Neoadjuvant administration of @entity3597 expressing interleukin-12 combined with attenuated @entity2491 eradicates XXXX @entity3 and achieves long-term survival in immunocompetent @entity19 .

@entity1 @entity2491 @entity3598 @entity0 @entity5 @entity19 @entity3 @entity3597 @entity204
BACKGROUND: Metastatic @entity0 is a major cause of @entity204 among @entity1 worldwide; therefore efficient therapeutic strategies are extremely needed. In this work we have developed a gene therapy- and bacteria-based combined neoadjuvant approach and evaluated its antitumor effect in a clinically relevant animal model of metastatic @entity0 . METHODS: 2*10(8) particles of a @entity3597 vector expressing interleukin-12 ( @entity3598 -IL-12) and/or 2*10(7) units of an aroC (-) @entity2491 (LVR01) were injected into 4T1 @entity5 nodules orthotopically implanted in @entity19 . @entity5 were surgically resected and long-term survival was determined. IL-12 and interferon-y were quantified by Enzyme-Linked ImmunoSorbent Assay, bacteria was visualized by inmunohistochemistry and the number of lung @entity3 was calculated with a clonogenic assay. RESULTS: @entity3598 -IL-12 and LVR01 timely inoculated and followed by surgical resection of @entity5 succeeded in complete inhibition of lethal lung @entity3 and long-term survival in 90% of treated @entity19 . The combined therapy was markedly synergistic compared to each treatment alone, since @entity3598 -IL-12 monotherapy showed a potent antiangiogenic effect, being able to inhibit @entity5 growth and extend survival, but could not prevent establishment of distant @entity3 and @entity204 of @entity5 -excised animals. On the other hand, LVR01 alone also showed a significant, although limited, antitumor potential, despite its ability to invade @entity0 cells and induce granulocyte recruitment. The efficacy of the combined therapy depended on the order in which both factors were administered; inasmuch the therapeutic effect was only observed when @entity3598 -IL-12 was administered previous to LVR01, whereas administration of LVR01 before @entity3598 -IL-12 had negligible antitumor activity. Moreover, pre-treatment with LVR01 seemed to suppress @entity3598 -IL-12 antiangiogenic effects associated to lower IL-12 expression in this group. Re-challenged @entity19 were unable to reject a second 4T1 @entity5 ; however 100% of them could be totally cured by applying the same neoadjuvant combined regimen. To our knowledge, these are the most encouraging results obtained to date in a post-operatory setting using the highly aggressive 4T1 animal model. CONCLUSIONS: @entity3598 -IL-12-based gene therapy combined with @entity2491 LVR01 neoadjuvant administration has a synergic antitumor effect and may be a promising therapeutic option to prevent and/or eradicate pre-operatory @entity3 in locally advanced @entity0 .
