are based on viruses to which humans have commonly been exposed. For example, the common "cold" virus, termed "adenovirus", has been highly useful as a virotherapy agent, however, its use would be potentially impacted by the presence of antibodies to human adenovirus in treated subjects. To address this key issue, we plan to use an adenovirus from a non-human primate as a virotherapy agent. In this regard, gorilla adenoviruses can be modified as readily as human adenoviruses. But gorilla adenoviruses are not recognized by antibodies against human adenovirus. In addition, they have been safely employed in human vaccine studies. On the basis of these considerations, we will modify gorilla adenovirus to produce a novel type of virotherapy agent. This new agent will embody the unique property of avoiding pre-formed immunity to human adenovirus. Our study here will allow us to test whether gorilla adenovirus can be modified in this manner and maintain its ability to kill human ovarian cancer tumor cells. In addition, we will seek to improve the specificity of the gorilla adenovirus agent as a means to improve its effectiveness. In this regard, the inability of current viruses to exclusively infect tumor cells represents the second key barrier that has limited virotherapy effectiveness. On this basis, we have developed a very novel method to incorporate anti-tumor antibodies into the virus outer shell, or "capsid", that provides the virus unique tumor specificity. This is based on the use of antibodies derived from the camel family. Such "nanobodies" have unique biological properties allowing them to function as part of the virus. We are the only group that has successfully accomplished this technical goal and are therefore uniquely positioned to address this barrier to virotherapy effectiveness. We thus will combine these two unique technologies to derive a tumor-targeted gorilla adenovirus virotherapy agent specifically designed for cancer of the ovary. We believe that by addressing the two major barriers to virotherapy effectiveness, our novel agent will embody optimized efficacy. We will validate this hypothesis in a murine model of human cancer of the ovary. The demonstration of the therapeutic utility of this new class of viropathy agent will enable us to begin the planning of a human clinical trial based upon our new virotherapy design concept.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810063
Entities
People
- David T. Curiel
Organizations
- United States Army
- Washington University in St. Louis