Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms

Abstract

Background: Oncolytic virotherapy is an upcoming treatment option for many tumor entities. But so far, a first oncolytic virus only was approved for advanced stages of malignant melanomas. Neuroendocrine tumors (NETs) constitute a heterogenous group of tumors arising from the neuroendocrine system at diverse anatomic sites. Due to often slow growth rates and (in most cases) endocrine non-functionality, NETs are often detected only in a progressed metastatic situation, where therapy options are still severely limited. So far, immunotherapies and especially immunovirotherapies are not established as novel treatment modalities for NETs. Methods: In this immunovirotherapy study, pancreatic NET (BON-1, QGP-1), lung NET (H727, UMC-11), as well as neuroendocrine carcinoma (NEC) cell lines (HROC-57, NEC-DUE1) were employed. The well characterized genetically engineered vaccinia virus GLV-1 h68, which has already been investigated in various clinical trials, was chosen as virotherapeutical treatment modality. Results: Profound oncolytic efficiencies were found for NET/NEC tumor cells. Besides, NET/NEC tumor cell bound expression of GLV-1 h68-encoded marker genes was observed also. Furthermore, a highly efficient production of viral progenies was detected by sequential virus quantifications. Moreover, the mTOR inhibitor everolimus, licensed for treatment of metastatic NETs, was not found to interfere with GLV-1 h68 replication, making a combinatorial treatment of both feasible. Conclusions: In summary, the oncolytic vaccinia virus GLV-1 h68 was found to exhibit promising antitumoral activities, replication capacities and a potential for future combinatorial approaches in cell lines originating from neuroendocrine neoplasms. Based on these preliminary findings, virotherapeutic effects now have to be further evaluated in animal models for treatment of Neuroendocrine neoplasms (NENs).

In Vitro Sensitivity of Neuroendocrine Neoplasms to an Armed Oncolytic Measles Vaccine Virus

“…When studying the viral growth kinetics of MeV-SCD in the presence and absence of everolimus in NEN tumor cells, we did not observe altered virus growth. Interestingly, in another study using the oncolytic vaccinia virus GLV-1h68, everolimus also neither impaired nor enhanced viral replication in NEN cells [29]. The same results were obtained for the later-discussed oncolytic herpes simplex virus talimogene laherparepvec (T-VEC) [28].…”

“…Interestingly, the vaccinia virus GLV-1h68 has also been shown to reduce several NET and NEC cell lines in a dose-dependent manner: three of them proved to be highly permissive towards the chosen criteria, three were defined as intermediate permissive, and no resistant NEN cell line was found, which has been interpreted as a pretty good result [29].…”

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

“…Talimogene laherparepvec is a first-generation, state-of-the-art HSV-1-based oncolytic virus that does not integrate its viral DNA into the host genome and that shows high oncolytic efficacy at low concentrations when applied to NETs and NECs [ 105 ]. GLV-1 h68 relies on vaccinia viruses that also do not disturb the host genome and have a good oncolytic effect against NETs and NECs [ 106 ].…”

Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies

“…The Lauer group demonstrated that GLV-1h68, which includes three expression cassettes encoding β-glucuronidase, β-galactosidase and green fluorescent protein (GFP), exhibits stable cytotoxicity in human NET cells of various anatomical origins and also a highly efficient production of progeny virus particles. Moreover, additional combination with the mTOR inhibitor everolimus, which is approved for treatment of metastatic NETs, did not impair replication of GLV-1h68 suggesting that combinatorial treatment is not an obstacle for further development of the approach [ 73 ].…”