Abstract
Several works have shown the feasibility of engineering functional blood vessels in vivo using human endothelial cells (ECs). Going further, we explored the therapeutic potential of neovessels after gene-modifying the ECs for the secretion of a therapeutic protein. Given that these vessels are connected with the host vascular bed, we hypothesized that systemic release of the expressed protein is immediate. As a proof of principle, we used primary human ECs transduced with a lentiviral vector for the expression of a recombinant bispecific αCEA/αCD3 antibody. These ECs, along with mesenchymal stem cells as a source of mural cells, were embedded in Matrigel and subcutaneously implanted in nude mice. High antibody levels were detected in plasma for 1 month. Furthermore, the antibody exerted a therapeutic effect in mice bearing distant carcinoembryonic-antigen (CEA)-positive tumors after inoculation of human T cells. In summary, we show for the first time the therapeutic effect of a protein locally secreted by engineered human neovessels.
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References
Koike N, Fukumura D, Gralla O, Au P, Schechner JS, Jain RK . Tissue engineering: creation of long-lasting blood vessels. Nature 2004; 428: 138–139.
Sanz L, Santos-Valle P, Alonso-Camino V, Salas C, Serrano A, Vicario JL et al. Long-term in vivo imaging of human angiogenesis: critical role of bone marrow-derived mesenchymal stem cells for the generation of durable blood vessels. Microvasc Res 2008; 75: 308–314.
Au P, Tam J, Fukumura D, Jain RK . Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 2008; 111: 4551–4558.
Melero-Martin JM, Khan ZA, Picard A, Wu X, Paruchuri S, Bischoff J . In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood 2007; 109: 4761–4768.
Melero-Martin JM, De Obaldia ME, Kang SY, Khan ZA, Yuan L, Oettgen P et al. Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 2008; 103: 128–130.
Sanz L, Kristensen P, Blanco B, Faceteau S, Russell SJ, Winter G et al. Single-chain antibody-based gene therapy: inhibition of tumor growth by in situ production of phage-derived human antibody fragments blocking functionally active sites of cell-associated matrices. Gene Therapy 2002; 15: 1049–1053.
Blanco B, Holliger P, Vile RG, lvarez-Vallina L . Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells. J Immunol 2003; 171: 1070–1077.
Compte M, Blanco B, Serrano F, Cuesta AM, Sanz L, Bernad A et al. Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA x anti-CD3 diabodies from lentivirally transduced human lymphocytes. Cancer Gene Ther 2007; 14: 380–388.
Holliger P, Hudson PJ . Engineered antibody fragments and the rise of single domains. Nat Biotechnol 2005; 23: 1126–1136.
Compte M, Cuesta AM, Sánchez-Martín D, Alonso-Camino V, Vicario JL, Sanz L et al. Tumor immunotherapy using gene-modified human mesenchymal stem cells loaded into synthetic extracellular matrix scaffolds. Stem Cells 2009; 27: 753–760.
Holliger P, Manzke O, Span M, Hawkins RE, Fleischmann B, Qinghua L et al. Carcinoembryonic antigen (CEA)-specific T-cell activation in colon carcinoma induced by anti-CD3 × anti-CEA bispecific diabodies and B7 × anti-CEA bispecific fusion proteins. Cancer Res 1999; 59: 2909–2916.
Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Know S et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008; 321: 974–977.
Holliger P, Prospero T, Winter G . ‘Diabodies:’ small bivalent and bispecific antibody fragments. Proc Natl Acad Sci USA 1993; 90: 6444–6448.
Perisic O, Webb PA, Holliger P, Winter G, Williams RL . Crystal structure of a diabody, a bivalent antibody fragment. Structure 1994; 2: 1217–1226.
Lazennec G, Jorgensen C . Concise review: adult multipotent stromal cells and cancer: risk or benefit? Stem Cells 2008; 26: 1387–1394.
Segal DM, Weiner GJ, Weiner LM . Bispecific antibodies in cancer therapy. Curr Opin Immunol 1999; 11: 558–562.
Sanz L, Blanco B, Alvarez-Vallina L . Antibodies and gene therapy: teaching old ‘magic bullets’ new tricks. Trends Immunol 2004; 25: 85–91.
Aboody KS, Najbauer J, Danks MK . Stem and progenitor cell-mediated tumor selective gene therapy. Gene Therapy 2008; 15: 739–752.
Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 49: 557–563.
Roth JC, Curiel DT, Pereboeva L . Cell vehicle targeting strategies. Gene Therapy 2008; 15: 716–729.
Eliopoulos N, Francois M, Boivin MN, Martienau D, Galipeau J . Neo-organoid of marrow mesenchymal stromal cells secreting interleukin-12 for breast cancer therapy. Cancer Res 2008; 68: 4810–4818.
Acknowledgements
This work was supported by grants from the Ministerio de Ciencia e Innovación (BIO2008-03233), the Comunidad Autónoma de Madrid (S-BIO-0236-2006) and the European Union (Immunonet–SUDOE) to LA-V; and from the Fondo de Investigación Sanitaria (PI061621) to LS. MC was supported by Instituto de Salud Carlos III (Contrato Rio Hortega, CM06/00055). DS-M was supported by a Comunidad Autónoma de Madrid/European Social Fund training grant (FPI-000531). LS is an investigator from the Ramón y Cajal Program (Ministerio de Ciencia e Innovación), co-financed by the European Social Fund. VAC is a predoctoral fellow from the Gobierno Vasco (BFI07.132).
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Compte, M., Alonso-Camino, V., Santos-Valle, P. et al. Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system. Gene Ther 17, 745–751 (2010). https://doi.org/10.1038/gt.2010.33
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DOI: https://doi.org/10.1038/gt.2010.33
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