Oncolytic viruses engineered for tumor-specific replication hold significant promise as cancer therapies, yet achieving adequate dosing and potency in patients with metastatic or advanced solid tumors has proven difficult, thereby restricting broader adoption. NG-350A is an innovative, plasma-stable adenovirus modified to encode a full-length agonist antibody against CD40, without compromising its inherent tumor-selective replication or cytotoxic capabilities. The safety and activity of NG-350A delivered either intravenously or intratumorally (IT) were investigated in a first-in-human phase Ia/Ib trial involving individuals with advanced/metastatic epithelial malignancies (NCT03852511). Separate dose-escalation cohorts were employed: intravenous dosing utilized four escalating levels with infusions scheduled on Days 1, 3, and 5 within a 57-day cycle, whereas IT dosing involved either a single injection on Day 1 or repeated injections on Days 1, 8, 15, and 22. The main goal was to establish safety and tolerability; additional aims included defining a recommended phase 2 dose, characterizing pharmacokinetics, and evaluating anti-vector immune responses. Twenty-five extensively pretreated participants were enrolled and treated (16 intravenous, 9 IT). Both administration routes proved safe and tolerable, showing no signs of toxicity linked to the transgene product or unintended viral replication outside tumors. Peak plasma concentrations (Cmax) of NG-350A rose proportionally with dose irrespective of route. Although neutralizing anti-adenoviral antibodies developed in nearly all patients, circulating vector genomes persisted detectably for up to 7 weeks post-final dose, most prominently at higher intravenous doses. Successful vector delivery into tumor tissue was confirmed by PCR in post-treatment biopsies from both cohorts; intravenous administration exhibited clear dose-dependency, with four individuals still harboring detectable vector DNA on Day 57. Evidence of active viral replication and transgene transcription (detection of transgene mRNA) occurred in 5/12 intravenous and 1/9 IT patients. Dosing triggered prolonged elevation of multiple inflammatory cytokines, with the most pronounced and durable responses seen at higher intravenous dose levels. This early-phase clinical evaluation delivered clear proof-of-mechanism for NG-350A, confirming effective tumor transduction, intra-tumoral replication, and functional transgene expression — especially via the intravenous route. The favorable safety profile, devoid of transgene- or off-target-related adverse events, underscores the vector’s stringent tumor selectivity even when administered systemically. Further assessment of intravenously delivered NG-350A is ongoing in combination with pembrolizumab (NCT05165433) and with concurrent chemoradiotherapy (NCT06459869).
