title: Anti-Tumor Effects after Adoptive Transfer of IL-12 Transposon-Modified Murine Splenocytes in the OT-I-Melanoma Mouse Model.
abstract: Adoptive transfer of gene modified T cells provides possible immunotherapy for patients with cancers refractory to other treatments. We have previously used the non-viral piggyBac transposon system to gene modify human T cells for potential immunotherapy. However, these previous studies utilized adoptive transfer of modified human T cells to target cancer xenografts in highly immunodeficient (NOD-SCID) mice that do not recapitulate an intact immune system. Currently, only viral vectors have shown efficacy in permanently gene-modifying mouse T cells for immunotherapy applications. Therefore, we sought to determine if piggyBac could effectively gene modify mouse T cells to target cancer cells in a mouse cancer model. We first demonstrated that we could gene modify cells to express murine interleukin-12 (p35/p40 mIL-12), a transgene with proven efficacy in melanoma immunotherapy. The OT-I melanoma mouse model provides a well-established T cell mediated immune response to ovalbumin (OVA) positive B16 melanoma cells. B16/OVA melanoma cells were implanted in wild type C57Bl6 mice. Mouse splenocytes were isolated from C57Bl6 OT-I mice and were gene modified using piggyBac to express luciferase. Adoptive transfer of luciferase-modified OT-I splenocytes demonstrated homing to B16/OVA melanoma tumors in vivo. We next gene-modified OT-I cells to express mIL-12. Adoptive transfer of mIL-12-modified mouse OT-I splenocytes delayed B16/OVA melanoma tumor growth in vivo compared to control OT-I splenocytes and improved mouse survival. Our results demonstrate that the piggyBac transposon system can be used to gene modify splenocytes and mouse T cells for evaluating adoptive immunotherapy strategies in immunocompetent mouse tumor models that may more directly mimic immunotherapy applications in humans.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Galvan
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: O'Neil
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Foster
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Leslie
authors.initials: L
authors.lastname: Huye
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Adham
authors.initials: A
authors.lastname: Bear
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, United States of America; Tennessee Valley Health Care, Department of Veterans Affairs, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Wilson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004251:DNA Transposable Elements; D006367:HeLa Cells; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013154:Spleen; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation*
chemical_list: D004251:DNA Transposable Elements; D018664:Interleukin-12