title: Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation.
abstract: 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: 42-84 months). 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.
authors: Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. dhfowler@helix.nih
authors: Daniel H
authors: DH
authors: Fowler
authors: Miriam E
authors: ME
authors: Mossoba
authors: Seth M
authors: SM
authors: Steinberg
authors: David C
authors: DC
authors: Halverson
authors: David
authors: D
authors: Stroncek
authors: Hahn M
authors: HM
authors: Khuu
authors: Frances T
authors: FT
authors: Hakim
authors: Luciano
authors: L
authors: Castiello
authors: Marianna
authors: M
authors: Sabatino
authors: Susan F
authors: SF
authors: Leitman
authors: Jacopo
authors: J
authors: Mariotti
authors: Juan C
authors: JC
authors: Gea-Banacloche
authors: Claude
authors: C
authors: Sportes
authors: Nancy M
authors: NM
authors: Hardy
authors: Dennis D
authors: DD
authors: Hickstein
authors: Steven Z
authors: SZ
authors: Pavletic
authors: Scott
authors: S
authors: Rowley
authors: Andre
authors: A
authors: Goy
authors: Michele
authors: M
authors: Donato
authors: Robert
authors: R
authors: Korngold
authors: Andrew
authors: A
authors: Pecora
authors: Bruce L
authors: BL
authors: Levine
authors: Carl H
authors: CH
authors: June
authors: Ronald E
authors: RE
authors: Gress
authors: Michael R
authors: MR
authors: Bishop
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004351:Drug Resistance / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D017710:Lymphocyte Transfusion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012074:Remission Induction; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D020123:Sirolimus