SUMMARY: Researchers in UCLA’s Department of Microbiology, Immunology & Molecular Genetics have developed an off-the-shelf cell therapy method for reduction of Graft vs Host Disease (GvHD) following hematopoietic stem cell transplantation. This approach uses engineered third-party iNKT’s to ameliorate severity of GvHD without negatively impacting treatment potency.
BACKGROUND: Worldwide it is estimated that over 40,000 patients undergo allogeneic hematopoietic stem cell transplantation to treat or cure various diseases including bone marrow failure syndrome, hematologic malignancies, and numerous immunodeficiencies. While the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the current standard of care for various maladies, it is not without drawbacks, as within the first year following the procedure up to 70% of patients experience some form of acute Graft vs Host Disease (GvHD). This is a potentially serious complication where the donor’s T cells (the graft) view the patient’s healthy cells (the host) as foreign, and attack and damage them. Amongst these patients, some develop a chronic condition of GvHD which can last several years to a lifetime. Despite the risks of GvHD, for various pathologies allo-HSCT is the only available form of curative treatment. As a result, there is an unmet need for and great interest in the development of additional accompanying treatment modalities that can reduce the severity of both acute and chronic GvHD. Previous approaches attempting to reduce GvHD have been thus far unsuccessful due to adverse side-effects or the inadvertent reduction of allo-HSCT’s efficacy.
INNOVATION: UCLA researchers led by Dr. Lili Yang from the Department of Microbiology, Immunology & Molecular Genetics previously developed a scalable method for engineering invariant natural killer T (iNKT) cells via TCR gene engineering of hematopoietic stem cells (HSCs) in vivo. They have now further expanded on this approach and developed an ex vivo culture method to produce third party human iNKT cells in mass. These third party / “off-the-shelf” cells have shown the capacity to effectively reduce the GvHD associated phenotypes through the elimination of antigen-presenting myeloid cells. Testing in both in vitro and xenograft preclinical models of lymphoma and leukemia demonstrated that these third-party HSC-iNKT cells reduced GvHD without dampening the treatment efficacy of transplanted allogeneic T cells. Taken together, the HSC-iNKT cells are a promising off-the-shelf cell therapy candidate for GvHD prophylaxis.
POTENTIAL APPLICATIONS: • Treatment of graft-vs-host disease • Supplementary treatment following allogeneic hematopoietic stem cell transplantation
ADVANTAGES: • Reduction of graft-vs-host disease • Better maintains graft vs disease activity than alternatives • Production and engineering of these HSC-iNKT cells is scalable: thousands of doses can be generated from a single donor • MHC matching is not needed
DEVELOPMENT-TO-DATE: HSC-iNKT cells have been developed and shown to closely resemble subsets of endogenous human iNKT cells in phenotype and functionality. Engineered iNKTs reduced GvHD as seen in in vitro preclinical models of lymphoma and leukemia and did not negatively impact allogeneic T cells activity.
Related Papers (from the inventors only): Li, Yan-Ruide et al. “Off-the-shelf third-party HSC-engineered iNKT cells for ameliorating GvHD while preserving GvL effect in the treatment of blood cancers.” iScience vol. 25,9 104859. 6 Aug. 2022, doi:10.1016/j.isci.2022.104859