GLV-1h68 vaccinia virus therapy of neuroendocrine tumors
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
... y 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. Further more, a highly efficient production of viral progenies was detected by sequential virus quantifications. More over, prospects of a combinatorial treatment of GLV-1h68 with the mTOR inhibitor everolimus, licensed for treatment of metastatic NETs, were assessed successfully. 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. This has been shown in a widespread spectrum of cancers in a preclinical setting and now has to be further evaluated for treatment of metastatic neuroendocrine cancer. Background 3 Neuroendocrine neoplasms (NENs) are rare tumors which are developing in widespread anatomical origins such as the pancreas, lung and intestine. Only the minority of tumors show hormonal functionality, so that approximately 70% of NENs are non-functional and therefore asymptomatic in early stages. Accordingly, patients frequently present only in late metastatic disease stages. This as well as the rising incidence makes NENs an upcoming challenge in oncology . NENs are subclassified into neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Generally, surgery is the treatment of choice for NENs in an early, still localized stage. In addition to classical chemotherapy and radiation, somatostatin analogues, peptide receptor radiotherapy, small molecule compounds such as sunitinib or everolimus are available for unresectable NETs . Treatment options for NECs are still often restricted to chemotherapy and radiation . Further therapy options for unresectable tumors such as several multi-kinase inhibitors or peptide receptor chemoradionuclide therapy are under development [4, 5] and also new therapeutic targets and treatment combination strategies are under extensive preclinical investigation . Only very few approaches using oncolytic virotherapy in NEN treatment have been described so far [7-10]: oncolytic viruses (OV) are engineered to specifically target tumor cells, to produce enormous amounts of viral progeny within and thus to damage them harshly, resulting in significant rates of tumor cell lysis, i.e. oncolysis. Furthermore, infections by OV were found to turn immunosuppressive "cold" tumor microenvironments into "hot" ones by attracting a significant influx of immune cells. As a result, profound and long-lasting antitumoral immune responses can be induced. The oncolytic virus employed in this study is a genetically modified DNA virus which has already been tested intensively in clinical settings. GLV-1h68 (proprietary name GL-ONC1) carries three separate transgenic expression cassettes (encoding β-glucuronidase, β-Vaccinia virus and cyclophosphamide results in synergistic antitumor effects in human lung adenocarcinoma bearing mice. , Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma.