Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers

• Published in: Molecular therapy Vol. 24; no. 8; pp. 1492 - 1501
• Main Authors: Downs-Canner, Stephanie, Guo, Zong Sheng, Ravindranathan, Roshni, Breitbach, Caroline J, O'Malley, Mark E, Jones, Heather L, Moon, Anne, McCart, Judith Andrea, Shuai, Yongli, Zeh, Herbert J, Bartlett, David L
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016; Elsevier Limited; Nature Publishing Group
• Subjects: Adult; Aged; Antibodies, Viral - immunology; Clinical trials; Combined Modality Therapy; Cytokines - metabolism; Drug dosages; FDA approval; Female; Genes; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - adverse effects; Genetic Vectors - genetics; Genetic Vectors - pharmacokinetics; Humans; Inflammation Mediators; Kinases; Liver cancer; Male; Melanoma; Metastasis; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neoplasms - diagnosis; Neoplasms - genetics; Neoplasms - mortality; Neoplasms - therapy; Oncolytic Virotherapy - adverse effects; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Oncolytic Viruses - immunology; Original; Patients; Poxviridae - genetics; Poxviridae - immunology; Poxvirus; Retreatment; Smallpox; Toxicity; Treatment Outcome; Uric acid; Vaccinia virus; Viral infections; Viruses; United States > US; Pittsburgh Pennsylvania
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2016.101

We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15–30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.