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), a maximum of 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 (n = 29), colorectal (n = 5), ovarian (n = 4), and biliary cancers (n = 3). Treatment was generally well tolerated. The most common LOAd703-related adverse events were pyrexia (76%), chills (39%), and fatigue (34%), mostly grade 1 to 2. The overall response rate (ORR) was 0 in the LOAd703 dose cohort 5 × 1010 viral particles (VP), 25% in 1 × 1011 VP, and 12% in 5 × 1011 VP. All patients with an objective response had pancreatic cancer and received first-line treatment (ORR, 35%). The TME showed a significant upregulation of Th1 immunity biomarkers at week 13 posttreatment 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.