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The safety of oncolytic adenovirus-mediated suicide and interleukin-12 ( IL 12 ) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/ mut TK SR39 rep -hIL-12) expressing yCD/ mut TK SR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 ( IL 12 ) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 10 11 , 3 × 10 11 , or 1 × 10 12 viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL 12 , interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/ mut TK SR39 rep -hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/ mut TK SR39 rep -hIL-12 DNA was detected in the blood of two patients. Elevated serum IL 12 , IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/ mut TK SR39 rep -hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5-20.0) months. The study maximum tolerated dose (MTD) was not reached., Competing Interests: K.N.B. and S.O.F. hold a patent “Methods and Composition for Cancer Therapy Using a Novel Adenovirus” (#7,815,902 B2) for an adenovirus similar to the one used in this study., (© 2020 The Authors.)