Oncolytic HSV1716, lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies in glioma, melanoma, H&NSCC, paediatric non-CNS solid tumours and malignant pleural mesothelioma. In total 82 patients have received HSV1716 and there has been no evidence of toxicity, no spread to surrounding normal tissue or no shedding in patients. The selectivity of HSV1716 for replication only in tumour cells and intimations of efficacy have been demonstrated.Autophagy is an adaptive response to multiple forms of cellular stress, including reactive oxygen species, nutrient and growth factor deprivation, hypoxia, DNA damage, damaged organelles or intracellular pathogens. The role of autophagy in cancer is unclear with conflicting evidence showing autophagy can both promote tumor progression by helping cells survive or, in contrast, act as a tumor suppressor mechanism . Although principally a cell survival mechanism, autophagy can have a defensive role by engulfing/degrading intracellular pathogens including viruses leading to the presentation of their intracellular antigens on the cell surface. During wild-type HSV-1 infection, ICP34.5 interferes with autophagy by binding beclin-1 (2) and, potentially, ICP34.5-deleted oncolytic HSV such as HSV1716 are therefore susceptible to autophagy-mediated inactivation. We investigated autophagy in several human cancer cell lines during both wild-type HSV-1 and oncolytic HSV1716 infection and noted the following results. Autophagy induction by HSV infection was cell type dependent with autophagy activation during both wild type and HSV1716 infections and, surprisingly, we noted that in SKOV3 cells, wild type but not HSV1716 induced an autophagy response. Further, in combination studies, chloroquine, an inhibitor of the autophagy-lysosomal pathway, was principally antagonistic with HSV1716, most probably by reducing the efficiency of viral replication. Therefore, our results suggest that optimal HSV1716 oncolysis requires a functional autophagy-lysosomal degradative pathway.
|Publication status||Published - 10 Apr 2014|
|Event||8th International Conference on Oncolytic Virus Therapeutics - Oxford, United Kingdom|
Duration: 10 Apr 2014 → 13 Apr 2014
|Conference||8th International Conference on Oncolytic Virus Therapeutics|
|Period||10/04/14 → 13/04/14|