Friday, April 4, 2025
4/4/2025
T cell migration and cardiovascular toxicity in immunotherapy - T cell migration and cardiovascular toxicity in immunotherapy. Adoptive T-cell transfer therapy has emerged as a promising therapeutic option with complete and durable responses in several disease conditions such as viral infection, autoimmune disease, atherosclerosis, and cancer. However, severe immune-mediated cardiovascular toxicities caused by cytokine release syndrome (CRS) are observed in most patients, and these adverse reactions remain a significant obstacle in developing effective and safe therapies. In studies conducted in the previous cycle of this grant, we showed that in vitro activated T cells are immediately sequestered at the perivascular space of non-specific tissue sites after the intravascular infusion. This non-specific accumulation is mediated by aberrant LFA-1 activation and may be closely associated with impaired T cell functions and increased risk of severe CRS and cardiovascular toxicity. In this study, we will build on these data and identify key mediators that can control the tissue-specific migration of adoptively transferred T cells and harness these mechanisms to increase the efficacy of T cell immunotherapy while reducing the risks associated with cardiovascular toxicity. To this end, we used (1) in vivo intravital multi- photon microscopy to determine the fate of the adoptively transferred therapeutic T cells after infusion and performed (2) an in vivo CRISPR–Cas9 knockout screen and (3) a high-throughput pharmacologic screening to discover key T cell-intrinsic mechanisms that regulate therapeutic CD8 T cell migration to targeted tissue sites. We will, (Aim 1) determine how clinically manufactured T cells interact with the endothelium in non-specific tissues after infusion and impact vascular barrier functions, (Aim 2) determine the molecular mechanisms that can minimize non-specific sequestration but improve specific T cell migration toward the target tissue site, and (Aim 3) determine whether the newly discovered T cell homing mechanisms (Aim 1 and Aim 2) are associated with therapeutic outcomes and the cardiovascular risk in patients. These studies will combine differential perturbations of novel mechanisms that regulate activated T cell migration in in vivo mouse models, state-of-the- art intravital multiphoton imaging, high-resolution pathway screenings, and assay analyses defining vascular inflammatory responses.
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).