Tumor microenvironment gene engineering with LOAd703 in patients with solid malignancies: LOKON002 phase I/IIb clinical trial.

PURPOSE: Patients with advanced cancer have a poor prognosis and need for novel treatments. LOAd703 is a tumor microenvironment (TME) gene engineering viral vector encoding genes targeting the CD40 and 4-1BB pathways. In this study, tolerability (primary endpoint), response activity, and the capacity to inflame the TME were evaluated. PATIENTS AND METHODS: In an open-label, single arm phase I/IIb clinical trial (NCT03225989), maximum eight intratumoral injections of LOAd703 were administered biweekly combined with a gemcitabine-based chemotherapy regimen, either standard-of-care treatment or conditioning gemcitabine if no standard options were available. Dose escalation followed a standard 3+3 design (phase I) and, to optimize dosage, the two highest dose levels were expanded in phase II. RESULTS: Forty-one patients were enrolled with pancreatic cancer (n=29), colorectal cancer (n=5), ovarian cancer (n=4) and biliary cancer (n=3). The treatment was overall well tolerated with the most common adverse events attributed to LOAd703 being pyrexia (76%), chills (39%) and fatigue (34%), mostly grade 1-2. The overall response rate (ORR) was 0 in the LOAd703 dose cohort 5x1010 viral particles (VP), 25% in 1x1011 VP, and 12% in 5x1011 VP. All patients with an objective response had pancreatic cancer and were treated in first line (ORR 35%). The TME showed a significant upregulation of Th1 immunity biomarkers at week 13 post treatment initiation. CONCLUSIONS: TME gene engineering using LOAd703 inflamed immune cold tumors and was followed by long term stabilized disease in several patients. Further evaluation of LOAd703 together with chemotherapy and/or checkpoint inhibitors is warranted.