Oncolytic Viruses: An Inventory of Shedding Data from Clinical Trials and Elements for the Environmental Risk Assessment

Abstract

Attenuated and/or genetically modified oncolytic viruses (OV) gain increasing interest as a promising approach for cancer therapy. Beside the assessment of subject safety, quality and efficacy aspects of medicinal products for human use, genetically modified viruses are also governed by EU regulatory frameworks requiring an environmental risk assessment (ERA). An important element to be assessed as part of the ERA is the incidence of exposure to OV of individuals, other than the trial subjects, and the environment. The evidence-based evaluation of shedding data is considered to be decisive in that context, as it may impact the OV capacity to be transmitted. This is particularly true for OV still able to (conditionally) replicate as opposed to replication-defective viral vectors commonly used in gene therapy or vaccination. To our knowledge, this article presents the most extensive and up-to-date review of shedding data reported with OV employed in clinics. Besides the identification of a topical need for improving the collection of shedding data, this article aims at providing an aid to the design of an appropriate shedding study, thereby relying on and further complementing principles described in existing guidelines issued by European and international institutions.

Keywords: biosafety; cancer; clinical trials; environmental risk assessment; oncolytic virus; shedding.

Figure 5

Routes of administration for oncolytic viruses in clinical trials. (a) Route of administration by type of oncolytic vectors. (b) Most commonly used administration routes in clinical trials. Most virus deliveries were performed by intratumoral route (n = 84). Other routes include, among others, intradermal injection (8/165), intramuscular injection (1/165) and hepatic arterial injection (4/165). (c) Route of administration by type of cancer. IT = intratumoral; IV = intravenous. Sarcomas also include soft-tissue sarcoma. Brain cancers include central nervous system (CNS) cancer, glioma and glioblastoma. Gynecologic malignancies include ovarian cancer, tubal cancer, endometrial cancer or peritoneal cancer. Abdominal cancers include liver cancer, colorectal cancer, pancreatic cancer, kidney cancer (renal cell cancer) and stomach cancer (gastric cancer).

Figure 1

Mechanism of action of oncolytic viruses. OV infect healthy cells but cannot replicate. High infection of cancer cells where OV replicate and package for the production of new viral particles. A high viral load inside the cell causes tumor cell lysis releasing viral particles and tumor antigens in the cancer microenvironment. The viral particles’ progeny can infect other tumor cells while the released tumor antigens stimulate the host anti-tumor immune response. TA = tumor antigen; DC = dendritic cell.

Figure 2

Type of oncolytic viruses used in oncolytic virus clinical trials. Based on the results obtained in the Supplementary Table S1 of this article, a graph representing the number of clinical trials that have been performed by type of oncolytic virus all over the world has been generated. Taken together, the number of clinical trials with Adenovirus and Herpesvirus represents slightly more than half of all clinical trials with OV.

Figure 3

On the left, the number of clinical trials that reported information on viral genome shedding (n = 70). On the right, the method of detection used during the shedding analyses, reported within the 70 clinical trials. The method “PCR” includes all types of PCR (quantitative PCR, real-time PCR, reverse transcription PCR, etc.). The infectivity test includes cell culture and plaque assays. Other methods include viruria and direct fluorescence hexon protein assay.

Figure 4

The number of clinical trials (by type of viral vector) for which the detection of viral genome was observed or was not observed in shedding samples.

Figure 6

Body fluids collected for the shedding analysis. The numbers reported in the graph correspond to the number of clinical trials in which the corresponding samples were collected. Other samples include, among others, dressing swabs, lesion swabs, rash swabs, pustules swabs, etc.

Figure 7

Possible risk-mitigation measures. The lines indicate observed trends in shedding results obtained from clinical trials involving OV. The thickness of the lines is proportional to shedding results per OV type.