First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor...

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Oncolytic viral therapy uses tumor-selective viruses to destroy cancer cells and stimulate antitumor immunity.
• The Western Reserve strain of vaccinia virus (VV), highly virulent in animal models, was engineered for tumor selectivity (vvDD) via targeted gene deletions.

Purpose of the Study:

• To evaluate the safety and tolerability of intratumoral vvDD in a first-in-human phase 1 dose escalation trial.
• To assess vvDD replication, spread to distant tumors, pharmacokinetics, pharmacodynamics, and clinical/immune responses in patients with advanced solid tumors.

Main Methods:

• Phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors.
• Dose escalation proceeded to a maximum feasible dose of 3 × 10^9 plaque-forming units (pfu) without dose-limiting toxicities.
• Evaluated safety, vvDD replication and spread, pharmacokinetics, pharmacodynamics, and clinical/immune responses.

Main Results:

• Intratumoral vvDD was well-tolerated, with dose escalation reaching 3 × 10^9 pfu without dose-limiting toxicities.
• Reproducible vvDD replication was observed in tumors; vvDD genomes/particles were recovered from injected and noninjected tumors.
• vvDD genomes were detected in blood, with acute detection in all patients at higher doses and delayed re-emergence in two patients. Fifteen patients showed symptoms consistent with ongoing vvDD replication.

Conclusions:

• Intratumoral vvDD administration is safe and well-tolerated in patients with advanced solid tumors.
• The oncolytic vaccinia virus demonstrated selective infection of injected and noninjected tumors.
• The study provides evidence of oncolytic activity and potential for triggering antitumor immune responses, warranting further clinical investigation.