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Updated: Jun 21, 2026
Induction of Alloantigen-specific Anergy in Human Peripheral Blood Mononuclear Cells by Alloantigen Stimulation with Co-stimulatory Signal Blockade
Published on: March 14, 2011
Expanded antigen-specific donor regulatory T cells for GVHD prevention
Joseph A Pidala1, Nicoletta Cieri2,3,4, Michael J Schell5
1Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center and Research Institute, Tampa, FL.
Minor histocompatibility antigen (mHAg)-specific alloreactive donor T cells cause graft-versus-host disease (GVHD) in matched related donor allogeneic hematopoietic cell transplantation (HCT). In a phase 1 trial, we expanded and infused (on day -2) mHAg-specific donor regulatory T cells (Treg) together with sirolimus-based pharmacologic prophylaxis to examine the safety and preliminary efficacy of this GVHD prevention approach. We used a 3+3 phase 1 design escalating Treg dose in 4 levels: 0.5 × 105/kg, 1 × 105/kg, 2 × 105/kg, and 4 × 105/kg. Dose-limiting toxicity (DLT) included grade 4 to 5 related infusion reactions, grade 4 to 5 unexpected organ toxicity, grade III to IV acute GVHD, or treatment-related death. Secondary and exploratory measures examined acute and chronic GVHD, survival outcomes, and Treg clone (TCR-seq) expansion in culture, in vivo longevity, and expansion after HCT. Fifteen patients were included (n = 3 each per dose levels 1-3, and n = 6 in dose level 4). No DLTs were observed, and 4 × 105/kg of Treg was identified as maximum tolerated dose. Median follow-up for survivors was 41.7 months (range, 14.5-72.8). The day 100 cumulative incidence of grade II to IV acute GVHD was 13%. National Institutes of Health moderate/severe chronic GVHD by 1 year was 6.7% and by 3 years was 20%. Overall survival was 73%. Treg clones expanded in culture and demonstrated post-HCT lineage fidelity, persistence, and in vivo expansion. This translational trial supports mHAg-specific expanded donor Treg as a novel GVHD prevention strategy and demonstrates that expanded donor Treg clones can persist and expand through 1 year after HCT. This trial was registered at www.clinicaltrials.gov as NCT01795573.
Minor histocompatibility antigen (mHAg)-specific alloreactive donor T cells cause graft-versus-host disease (GVHD) in matched related donor allogeneic hematopoietic cell transplantation (HCT). In a phase 1 trial, we expanded and infused (on day -2) mHAg-specific donor regulatory T cells (Treg) together with sirolimus-based pharmacologic prophylaxis to examine the safety and preliminary efficacy of this GVHD prevention approach. We used a 3+3 phase 1 design escalating Treg dose in 4 levels: 0.5 × 105/kg, 1 × 105/kg, 2 × 105/kg, and 4 × 105/kg. Dose-limiting toxicity (DLT) included grade 4 to 5 related infusion reactions, grade 4 to 5 unexpected organ toxicity, grade III to IV acute GVHD, or treatment-related death. Secondary and exploratory measures examined acute and chronic GVHD, survival outcomes, and Treg clone (TCR-seq) expansion in culture, in vivo longevity, and expansion after HCT. Fifteen patients were included (n = 3 each per dose levels 1-3, and n = 6 in dose level 4). No DLTs were observed, and 4 × 105/kg of Treg was identified as maximum tolerated dose. Median follow-up for survivors was 41.7 months (range, 14.5-72.8). The day 100 cumulative incidence of grade II to IV acute GVHD was 13%. National Institutes of Health moderate/severe chronic GVHD by 1 year was 6.7% and by 3 years was 20%. Overall survival was 73%. Treg clones expanded in culture and demonstrated post-HCT lineage fidelity, persistence, and in vivo expansion. This translational trial supports mHAg-specific expanded donor Treg as a novel GVHD prevention strategy and demonstrates that expanded donor Treg clones can persist and expand through 1 year after HCT. This trial was registered at www.clinicaltrials.gov as NCT01795573.
