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

Authors

Kenneth N. Barton, Henry Ford HealthFollow
Farzan Siddiqui, Henry Ford HealthFollow
Robert Pompa, Henry Ford HealthFollow
Svend O. Freytag, Henry Ford HealthFollow
Gazala Khan, Henry Ford HealthFollow
Irina Dobrosotskaya, Henry Ford HealthFollow
Munther Ajlouni, Henry Ford HealthFollow
Yingshu Zhang, Henry Ford HealthFollow
Jingfang Cheng, Henry Ford HealthFollow
Benjamin Movsas, Henry Ford HealthFollow
David Kwon, Henry Ford HealthFollow

Recommended Citation

Barton KN, Siddiqui F, Pompa R, Freytag SO, Khan G, Dobrosotskaya I, Ajlouni M, Zhang Y, Cheng J, Movsas B, and Kwon D. Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer. Mol Ther Oncolytics 2021; 20:94-104.

Document Type

Article

Publication Date

3-26-2021

Publication Title

Mol Ther Oncolytics

Abstract

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/mutTK(SR39) rep-hIL-12) expressing yCD/mutTK(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/mutTK(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/mutTK(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/mutTK(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.

PubMed ID

33575474

Volume

20

First Page

94

Last Page

104