Saturday, May 17, 2025
5/17/2025
EPIGENETIC REPROGRAMMING OF T CELL EXHAUSTION TO ENHANCE TUMOR IMMUNOTHERAPY - SUMMARY: Chimeric antigen receptor (CAR) T cell therapy has been shown to be curative for relapsed/refractory B-ALL; however autologous AML CAR T cells exhibit limited expansion and anti-tumor response. The myeloid tumor microenvironment is well-established as being immunosuppressive, but recently our group has reported a subset of myelodysplastic syndrome (MDS) patients with unprecedent response to immune checkpoint blockade (ICB) therapy. Notably, this striking clinical response to ICB was coupled to mutation of the epigenetic regulator ASXL1 among the patient’s T cells. We have extended this finding by validating that deliberate disruption of ASXL1 in murine and human T cells prevents their dysfunction in suppressive tumor and viral microenvironments. Our preliminary investigation of suppressive factors among the serum of AML samples revealed elevated levels of the damage-associated molecular patterns (DAMPs) molecule S100A9 relative to the serum from B-ALL patients. Moreover, S100A9 is able to activate naïve T cells in the absence of antigen. Based on our published and unpublished work, we hypothesize that DAMPs produced from suppressive tumor microenvironments imprint terminal differentiation programs among endogenous T cells used for therapy. Therefore, the aims of our proposal are 1) To investigate DAMP-induced epigenetic programs during T cell dysfunction. 2) To determine if myeloid-associated immunosuppression promotes an ASXL1-mediated exhaustion program in CAR T cells. 3) To determine if ASXL1 disruption protects allogenic CAR T cells from the immunosuppressive microenvironment of AML. The research proposed here will broadly identify the interactions between innate sensors in a suppressive tumor microenvironment that result in epigenetic enforcement of endogenous T cell terminal differentiation. These findings will be applied to test the hypothesis that DAMPs specifically limit the antitumor functions of AML CAR T cells through an ASXL1 dependent mechanism. The mechanism will be extended to endogenous and CAR T cell samples collected from patients in an actively enrolling clinical study at St Jude assessing CD123 CAR T cells for patients with AML. Completion of these studies will not only work toward identifying epigenetic mechanisms that can be engineered to protect CAR T cells from leukemia-induced dysfunction, but will also identify predictive biomarkers that will guide CAR T cell manufacturing and clinical assessment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).