Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

Daniel H. Fowler, Miriam E. Mossoba, Seth M. Steinberg, David C. Halverson, David Stroncek, Hahn M. Khuu, Frances T. Hakim, Luciano Castiello, Marianna Sabatino, Susan F. Leitman, Jacopo Mariotti, Juan C. Gea-Banacloche, Claude Sportes, Nancy M. Hardy, Dennis D. Hickstein, Steven Z. Pavletic, Scott Rowley, Andre Goy, Michele Donato, Robert KorngoldAndrew Pecora, Bruce L. Levine, Carl H. June, Ronald E. Gress, Michael R. Bishop

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4+ T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4+ Th2 and Th1 cells relative to regulatory T cells and CD8+ T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at as #NCT 00077480.

Original languageEnglish (US)
Pages (from-to)2864-2874
Number of pages11
Issue number15
StatePublished - Apr 11 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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