Abstract
<jats:p><div>Abstract Purpose:<p>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.</p> Patients and Methods:<p>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.</p> Results:<p>Forty-one patients were enrolled with pancreatic (<i>n</i> = 29), colorectal (<i>n</i> = 5), ovarian (<i>n</i> = 4), and biliary cancers (<i>n</i> = 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 × 10<sup>10</sup> viral particles (VP), 25% in 1 × 10<sup>11</sup> VP, and 12% in 5 × 10<sup>11</sup> 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.</p> Conclusions:<p>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.</p></div></jats:p>