First-in-man Study of Western Reserve Strain Oncolytic Vaccinia Virus: Safety, Systemic Spread, and Antitumor Activity
| Autor: | Lekshmi Ramalingam, Caroline J. Breitbach, Eva Wieckowski, Zong Sheng Guo, Pawel Kalinski, Herbert J. Zeh, Stephanie Downs-Canner, Kang Hu, Heather L. Jones, Anne Moon, John C. Bell, Stephen H. Thorne, J. Andrea McCart, Manijeh Daneshmand, David L. Bartlett, Mark E. O'Malley, Uma N. M. Rao, Tae-Ho Hwang, David H. Kirn |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Skin Neoplasms Dose-Response Relationship Immunologic Breast Neoplasms Vaccinia virus Biology Injections Intralesional Virus Replication Virus 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Pharmacokinetics Cell Line Tumor Drug Discovery Genetics medicine Animals Humans Molecular Biology Melanoma 030304 developmental biology Aged Pharmacology Oncolytic Virotherapy 0303 health sciences First-in-man study Middle Aged medicine.disease Virology 3. Good health Oncolytic virus Pancreatic Neoplasms Oncolytic Viruses chemistry 030220 oncology & carcinogenesis Cancer cell Colonic Neoplasms Molecular Medicine Original Article Female Vaccinia Gene Deletion |
| Popis: | Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity. |
| Databáze: | OpenAIRE |
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