K23 Resubmission - Impact of adoptive T cell therapy on immunity to SARS-CoV-2 after bone marrow transplant

The overarching goal of this proposal is the development of the candidate into an independent investigator in the field of immune modulatory cell therapy for critically ill children, particularly those post hematopoietic stem cell transplant (HSCT). With her clinical and research background in pediatric critical care and T cell immunotherapy, she is ideally positioned to fully realize the benefits of an NIH Mentored Career Development Award. This research proposal seeks to establish the safety and preliminary efficacy of adoptive immunotherapy with donor-derived SARS-CoV-2-specific T cells (CST) for prophylaxis against SARS-CoV-2 infection in patients post HSCT by conducting an FDA- and IRB-approved phase I clinical trial (NCT 05141058) and to develop CSTs genetically engineered to maintain antiviral activity in the presence of the commonly used lymphodepleting agent, alemtuzumab. The specific aims of the proposal are: 1) to determine whether infusion of donor-derived CSTs safely enhances antiviral immunity to SARS-CoV-2 in patients early (<4 months) post HSCT, and 2) to genetically engineer CSTs to retain antiviral activity in vitro in the presence of alemtuzumab. Together, these aims will establish the safety and preliminary efficacy of CST prophylaxis in the post HSCT population and lay the foundation for a "next generation" of virus-specific T cells (VST) engineered to resist immunosuppressive peri- transplant drugs. In addition, they will develop the candidate's expertise in T cell immunobiology, high throughput sequencing, gene editing, and early phase clinical trials. The candidate has assembled an outstanding advisory team who are highly qualified to guide her in the pursuit of her career and research goals. Her primary mentor and co-mentor, Drs. Catherine Bollard and Michael Keller, are world-renowned experts in immune modulatory cellular therapy and T cell immunobiology. Dr. Matthew Porteus, a pioneer in the field of gene therapy, will guide her work developing genetically engineered CSTs. In addition, Dr. Patrick Hanley, Director of the Good Manufacturing Processes Laboratory at Children's National Hospital, will oversee production of the CST product (IND 27588); Dr. Rick Jones will advise and oversee trial conduct at Johns Hopkins Medical Institutions (JHMI); and Dr. Wei Li will provide bioinformatic support for both CRISPR and high throughput sequencing experiments. A selection of focused coursework and seminars will facilitate investigator independence by the end of the award period. The candidate will benefit from a superb academic environment and extensive resources available through the Center for Cancer and Immunology Research, the Genetic Medicine Research Center, and the Clinical and Translational Science Institute at Children's National, as well as from in-person training in gene editing in the Porteus laboratory. In summary, this proposal describes a plan that is relevant, feasible, and will provide the necessary mentorship and training to promote the candidate's development into an independent clinician scientist in the field of cellular immune modulatory therapy.