Hematopoietic stem cell transplantation (HSCT) holds the potential for cure of a variety of malignant and non-malignant hematologic disorders. However, the severe acute and chronic toxicities imposed by the chemotherapy- and irradiation-based conditioning regimens used to prepare recipients for transplant may preclude them from accessing the lifesaving benefits of HSCT. My research seeks to address this urgent and unmet need by developing minimally toxic, immunotherapeutic conditioning strategies which enable the therapeutic benefits of HSCT with minimal injury to the recipient.

During my postdoctoral training in Dr. John DiPersio’s lab, I discovered a novel allogeneic HSCT conditioning strategy combining Janus kinase 1/2 inhibitors with CD45- or CD117-targeted antibody-drug conjugates (ADC), which enabled stable engraftment between fully MHC-mismatched mice with >99% myeloid lineage donor chimerism. Notably, compared to conditioning with irradiation,  ADC-based conditioning in murine models did not promote graft-versus-host disease. Several projects stemming from this work seek to optimize antibody-based conditioning regimens to better achieve the therapeutic goals of transplant in specific disease settings. For example, we developed highly-potent, fully myeloablative ADCs designed for HSCT conditioning in the context of acute myeloid leukemia, for which induction of full donor chimerism and maximal antileukemia benefit enabled by the conditioning regimen affords protection from relapse. For non-malignant diseases like sickle cell disease, in which antileukemia benefit is not needed and mixed chimerism is sufficient for cure, we are developing toxic payload-free regimens able to achieve cure with as few toxicities as possible when used in conjunction with either allogeneic HSCT or autologous gene therapy.