Intraperitoneal Oncolytic and Tumor Vaccination Therapy with Replication-Competent Recombinant Virus: The Herpes Paradigm

George      Coukos; Maria   Cecilia   Courreges; Fabian      Benencia

Abstract

The biological therapy of tumors using live viruses was first proposed a century ago but was abandoned due to potential virulence of wild-type strains. Thanks to advances in recombinant technology, replication-restricted strains have been genetically engineered, which replicate selectively within tumor cells. Examples include replication-competent mutants of herpes simplex virus (HSV), adenovirus, vesicular stomatitis virus, reovirus and measles virus. Replication-restricted oncolytic viruses are able to propagate selectively within solid tumor nodules exerting direct antitumor activity by killing infected tumor cells at the completion of a replicative cycle. In the process, they generate an intratumoral inflammatory response, which under the appropriate circumstances, may trigger the activation of an adaptive antitumor immune response, a process that has been named in situ tumor vaccination. Recombinant HSV may offer distinct advantages in oncolytic therapy of epithelial tumors. HSV is highly infectious to tumors of epithelial origin, resulting in high efficacy, there is considerable redundancy in HSV receptors, which makes the loss of HSV receptors by tumors due to mutations less likely and potent anti-herpetic drugs are commercially available, which may be used clinically to control undesired side effects. Herewith we describe the use of oncolytic viral therapy against intraperitoneal malignancies with special emphasis on oncolytic herpes simplex virus. We review the preclinical evidence on the efficacy and safety of intraperitoneal applications of HSV and discuss the rationale for its use for oncolytic therapy and in situ tumor vaccination of intraperitoneal tumors.

Keywords: oncolytic hsv, tumor vaccination therapy, herpes paradigm, replication-competent recombinant virus, herpes simplex virus