RESUMO
Helicobacter pylori neutrophil-activating protein (NAP) is a major virulence factor and powerful inducer of inflammatory reaction and Th1-polarized immune response. Here, we evaluated the therapeutic efficacy of measles virus (MV) strains engineered to express secretory NAP forms against metastatic breast cancer. Recombinant viruses encoding secretory NAP forms (MV-lambda-NAP and MV-s-NAP) efficiently infect and destroy breast cancer cells by cell-to-cell viral spread and large syncytia formation independently of hormone receptor status. Intrapleural administration of MV-s-NAP doubled the median survival in a pleural effusion xenograft model: 65 days as compared to 29 days in the control group (P < 0.0001). This therapeutic effect correlated with a brisk Th1 type cytokine response in vivo. Secretory NAP was expressed at high levels by infected tumor cells and increased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-12/23 cytokine concentrations were detected in the pleural effusion. In an aggressive model of lung metastatic breast cancer, MV-lambda-NAP and MV-s-NAP also significantly improved survival of the treated animals (P < 0.05) as compared to the control MV strain. These data suggest that potent immunomodulators of bacterial origin, such as H. pylori NAP, can enhance the antitumor effect of oncolytic viruses and support the feasibility and potential of a combined viroimmunotherapy approach.
Assuntos
Proteínas de Bactérias/genética , Neoplasias da Mama/terapia , Helicobacter pylori , Fatores Imunológicos/genética , Vírus do Sarampo/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Animais , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Ordem dos Genes , Helicobacter pylori/imunologia , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Nus , Camundongos Transgênicos , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Derrame Pleural Maligno/imunologia , Replicação Viral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The sodium-iodide symporter (NIS) is primarily a thyroid protein, providing for the accumulation of iodide for biosynthesis of thyroid hormones. Native NIS expression has made possible the use of radioactive iodide to image and treat thyroid disease successfully. The current study, using adult male beagle dogs, was carried out in preparation for a Phase I clinical trial of adenovirus-mediated NIS gene (approved symbol SLC5A5) therapy for prostate cancer. Direct intraprostatic injection of virus (Ad5/CMV/NS) was followed by iv injection of 3 mCi 123I and serial image acquisition. The dogs were then given a therapeutic dose of 131I (116 mCi/m2) and observed for 7 days. SPECT/CT fusion imaging revealed clear images of the NIS-transduced prostates. Dosimetry calculations revealed an average absorbed dose to the prostate of 23 +/- 42 cGy/mCi 131I, with acceptably low radiation doses to other organs. This study demonstrated the successful introduction of localized NIS expression in the prostate gland of dogs, with no vector-related toxicity observed. None of the animals experienced any surgical complications, and serum chemistry panels showed no significant change following therapy. The results presented provide further evidence of the safety and efficacy of NIS as a therapeutic gene and support translation of this work into the clinical setting.