Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer

• Published in: Molecular therapy. Oncolytics Vol. 20; pp. 94 - 104
• Main Authors: Barton, Kenneth N., Siddiqui, Farzan, Pompa, Robert, Freytag, Svend O., Khan, Gazala, Dobrosotskaya, Irina, Ajlouni, Munther, Zhang, Yingshu, Cheng, Jingfang, Movsas, Benjamin, Kwon, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: clinical trials; cytokines; gene therapy; immunomodulation; metastasis; Original; pancreatic cancer; immunomodulation; gene therapy; pancreatic cancer; clinical trials; cytokines; metastasis
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2020.11.006

The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 1011, 3 × 1011, or 1 × 1012 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 IL12, 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/mutTKSR39rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39rep-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. [Display omitted] A phase I dose-escalation study was conducted to demonstrate the safety of oncolytic adenovirus-mediated suicide and interleukin-12 gene therapy combined with chemotherapy in metastatic pancreatic cancer patients. Our approach was shown to be safe, and there are indications of efficacy in patients who received the highest adenovirus dose.