Abstract
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.
Highlights
According to the American Cancer Society, there will be an estimated 57,600 new cases of pancreatic cancer in 2020.1 Of those new cases, approximately 50% will be diagnosed as advanced or metastatic disease
We explored the concept of combining our suicide gene therapy with a cytokine to promote the immune system activation against tumors
Ad5-yCD/mutTKSR39rep-hIL-12 doses were escalated from 1 Â 1011 to 1 Â 1012 vp in three half-log steps followed by 7 days of 5-FC prodrug therapy starting on day 2 and chemotherapy starting 21 days after adenovirus injection
Summary
According to the American Cancer Society, there will be an estimated 57,600 new cases of pancreatic cancer in 2020.1 Of those new cases, approximately 50% will be diagnosed as advanced or metastatic disease. Standard treatment options for these patients include systemic therapy with and without radiation.[3,4] For patients with good performance scores, FOLFIRINOX (leucovorin, 5-fluorouracil [5-FU], irinotecan, oxaliplatin) or gemcitabine + albumin-bound paclitaxel has become the standard of care. Even with these first-line therapies, the overall survival of metastatic pancreatic cancer patients is 11.1 and 6.8 months for patients who received FOLFIRINOX and gemcitabine + albuminbound paclitaxel, respectively.[5] Toxicities associated with FOLFIRINOX limit its widespread application in patients with poor performance status. Owing to the limited survival duration of patients with metastatic pancreatic cancer, novel and alternative therapies are desperately needed
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