Non-genotoxic hematopoietic stem cell transplantation conditioning regimen.
Hematopoietic stem cell transplantation (HSCT) is a critical therapy for a range of malignant and non‑malignant blood disorders, including leukemia, multiple myeloma, immune deficiencies, and inherited metabolic diseases. Successful transplantation requires a conditioning regimen to eliminate diseased or defective host stem cells, prevent graft rejection, and create space for donor cell engraftment. The current standard of care relies on highly genotoxic chemotherapy agents such as busulfan and/or total body irradiation, which are effective but associated with significant acute and long‑term toxicities. These side effects include organ damage, impaired fertility, secondary malignancies, and increased transplant‑related mortality, particularly in patients with underlying immunologic or DNA repair defects. Reduced‑intensity and antibody‑based conditioning strategies have been explored to lower toxicity but often fail to achieve sufficient immune ablation or require combination with additional cytotoxic agents. As a result, there remains a significant unmet need for safer, more targeted conditioning approaches that can reliably support engraftment while minimizing off‑target toxicity and long‑term complications.
Researchers at Emory University have developed a novel cell‑based immunotherapy approach designed to target leukemia and related hematologic conditions more precisely. The technology involves engineering immune cells to express a synthetic surface receptor that recognizes proteins commonly found on hematopoietic stem cells, leukemia cells, and abnormal blood‑forming stem cells. Unlike traditional antibody‑based targeting, this approach uses natural receptor ligands to selectively engage the hematopoietic stem cell or the disease‑relevant cell populations. Once the engineered immune cells bind their targets, internal signaling domains activate the immune cell to eliminate the targeted cells. The platform can be applied across multiple immune cell types and may be used alone or alongside standard treatments such as chemotherapy or stem cell transplantation. This strategy aims to improve treatment specificity and effectiveness while reducing damage to healthy tissues, addressing a key limitation of current leukemia and transplant conditioning therapies.
Proof of concept demonstrated.
Publication
Zoine, J. T., Prince, C., Story, J. Y., Branella, G. M., Lytle, A. M., Fedanov, A., Alexander, J. S., Porter, C. C., Doering, C. B., Spencer, H. T., & Chandrakasan, S. (2022). Thrombopoietin based CAR T cells demonstrate in vitro and in vivo cytotoxicity to MPL positive acute myelogenous leukemia and hematopoietic stem cells. Gene Therapy, 29(5), 1–12. https://doi.org/10.1038/s41434-021-00283-5