Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML

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Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML

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Title: Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML
Author: Huang, Ju; Liu, Yuanfeng; Au, Bryan C; Barber, Dwayne L; Arruda, Andrea; Schambach, Axel; Rothe, Michael; Minden, Mark D; Paige, Christopher J; Medin, Jeffrey A

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Citation: Huang, Ju, Yuanfeng Liu, Bryan C Au, Dwayne L Barber, Andrea Arruda, Axel Schambach, Michael Rothe, Mark D Minden, Christopher J Paige, and Jeffrey A Medin. 2016. “Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML.” Molecular Therapy. Methods & Clinical Development 3 (1): 16074. doi:10.1038/mtm.2016.74. http://dx.doi.org/10.1038/mtm.2016.74.
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Abstract: Interleukin-12 (IL-12) is a potent cytokine that may be harnessed to treat cancer. To date, nearly 100 IL-12-based clinical trials have been initiated worldwide. Yet systemic administration of IL-12 is toxic. Different strategies are being developed to reduce such toxicities by restricting IL-12 distribution. Our previous studies employed lentivector-mediated expression of murine IL-12 in tumor cells and demonstrated effective protection in both mouse leukemia and solid tumor challenge models. In this study, we carried out preclinical validation studies using a novel lentivector to engineer expression of human IL-12 in acute myeloid leukemia blast cells isolated from 21 patients. Acute myeloid leukemia cells were transduced with a bicistronic lentivector that encodes the human IL-12 cDNA as a fusion, as well as a LNGFR (ΔLNGFR)/mutant thymidylate kinase cassette as a marking and cell-fate control element. A range of 20–70% functional transduction efficiencies was achieved. Transduced acute myeloid leukemia cells produced bioactive IL-12 protein and displayed dose-dependent sensitivity to the prodrug 3′-azido-3′-deoxythymidine. In vitro immortalization assays using transduced mouse hematopoietic stem cells demonstrated minimal genotoxic risk from our IL-12 vector. Scale-up transduction and cell processing was subsequently validated in a GMP facility to support our (now approved) Clinical Trial Application (CTA).
Published Version: doi:10.1038/mtm.2016.74
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142463/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29738926
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