Expanded antigen-specific donor regulatory T cells for GVHD prevention
Joseph A Pidala, Nicoletta Cieri, Michael J Schell, Xiaofei Song, Yiren Shao, Biwei Cao, Dongliang Du, Ram Thapa, Brian C Betts, William Janssen, Christopher Cubitt, Sean J Yoder, Mandy Flannery O'Leary, Francisca Beato, Anandharaman Veerapathran, Meghan A Menges, Michelle Burton, Nelli Bejanyan, Omar Alexis Castaneda-Puglianini, Hany Elmariah, Rawan G. Faramand, Hugo F. Fernandez, Doris K Hansen, Michael D Jain, Farhad Khimani, Aleksandr Lazaryan, Hien D Liu, Frederick L. Locke, Abu-Sayeef Mirza, Asmita Mishra, Michael Nieder, Taiga Nishihori, Leonel Ochoa, Lia E Perez, Fabiana Perna, Reshma Ramlal, Nancy Eunice Torres, Claudio AnasettiMinor histocompatibility antigen (mHAg)-specific alloreactive donor T cells cause graft vs. host disease (GVHD) in matched related donor allogeneic hematopoietic cell transplantation (HCT). In a phase I trial, we expanded and infused (on day -2) mHAg-specific donor regulatory T cells (Treg) together with sirolimus-based pharmacologic prophylaxis to examine safety and preliminary efficacy of this GVHD prevention approach. We employed a 3+3 phase I design escalating Treg dose in 4 levels: 0.5 x 105/kg, 1 x 105/kg, 2 x 105/kg, and 4 x 105/kg. Dose-limiting toxicity (DLT) included grade 4-5 related infusion reaction, grade 4-5 unexpected organ toxicity, grade III-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, and in-vivo longevity and expansion post-HCT. 15 subjects were included (N=3 each per dose levels 1-3, and N=6 in dose level 4). No DLT were observed, and 4 x 105/kg Treg was identified as MTD. Median follow up for survivors was 41.7 months (range 14.5-72.8). The day 100 cumulative incidence of grade II-IV acute GVHD was 13% (95% CI 2-35%). NIH moderate/severe chronic GVHD by 1 year was 6.7% (95% CI 0.36-27%) and by 3 years was 20% (95%CI 4.4-44%). Overall survival was 73% (95% CI 54-100%). 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 expanded donor Treg clones can persist and expand through one-year post-HCT. NCT01795573