Journal
STEM CELLS
Volume 27, Issue 3, Pages 753-760Publisher
WILEY
DOI: 10.1634/stemcells.2008-0831
Keywords
Mesenchymal stem cell; Cancer; Immunotherapy; Gene therapy
Categories
Funding
- Ministerio de Ciencia e Innovacion [BIO2005-04794]
- Comunidad Autonoma de Madrid [S-BIO-0236-2006]
- Fondo de Investigacion Sanitaria [PI061621]
- Instituto de Salud Carlos III [CM06/00055]
- Comunidad Autonoma de Madrid/European Social Fund [FPI- 000531]
- Gobierno Vasco [BFI07.132]
- European Social Fund
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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 con. ne MSCs to a determined location, compatible with a clinical application. Human MSCs genetically modified to express luciferase (MSCluc), 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 (alpha CEA)/alpha CD3 diabody (MSCdAb) 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 alpha CEA/alpha CD3 diabody activated T cells and promoted tumor cell lysis. Reduction of tumor growth in MSCdAb-treated mice was statistically significant compared with animals that only received MSCluc. In summary, we report here for the first time that human MSCs genetically engineered to secrete a bispecifi diabody, seeded in an sECM scaffold and implanted in a location distant from the primary tumor, induce an effective antitumor response and tumor regression.
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