The overarching goal of this proposal is the development of the candidate into an independent investigator in the field of adoptive immunotherapy. With his clinical background in immunology and research experience in human immunobiology, the candidate is ideally positioned to fully realize the benefits of an NIH Mentored Career Development Award. The research proposal seeks to evaluate the use of adoptively transferred, virus-specific T-cells to treat viral infections in patients with primary immunodeficiency disorders (PID) who have not yet undergone hematopoietic stem cell transplantation.
The specific aims of the project are: 1) To determine the safety and feasibility of banked, partially matched virus-specific T-cells for treatment of viral infections in primary immunodeficiency patients prior to hematopoietic stem cell transplantation, and 2) To determine whether virus-specific T-cells restore immunity against targeted viruses in patients. Collectively, these aims will determine if antiviral T-cell therapy may be a safe and effective bridge to transplantation for patients with primary immunodeficiency disorders, and will identify the optimal approach to using ?off the shelf? banked T-cell products to combat viral infections, which has the potential to benefit a broad range of immune suppressed patients. The candidate has assembled an outstanding advisory team, who are highly qualified to guide him in the pursuit of his research and career goals. The primary mentor is Dr. Catherine Bollard, a world-renowned expert on adoptive T-cell therapies. The candidate's two co- mentors include Dr. Jordan Orange, a leading expert on primary immunodeficiency disorders and immunobiology, and Dr. Anamaris Colberg-Poley, a distinguished systems biologist and virologist. He will also collaborate with Dr. Daniel Douek (NIAID), a highly respected T-cell biologist, to pursue studies of virus-specific T-cell persistence and activity in vivo via TCR? sequencing. The candidate will participate in coursework and focused seminars designed to promote investigator independence by the end of the award period. The candidate will benefit from an ideal academic environment and extensive resources in the Center for Cancer and Immunology Research and the Clinical and Translational Science Institute at Children's National, as well as from supplemental training through Dr. Orange's Center for Human Immunobiology at Baylor College of Medicine, and Dr. Douek's Vaccine Research Center at NIH. In summary, this proposal describes a plan that is relevant, feasible, and will provide the necessary mentorship and training to allow the candidate to develop into an independent clinician- scientist in the field of adoptive immunotherapy for patients with PID.
Adoptive immunotherapy with banked virus-specific T-cells has been an effective treatment for viral infections in immune compromised patients, and may be an effective salvage therapy for primary immunodeficiency patients with persistent viral infections who have not yet undergone hematopoietic stem cell transplantation. Evaluating the safety and feasibility of this therapy could advance the care of primary immunodeficiency patients. Through characterization of antiviral immune reconstitution after T- cell therapy, including the phenotype, viral specificity, and persistence of infused cells, this project will also advance the understanding of third-party T-cell therapy for a variety of indications.
