# Enhancing Treg Therapeutic Efficacy in GVHD with CARs > **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2021 · $40,180 ## Abstract 1 Project Summary/Abstract 2 3 Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematological disorders 4 but its efficacy is limited by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality after 5 HSCT. With current prophylactic measures 20-70% of HSCT patients develop GVHD and are left susceptible to 6 infection, tumor recurrence, and secondary malignancies. Pre-clinical and clinical studies show adoptive transfer 7 of regulatory T cells (Treg) is highly effective at preventing GVHD. Clinical translation has been hindered by low 8 Treg frequency in the blood, variable suppressive capacity of polyclonal Tregs, and the need to infuse high doses 9 to reproducibly suppress disease. Antigen-specific Tregs have been shown to be more potent than polyclonal 10 Tregs in autoimmune models and in solid organ transplants where HLA-A2 specific Tregs are given to suppress 11 responses against HLA-A2 disparate grafts. While this approach targets one of the most commonly mismatched 12 antigens, HLA-A2 is present in only 20% of African American and 34% of Hispanic patients. To overcome these 13 limitations, I will use chimeric antigen receptors (CAR) to redirect Tregs towards human CD19 (hCD19) B cells 14 using an FDA approved construct containing the 4-1BB co-stimulatory domain (CAR19). Unexpectedly, my 15 preliminary data with CAR19 Tregs demonstrate dual and opposing properties of GVHD suppression and killing 16 of leukemia cells including graft-versus-leukemia (GVL). Thus, my goal is to use Tregs specific for hCD19 present 17 on malignant B cells to mediate GVL and on non-malignant B cells to deplete these host antigen presenting cells 18 during the critical GVHD induction phase. I will use a murine major MHC mismatch model where recipient mice 19 express hCD19 on B cells. My preliminary studies demonstrate CAR19 Tregs improve GHVD survival and cause 20 hCD19 B cell depletion early after HSCT. We also found CAR19 Tregs mediate targeted killing of hCD19 21 lymphoma cells in vitro and maintained GVL in vivo unlike control Tregs. Understanding how CAR19 Tregs utilize 22 cytolysis for GVL while suppressing GVHD will help expand our understanding of CAR Treg biology and design 23 to maximize their use in allo-HSCT. I hypothesize CAR19 Tregs are bifunctional in their ability to suppress 24 excessive and deleterious immune responses (GVHD, CRS) and concurrently induce GVL effects. The findings 25 from this research proposal will elucidate the mechanisms by which CAR19 Tregs confer higher protection than 26 control Tregs or even CAR19 T cells at ameliorating GVHD, preventing cytokine release syndrome (CRS), and 27 uniquely promoting anti-tumor responses. The novel approach of redirecting CAR Tregs to tumor antigens opens 28 a new therapeutic avenue to prevent GVHD and improve allo-HSCT outcomes. ## Key facts - **NIH application ID:** 10312590 - **Project number:** 1F30HL156312-01A1 - **Recipient organization:** UNIVERSITY OF MINNESOTA - **Principal Investigator:** Sara Bolivar Wagers - **Activity code:** F30 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $40,180 - **Award type:** 1 - **Project period:** 2021-09-13 → 2024-07-12 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10312590 ## Citation > US National Institutes of Health, RePORTER application 10312590, Enhancing Treg Therapeutic Efficacy in GVHD with CARs (1F30HL156312-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312590. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*