The overall goals of Project 2 are 1) to study the mechanisms responsible for the efficacy of the HSVtk/GCV system in eradicating tumors and 2) to optimize and further characterize the treatment of malignant mesothelioma using the Herpes Simplex thymidine kinase (HSVtk) gene carried in recombinant viral vectors. Preliminary data indicate that administration of a """"""""first generation"""""""" adenovirus (Ad) vector containing the Herpes Simplex thymidine kinase (HSV) gene driven from a Rous Sarcoma Virus(RSV) promoter (Ad.RSVtk), in conjunction with the antiviral drug gancichovir (GCV), can eradicate established tumor in a model of human malignant mesothelioma growing within the peritoneal cavity of immunodeficient mice. This process appears to depend on a powerful """"""""bystander effect"""""""" whereby only a relatively small percentage of cells need to be transduced with the Ad.RSVtk gene. These experiments suggest that this system may be of efficacy in treating certain human cancers, such as malignant mesothelioma and others that grow in defined anatomic spaces. Before such a goal is reached, however, a number of important questions about the mechanisms by which tumor eradication is effected , the optimal mode of delivery, and the role of the immune system must be answered. In addition, it will be critical to optimize the system by evaluating the ability of improved viral vectors containing HSVtk generated in Project 1 to treat tumor. A major focus of this proposal will be to study possible mechanisms by which the HSVtk/GCV system eradicates tumor. Experiments examining the role of the role of the immune system, vascular system, and gap junctional transfer of toxic metabolites will be conducted. The treatment of malignant mesothelioma using the first generation Ad.RSVtk vector will be further characterized and optimized by developing and evaluating models of pleural mesothelioma in immunodeficient (nude) rats and immunocompetent animals (Fischer rat). Finally, the efficacy of second generation adenoviruses containing HSVtk and newly developed viral vectors containing hSVtk generated in Project 1 in treating models of mesothelioma in immunodeficient and immunocompetent animals will be studied. The information gained about he mechanisms and optimization of the HSVtk/GCV system and the testing of new vectors designed in Project 1 (i.e. adeno- associated virus) will be critical in designing and implementing new clinical trials in Project 3.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Aggarwal, Charu; Haas, Andrew R; Metzger, Susan et al. (2018) Phase I Study of Intrapleural Gene-Mediated Cytotoxic Immunotherapy in Patients with Malignant Pleural Effusion. Mol Ther 26:1198-1205
Moon, Edmund K; Wang, Liang-Chuan S; Bekdache, Kheng et al. (2018) Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. Oncoimmunology 7:e1395997
Klampatsa, Astero; Haas, Andrew R; Moon, Edmund K et al. (2017) Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM). Cancers (Basel) 9:
Moon, Edmund K; Ranganathan, Raghuveer; Eruslanov, Evgeniy et al. (2016) Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer. Clin Cancer Res 22:436-47
Liu, X; Barrett, D M; Jiang, S et al. (2016) Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice. Blood Cancer J 6:e430
Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang et al. (2016) A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors. Cancer Res 76:1578-90
O'Hara, Mark; Stashwick, Caitlin; Haas, Andrew R et al. (2016) Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy. Immunotherapy 8:449-60
Sterman, Daniel H; Alley, Evan; Stevenson, James P et al. (2016) Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFN? Combined with Chemotherapy. Clin Cancer Res 22:3791-800
Newick, Kheng; O'Brien, Shaun; Sun, Jing et al. (2016) Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization. Cancer Immunol Res 4:541-51
Liu, Xiaojun; Jiang, Shuguang; Fang, Chongyun et al. (2015) Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice. Cancer Res 75:3596-607

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