Utilizing TGF-beta Resistant Natural Killer Cells for Adoptive Transfer to Overcome Tumor Immune Evasion
Abstract
Background and Military Relevance: We propose to use natural killer (NK) cells, a major component of the body s immune system, to develop a more effective approach to the treatment of neuroblastoma, a tumor arising in the nervous system that is nearly always fatal when it spreads beyond its original site in older children. The failure of chemotherapy and radiation therapy to make a significant impact on advanced neuroblastoma led us to explore novel strategies, based on the precise selective action of NK cells that would destroy neuroblastoma cells without harming normal tissue. This research may be especially beneficial to the children or grandchildren of war Veterans who were exposed to toxic chemicals, such as those contaminated with dioxin -- agent orange, for example -- which have been linked to a higher incidence of neuroblastoma and other tumors. We anticipate that the group receiving the most benefit from our NK cell treatment strategy will be young patients with advanced neuroblastoma who have residual tumor cells after stem cell transplantation and are too debilitated to receive intensive chemotherapy. Research Plan/Objective: Very briefly, we are testing NK cells that have been modified with an artificial molecule that resists the immunosuppressive effects of a tumor growth factor called TGF-beta, one of the chief defenses of cancer against the immune system. The reasoning behind this modification is that making NK cells insensitive to the suppressive signals of TGF-beta should allow them to unleash their full immune potential against nearby tumor cells. To ensure an abundant supply of NK cells for research purposes, we will isolate them from umbilical cord blood because it offers a reliable source of immune cells whose "na?ve" or relatively primitive characteristics should allow them to persist and expand after they are infused into patients. It also enables us to rapidly select a suitably matched frozen cord blood unit for expansion of the NK cell component before each treatment. With over 600,000 banked cord blood units worldwide, we expect to have an excellent chance of identifying an appropriate NK cell match for each patient who becomes eligible for immunotherapy. This opportunity is lost when cord blood-derived NK cells are not an option and blood donors must be found among family members or in the general population. Projected Timeline: Over the 2 years of funding provided by this grant, we plan to test whether our TGF-beta-resistant NK cells are able to kill neuroblastoma cells in the laboratory (Year 1) and then evaluate if they are safe and effective in mice with this tumor (Year 2). Once the results of these animal experiments are generated and found to support further research, we will seek regulatory approval to grow large numbers of TGF-beta-resistant NK cells and to inject them into patients who have undergone stem cell transplantation for advanced neuroblastoma. Impact on Cancer Research and Patient Care: If successful, our studies will demonstrate the safety and feasibility of targeting a sophisticated tumor evasion tactic as a primary form of immunotherapy. This advance would have a substantial impact on the cancer research field, as it would provide an attractive "off-the-shelf" strategy of immunotherapy for any tumor that is sensitive to the adverse effects of TGF-beta, thus providing a compelling rationale for its wide use in cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510334
Entities
People
- Catherine Bollard
Organizations
- United States Army