Oncolytic virotherapy is an effective immunotherapeutic approach for cancer treatment via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines and promotion of antitumor T cell responses. Solid tumors limit the effectiveness of immunotherapeutics in diverse ways such as secretion of immunosuppressive cytokines and expression of immune inhibitory ligands to inhibit antitumor T cell function. Blocking programmed cell death protein (PD)-1 signaling, which mediates T cell suppression via engagement of its inhibitory ligands, PD-L1 or PD-L2, is of particular interest due to recent successes in many types of cancer. In syngeneic murine rhabdomyosarcoma models, we found that M3-9-M (MHC I high) but not 76-9 (MHC I low) tumors respond to oncolytic herpes simplex virus-1 (oHSV-1) and PD-1 blockade combination therapy. In addition, the therapeutic outcomes in M3-9-M tumor models correlated with the increased incidence of CD4+ and CD8+ T cells but not with the CD4+CD25+Foxp3+ regulatory T cell populations in the tumor. Overall, our data suggest the combination of PD-1 blockade and oHSV-1 may be an effective treatment strategy for childhood soft tissue sarcoma.
Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an anti-tumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the transforming growth factor beta receptor 1 (TGF-βR1) inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma. Mice that received HSV1716 or A8301 alone showed little to no benefit in efficacy and survival over controls. Conversely, mice given combination therapy exhibited tumor stabilization throughout the treatment regimen, which was reflected in significantly prolonged survival times including some complete responses. In vitro cell viability and virus replication assays showed that the rhabdomyosarcoma cell lines were generally insensitive to HSV1716 and A8301. Likewise, in vivo virus replication assays showed that HSV1716 titers moderately decreased in the presence of A8301. The enhanced efficacy instead appears to be dependent on the generation of an improved anti-tumor T cell response as determined by its loss in athymic nude mice and following in vivo depletion of either CD4+ or CD8+ cells. These data suggest TGF-β inhibition can augment the immunotherapeutic efficacy of oncolytic herpes virotherapy.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.