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-1h68, 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-1h68-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-1h68 replication, making a combinatorial treatment of both feasible. Conclusions: In summary, the oncolytic vaccinia virus GLV-1h68 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).

Immunotherapy in Gastroenteropancreatic Neuroendocrine Neoplasia

“…Susceptibility to GLV-1 h68 treatment was found to be dose-dependent. Comparing these results to other OVs already tested in NENs, GLV-1 h68 showed favorable cytotoxicity for pan-NETs and NECs [113]. The oHSV T-VEC was found to be particularly effective in lung and pan-NETs previously.…”

“…GLV-1 h68 showed favorable cytotoxicity for pan-NETs and NECs [113]. The oHSV T-VEC was found to be particularly effective in lung and pan-NETs previously.…”

“…After preclinically testing T-VEC in human NEC, Kloker et al [113] evaluated the potential of GLV-1 h68 to kill cells originating from NEC. GLV-1 h68 (proprietary name GL-ONC1) carries 3 separate transgenic expression cassettes (encoding β-glucuronidase, β-galactosidase, and the Ruc-GFP marker gene) inserted into a VACV backbone derived from the Lister strain.…”

“…Furthermore, it was found that everolimus does not influence GLV-1 h68 replication negatively. The combinatorial treatment of the GLV-1 h68 with everolimus was slightly superior and significantly more effective than any single agent treatment to deplete tumor cells in the panel of human NET/NEC cell lines, making this combined treatment modality feasible for further investigations [113].…”

Drug Development in Neuroendocrine Tumors: What Is on the Horizon?

“…It was found that GLV-1 h68 is able to infect and reduce tumor cell masses in six NET and NEC cell lines in a dose-dependent manner. High titers of extracellular viral payload were observed [91].…”