Journal
BLOOD ADVANCES
Volume 5, Issue 5, Pages 1425-1436Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2020003219
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Funding
- National Institutes of Health from the National Heart, Lung, and Blood Institute [R01 HL11879, R01 HL56067, R01 HL114512]
- National Institutes of Health from the National Institute of Allergy and Infectious Diseases [R37 AI34495]
- National Institutes of Health from the National Cancer Institute [P01 CA065493]
- National Institutes of Health National Heart, Lung, and Blood Institute Production Assistance for Cellular Therapies (PACT) [0062]
- Children's Cancer Research Fund
- Leukemia & Lymphoma Translational Research [R6029]
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The study showed that iTregs can be safely delivered at high doses in adults with high-risk malignancy receiving HLA-identical sibling donor PBSCs in the context of CSA/MMF, without severe toxicities.
Human CD4(+)25(-) T cells cultured in interleukin 2 (IL-2), rapamycin, and transforming growth factor beta (TGF beta) along with anti-CD3 monoclonal antibody-loaded artificial antigenpresenting cells generate FoxP3(+) induced regulatory T cells (iTregs) with potent suppressive function. We performed a phase 1, single-center, dose-escalation study to determine the safety profile of iTregs in adults with high-risk malignancy treated with reduced-intensity conditioning and mobilized peripheral blood stem cells (PBSCs) from HLA-identical sibling donors. Sixteen patients were enrolled and 14 were treated (2 productions failed to meet desired doses). One patient each received 3.0 x 10(6)/kg, 3.0 x 10(7)/kg, and 3.0 x 10(8)/kg iTregs with corresponding T-conventional-to-iTreg ratios of 86:1, 8:1, and 1:2. After 3 patients received 3.0 x 10(8)/kg in the presence of cyclosporine (CSA) and mycophenolate mofetil (MMF) with no dose-limiting toxicities, subsequent patients were to receive iTregs in the presence of sirolimus/MMF that favors Foxp3 stability based on preclinical modeling. However, 2 of 2 developed grade 3 acute graft-versus-host disease (GVHD), resulting in suspension of the sirolimus/MMF. An additional 7 patients received 3.0 x 10(8)/kg iTregs with CSA/MMF. In the 14 patients treated with iTregs and CSA/MMF, there were no severe infusional toxicities with all achieving neutrophil recovery (median, day 13). Of 10 patients who received 3.0 x 10(8)/kg iTregs and CSA/MMF, 7 had no aGVHD, 2 had grade 2, and 1 had grade 3. Circulating FoxP3(+) iTregs were detectable through day 14. In summary, iTregs in the context of CSA/MMF can be delivered safely at doses as high as 3 x 10(8)/kg.
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