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

• Published in: Blood Vol. 121; no. 15; pp. 2864 - 2874
• Main Authors: Fowler, Daniel H., Mossoba, Miriam E., Steinberg, Seth M., Halverson, David C., Stroncek, David, Khuu, Hahn M., Hakim, Frances T., Castiello, Luciano, Sabatino, Marianna, Leitman, Susan F., Mariotti, Jacopo, Gea-Banacloche, Juan C., Sportes, Claude, Hardy, Nancy M., Hickstein, Dennis D., Pavletic, Steven Z., Rowley, Scott, Goy, Andre, Donato, Michele, Korngold, Robert, Pecora, Andrew, Levine, Bruce L., June, Carl H., Gress, Ronald E., Bishop, Michael R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2013; American Society of Hematology
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; Clinical Trials and Observations; Cytokines - immunology; Cytokines - metabolism; Drug Resistance - immunology; Female; Gene Expression Profiling; Graft vs Host Disease - etiology; Graft vs Host Disease - immunology; Hematologic Neoplasms - immunology; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacology; Lymphocyte Transfusion - methods; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Remission Induction; Sirolimus - administration & dosage; Sirolimus - pharmacology; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - transplantation; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - transplantation; Time Factors; Transplantation, Homologous; Treatment Outcome; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-446872

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. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480. •Donor T-Rapa cells were composed of Th1 and Th2 effectors with a reproducible gene expression profile.•Preemptive T-Rapa donor lymphocyte infusion was safe and associated with donor engraftment without excessive GVHD.