title: Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds.
abstract: Mesenchymal stem cells (MSCs) are appealing as gene therapy cell vehicles given their ease of expansion and transduction. However, MSCs exhibit immunomodulatory and proangiogenic properties that may pose a risk in their use in anticancer therapy. For this reason, we looked for a strategy to confine MSCs to a determined location, compatible with a clinical application. Human MSCs genetically modified to express luciferase (MSC(luc)), seeded in a synthetic extracellular matrix (sECM) scaffold (sentinel scaffold) and injected subcutaneously in immunodeficient mice, persisted for more than 40 days, as assessed by bioluminescence imaging in vivo. MSCs modified to express a bispecific alpha-carcinoembryonic antigen (alphaCEA)/alphaCD3 diabody (MSC(dAb)) and seeded in an sECM scaffold (therapeutic scaffolds) supported the release of functional diabody into the bloodstream at detectable levels for at least 6 weeks after implantation. Furthermore, when therapeutic scaffolds were implanted into CEA-positive human colon cancer xenograft-bearing mice and human T lymphocytes were subsequently transferred, circulating alphaCEA/alphaCD3 diabody activated T cells and promoted tumor cell lysis. Reduction of tumor growth in MSC(dAb)-treated mice was statistically significant compared with animals that only received MSC(luc). In summary, we report here for the first time that human MSCs genetically engineered to secrete a bispecific diabody, seeded in an sECM scaffold and implanted in a location distant from the primary tumor, induce an effective antitumor response and tumor regression.
authors.affiliation: Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Compte
authors.forename: Angel M
authors.initials: AM
authors.lastname: Cuesta
authors.forename: David
authors.initials: D
authors.lastname: Sánchez-Martín
authors.forename: Vanesa
authors.initials: V
authors.lastname: Alonso-Camino
authors.forename: José Luís
authors.initials: JL
authors.lastname: Vicario
authors.forename: Laura
authors.initials: L
authors.lastname: Sanz
authors.forename: Luís
authors.initials: L
authors.lastname: Alvarez-Vallina
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000628:therapy; D005109:Extracellular Matrix; D015316:Genetic Therapy / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016086:Lentivirus / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology; D054457:Tissue Scaffolds; D023041:Xenograft Model Antitumor Assays