Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility

Abstract

Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is less than 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic HSV, Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002

“…The in vitro HSV entry molecule expression and cytotoxicity data suggest that SARC-45 may be more susceptible than SARC-28 to infection with M002; however, the virus replicated equally in both cell lines after 24 hr of infection, and entry receptor molecule expression does not always correlate with higher viral entry. 23 Our in vivo studies examining the response to a single dose of M002 in immunocompromised mice bearing SARC-28 and SARC-45 in an immunoprivileged location confirmed the significant oncolytic effect of M002 in the absence of an adaptive host immune system. Previous studies demonstrated that human alveolar and embryonal rhabdomyosarcoma and renal sarcoma cell lines with high expression of CD111 were sensitive to in vitro killing by oHSV.…”

Third‐generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice

“…However, T‐01 had no detectable effect on HLE and JHH‐5 cells, likely because of the relatively low levels of T‐01 replication (Figure ). It cannot negate the possibility that the entry efficiency of T‐01 into cells and/or the expression levels of HSV receptors on cell lines used were involved in the cytopathic activities of T‐01 in addition to the levels of T‐01 replication . Such information may help to elucidate why some tumors are highly sensitive to oHSV, and may lead to methods for selecting patients with the most sensitive tumors in oHSV therapy.…”

Selective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant Cells

“…There is abundant evidence that HSV-1 mutants deficient in the ␥ 1 34.5 gene have oncolytic activities. This has been shown for tumors, including in the brain, colon, ovarian, breast, liver, and skin, in immunodeficient as well as in immunocompetent preclinical models (24)(25)(26)(27)(28)(29)(30)(31). However, the antitumor outcomes vary widely.…”

“…For example, HSV1716 is highly potent against hepatocellular carcinoma (30). With respect to neuroblastomas, HSV1716 exhibits activities from a complete response in the CHP-134 model to a mild effect in the SK-N-AS model (31). The underlying events are complex, but the nature of virus-host interactions seems a determinant.…”