title: Development of a successful antitumor therapeutic model combining in vivo dendritic cell vaccination with tumor irradiation and intratumoral GM-CSF delivery.
abstract: Vaccination of dendritic cells (DC) combined with GM-CSF secreting tumor cells has shown good therapeutic efficacy in several tumor models. Nevertheless, the engineering of GM-CSF secreting tumor cell line could represent a tedious step limiting its application for treatment in patients. We therefore developed in rats, an "all in vivo" strategy of combined vaccination using an in vivo local irradiation of the tumor as a source of tumor antigens for DC vaccines and an exogenous source of GM-CSF. We report here that supplying recombinant mGM-CSF by local injections or surgical implantation of osmotic pumps did not allow reproducing the therapeutic efficacy observed with in vitro prepared combined vaccines. To bypass this limitation possibly due to the short half-life of recombinant GM-CSF, we have generated adeno-associated virus coding for mGM-CSF and tested their efficacy to transduce tumor cells in vitro and in vivo. The in vivo vaccines combining local irradiation and AAV2/1-mGM-CSF vectors showed high therapeutic efficacy allowing to cure 60% of the rats with pre-implanted tumors, as previously observed with in vitro prepared vaccines. Same efficacy has been observed with a second generation of vaccines combining DC, local tumor irradiation, and the controlled supply of recombinant mGM-CSF in poloxamer 407, a biocompatible thermoreversible hydrogel. By generating a successful "all in vivo" vaccination protocol combining tumor radiotherapy with DC vaccines and a straightforward supply of GM-CSF, we have developed a therapeutic strategy easily translatable to clinic that could become accessible to a much bigger number of cancer patients.
authors.affiliation: Interdisciplinary Research Institute (IRIBHM), Université Libre de Bruxelles, Faculty of Medicine, route de Lennik 808, Brussels, Belgium. g_driessens@hotmail.com
authors.forename: Gregory
authors.initials: G
authors.lastname: Driessens
authors.forename: Lise
authors.initials: L
authors.lastname: Nuttin
authors.forename: Alain
authors.initials: A
authors.lastname: Gras
authors.forename: Julie
authors.initials: J
authors.lastname: Maetens
authors.forename: Stephane
authors.initials: S
authors.lastname: Mievis
authors.forename: Marylène
authors.initials: M
authors.lastname: Schoore
authors.forename: Thierry
authors.initials: T
authors.lastname: Velu
authors.forename: Liliane
authors.initials: L
authors.lastname: Tenenbaum
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
authors.forename: Catherine
authors.initials: C
authors.lastname: Bruyns
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D015552:Injections, Intralesional; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000532:radiotherapy* / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor