T Cell Precursor-Induced Immune Reprogramming After Hematopoietic Stem Cell Transplantation

About This Grant

PROJECT SUMMARY/ABSTRACT Although allogeneic hematopoietic cell transplantation (HCT) remains the only curative option for many hematologic malignancies, its effectiveness is often undermined by prolonged immune deficiency following myeloablative conditioning. This leaves patients vulnerable to infections and relapse—the two leading causes of post-HCT mortality. This proposal investigates a novel, clinically translatable strategy to accelerate immune reconstitution through the adoptive transfer of ex vivo- generated T cell precursors (PreTs). These PreTs are derived from donor hematopoietic stem and progenitor cells (HSPCs) using a Good Manufacturing Practice-compliant Notch ligand-based platform. Preliminary data demonstrate that PreTs efficiently mature into T cells in vivo and promote de novo thymopoiesis, leading to functional antiviral and antitumor immunity without inducing graft- versus-host disease (GVHD) in murine allogeneic HCT models. In addition, PreT therapy enhances the generation of donor HSPC-derived innate immune cells, including NK cells, neutrophils, and monocytes, suggesting a broad immunoregenerative role that extends beyond adaptive immunity. The hypothesis of this project is that PreTs prevent infection and relapse by restoring T cell immunity alongside two T cell-independent mechanisms: (1) lineage plasticity, whereby PreTs give rise to NK cells with effector function; and (2) reprogramming of donor HSPCs to enhance their function and myeloid output. These mechanisms will be tested using fate mapping, single-cell multiomics, and functional assays in murine HCT, infection, and relapse models. This project addresses a central challenge in HCT: the lack of therapies that broadly accelerate immune recovery without exacerbating GVHD. It also provides a strong foundation for the candidate’s transition to research independence. Dr. Jennifer Tsai, MD, PhD, is a physician-scientist at Memorial Sloan Kettering Cancer Center (MSK). This K08 award will support her development through targeted training in molecular immune- oncology, single-cell immunogenomics, and translational research. Her career development plan includes close mentorship from Drs. Joseph Sun and Omar Abdel-Wahab, both of whom have outstanding records of mentoring scientists and physician-scientists to research independence. Their mentorship will be accompanied by formal coursework, computational training, and guidance from a multidisciplinary advisory committee with complementary fields of expertise and strong track records of collaboration. Along with exceptional mentorship, a highly engaged advisory team, and robust institutional support at MSK, this K08 award will position Dr. Tsai to launch an R01-funded career advancing next-generation cellular immunotherapies for transplantation and cancer.