Advanced Pancreatic Cancer: Oncolytic Virus–Based Immunostimulatory Gene Therapy Plus Chemotherapy

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In a single-center phase I/II study (LOKON001) reported in The Lancet Oncology, Musher et al found that treatment with an oncolytic virus–based immunostimulatory gene therapy (LOAd703) plus chemotherapy was feasible and safe in patients with unresectable or metastatic pancreatic ductal adenocarcinoma.

As stated by the investigators, “Pancreatic ductal adenocarcinoma is characterized by low immunogenicity and an immunosuppressive tumor microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumor regression in preclinical models.”

Study Details

In arm 1 of the trial, reported herein, 21 treatment-naive or previously treated patients were enrolled at the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine between December 2016 and October 2019.  Patients were assigned to receive three dose levels of LOAd703, consisting of 500 μL of LOAd703 at 5 × 1010 (dose 1, n =  3), 1 × 1011 (dose 2, n = 4), or 5 × 1011 (dose 3, n = 14) viral particles per injection; injection was performed endoscopically or percutaneously into the pancreatic tumor or a metastasis every 2 weeks for six injections. All patients received 28-day cycles of nab-paclitaxel at 125 mg/m² plus gemcitabine at 1,000 mg/m² for up to 12 cycles.

Key Findings

Among all patients, the most common grade 3 or 4 adverse events were lymphopenia (53%), neutropenia (53%), anemia (53%), leukopenia (34%), and hypertension (29%). The most common adverse events of any grade attributed to LOAd703 were fever (67%); fatigue (38%); chills (33%); and elevated liver enzymes including alanine aminotransferase (24%), alkaline phosphatase (19%), and aspartate aminotransferase 19% (all grade 1 or 2 except for grade 3 in 1 patient). The most common serious adverse events were fever (29%), sepsis (19%), anemia (14%), limb edema (14%), and lower gastrointestinal bleeding (14%). Maximum tolerated dose was not reached, indicating that dose 3 was the highest safe dose to be used in combination with nab-paclitaxel plus gemcitabine.

Among 16 patients who underwent T-cell assays, proportions of CD8-positive effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%). Among 18 patients evaluable for response, 8 (44%, 95% confidence interval [CI] = 25%–66%) had objective responses, which were all partial. The disease control rate was 94% (95% CI = 74%–99%).

The investigators concluded, “Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing.”

Benjamin L. Musher, MD, of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Lokon Pharma, Swedish Research Council, and others. For full disclosures of the study authors, visit

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