Abstract
Adoptive transfer of donor-derived T lymphocytes expressing a safety switch may promote immune reconstitution in patients undergoing haploidentical hematopoietic stem cell transplant (haplo-HSCT) without the risk for uncontrolled graft versus host disease (GvHD). Thus, patients who develop GvHD after infusion of allodepleted donor-derived T cells expressing an inducible human caspase 9 (iC9) had their disease effectively controlled by a single administration of a small-molecule drug (AP1903) that dimerizes and activates the iC9 transgene. We now report the long-term follow-up of 10 patients infused with such safety switch-modified T cells. We find long-term persistence of iC9-modified (iC9-T) T cells in vivo in the absence of emerging oligoclonality and a robust immunologic benefit, mediated initially by the infused cells themselves and subsequently by an apparently accelerated reconstitution of endogenous naive T lymphocytes. As a consequence, these patients have immediate and sustained protection from major pathogens, including cytomegalovirus, adenovirus, BK virus, and Epstein-Barr virus in the absence of acute or chronic GvHD, supporting the beneficial effects of this approach to immune reconstitution after haplo-HSCT. This study was registered at www.clinicaltrials.gov as #NCT00710892.
© 2014 by The American Society of Hematology.
Publication types
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Clinical Trial, Phase I
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Research Support, N.I.H., Extramural
MeSH terms
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Adolescent
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Aspergillosis / immunology
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Aspergillosis / microbiology
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Aspergillosis / prevention & control
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Aspergillus fumigatus / immunology
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Caspase 9 / biosynthesis
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Caspase 9 / genetics*
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Child
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Child, Preschool
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Enzyme Induction / drug effects
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Female
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Follow-Up Studies
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Graft vs Host Disease / immunology
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Graft vs Host Disease / prevention & control
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Hematopoietic Stem Cell Transplantation / methods*
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Humans
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Immunotherapy, Adoptive / methods
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Lymphoma, Large-Cell, Anaplastic / immunology
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Lymphoma, Large-Cell, Anaplastic / therapy
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Male
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Myelodysplastic Syndromes / immunology
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Myelodysplastic Syndromes / therapy
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Organic Chemicals / administration & dosage
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Organic Chemicals / therapeutic use
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / immunology
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / therapy
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / transplantation*
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Time Factors
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Transgenes / genetics*
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Transplantation, Homologous
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Treatment Outcome
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Virus Diseases / immunology
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Virus Diseases / prevention & control
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Virus Diseases / virology
Substances
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Organic Chemicals
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Caspase 9
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AP 1903 reagent
Associated data
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ClinicalTrials.gov/NCT00710892