Thursday, December 26, 2024
12/26/2024
Adoptive transfer T cell-based immunotherapies and checkpoint inhibitor immunotherapy have shown significant promise in the treatment of cancers. However, checkpoint inhibitor therapy still fails in a majority of patients and chimeric antigen receptor (CAR)-T cells are ineffective against most solid tumors. In large part, these failures are due to the fact that frequently tumors are mostly devoid of T cells or that T cells are present only in the tumor-surrounding stroma but largely excluded from the tumor mass. Tumors are often surrounded by extensive collagen-rich extracellular matrix (ECM) structures, which impede the entry of T cells into the tumor mass. T cell paucity or exclusion from the tumor site correlate with poor prognosis, limited efficacy of checkpoint inhibitor immunotherapies, and ineffectiveness of CAR-T cell therapy against solid tumors. Most cellular tumor immunotherapy approaches to date have focused on reversing T cell exhaustion and increasing persistence of tumor-specific T cells and CAR-T cells. However, these approaches generally do not solve the issue of recruitment and infiltration of therapeutic T cells into the tumor. The overall goal of this proposal is to engineer T cells to enhance their migration into tumors to increase their anti-tumor activity in ‘cold’ tumors and tumors that exclude T cells from the tumor mass. Our exploratory R21 proposal specifically addresses the unmet need to improve migration of T cells into tumors by creating T cells with increased capacity to migrate through restrictive environments. We have found that Formin-like-1 (FMNL1) promotes efficient T cell extravasation, motility through confined environments, and interstitial migration in vivo. Furthermore, our preliminary data using a melanoma model show that overexpression of FMNL1 significantly increases the number of tumor-specific T cells present at the tumor site. Thus, we hypothesize that T cells engineered to overexpress FMNL1, or its active mutants, will have increased trafficking to the tumor site, deeper infiltration into the tumor mass, and enhanced anti-tumor activity. We will test our hypothesis with the following Aims: Aim 1. Determine if overexpression of FMNL1 or its active mutants enhances tumor-specific T cell migration and accumulation within tumors. Aim 2. Determine if T cells engineered to overexpress FMNL1 have increased anti-tumor activity and improve the efficacy of checkpoint inhibitor therapy. Overall, we will establish and validate a platform for T cell bioengineering to improve T cell migration into tumor sites that can be applied to tumor-infiltrating lymphocyte (TIL) transfer therapy and CAR-T cell therapy for solid tumors. Our novel approach can both improve the ability of T cells to extravasate at the tumor site, and enhance the capacity of T cells to migrate through restrictive tissue barriers to infiltrate the tumor mass. From a future translational standpoint, an additional advantage of this system is that the T cell infiltration enhancement provided by FMNL1 is not limited to a particular tumor antigen and is not MHC restricted. Overall, our work has the potential to significantly improve the treatment of solid tumors using adoptive T cell transfer therapies.
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).