PCM-09COMPARISON OF THE SENSITIVITIES OF PEDIATRIC HIGH-GRADE BRAIN TUMOR VERSUS ADULT GLIOBLASTOMA XENOGRAFTS TO ENGINEERED ONCOLYTIC HERPES SIMPLEX VIROTHERAPY
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PROVIDER: S-EPMC4903739 | biostudies-literature | 2016 May
REPOSITORIES: biostudies-literature
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Project description:PurposeGlioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), has been implicated in this recurrence. The chemotherapeutic agent etoposide is generally reserved for treating recurrent tumors; however, its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low-dose etoposide with an oncolytic HSV to enhance antitumor activity and limit drug toxicity.Experimental designIn vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47Δ alone, or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method, and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events, and histologic detection of apoptosis.ResultsGSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47Δ was similar. Combining G47Δ with low-dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low-dose etoposide with G47Δ significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors.ConclusionsThe combination of low-dose etoposide with G47Δ increases survival of mice-bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.
| S-EPMC3229640 | biostudies-literature
Project description:Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), 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.
| S-EPMC4742391 | biostudies-literature
Project description:Vaccines and immunotherapeutic approaches to cancers with the advent of immune checkpoint inhibitors and chimeric antigen receptor-modified T cells have recently demonstrated preclinical success and entered clinical trials. Despite advances in these approaches and combinatorial therapeutic regimens, depending on the nature of the cancer and the immune and metabolic landscape within the tumor microenvironment, current immunotherapeutic modalities remain inadequate. Recent clinical trials have demonstrated clear evidence of significant, and sometimes dramatic, antitumor activity, and long-term survival effects of a variety of oncolytic viruses (OVs), particularly oncolytic herpes simplex virus (oHSV). Acting as a multifaceted gene therapy vector and potential adjuvant-like regimens, oHSV can carry genes encoding immunostimulatory molecules in its genome. The oncolytic effect of oHSV and the inflammatory response that the virus stimulates provide a one-two punch at attacking tumors. However, mechanisms underlying oHSV-induced restoration of intratumoral immunosuppression demand extensive research in order to further improve its therapeutic efficacy. In this review, we discuss the current OV-based therapy, with a focus on the unique aspects of oHSV-initiated antiviral and antitumor immune responses, arising from virus-mediated immunological cell death to intratumoral innate and adaptive immunity.
| S-EPMC5483455 | biostudies-other
Project description:Short-term nutritional restriction (fasting) has been shown to enhance the efficacy of chemotherapy by sensitizing cancer cells and protecting normal cells in a variety of cancer models, including glioblastoma (GBM). Cancer cells, unlike normal cells, respond to fasting by promoting oncogenic signaling and protein synthesis. We hypothesized that fasting would increase the replication of oncolytic herpes simplex virus (oHSV) in GBM. Patient-derived GBM cell lines were fasted by growth in glucose and fetal calf serum restricted culture medium. "Transient fasting", 24-hour fasting followed by 24-hour recovery in complete medium, increased late virus gene expression and G47Δ yields about 2-fold in GBM cells, but not in human astrocytes, and enhanced G47Δ killing of GBM cells. Mechanistically, "transient fasting" suppressed phosphorylation of the subunit of eukaryotic initiation factor 2α (eIF2α) and c-Jun N-terminal kinases (JNK) in GBM cells, but not in astrocytes. Pharmacological inhibition of JNK also increased G47Δ yield. In vivo, transient fasting (48-hour food restriction and 24-hour recovery) doubled luciferase activity after intratumoral G47Δ-US11fluc injection into orthotopic GBM xenografts. Thus, "transient fasting" increases G47Δ replication and oncolytic activity in human GBM cells. These results suggest that "transient fasting" may be effectively combined to enhance oncolytic HSV therapy of GBM.
| S-EPMC4859661 | biostudies-literature
Project description:Glioblastoma (GBM) is a lethal primary malignant brain tumor with no current effective treatments. The recent emergence of immuno-virotherapy and FDA approval of T-VEC have generated a great expectation towards oncolytic herpes simplex viruses (oHSVs) as a promising treatment option for GBM. Since the generation and testing of the first genetically engineered oHSV in glioma in the early 1990s, oHSV-based therapies have shown a long way of great progress in terms of anti-GBM efficacy and safety, both preclinically and clinically. Here, we revisit the literature to understand the recent advancement of oHSV in the treatment of GBM. In addition, we discuss current obstacles to oHSV-based therapies and possible strategies to overcome these pitfalls.
| S-EPMC7917312 | biostudies-literature
Project description:Oncolytic viruses (OV) are a class of antitumor agents that selectively kill tumor cells while sparing normal cells. Oncolytic herpes simplex virus (oHSV) has been investigated in clinical trials for patients with the malignant brain tumor glioblastoma for more than a decade. These clinical studies have shown the safety of oHSV administration to the human brain, however, therapeutic efficacy of oHSV as a single treatment remains unsatisfactory. Factors that could hamper the anti-glioblastoma efficacy of oHSV include: attenuated potency of oHSV due to deletion or mutation of viral genes involved in virulence, restricting viral replication and spread within the tumor; suboptimal oHSV delivery associated with intratumoral injection; virus infection-induced inflammatory and cellular immune responses which could inhibit oHSV replication and promote its clearance; lack of effective incorporation of oHSV into standard-of-care, and poor knowledge about the ability of oHSV to target glioblastoma stem cells (GSCs). In an attempt to address these issues, recent research efforts have been directed at: (1) design of new engineered viruses to enhance potency, (2) better understanding of the role of the cellular immunity elicited by oHSV infection of tumors, (3) combinatorial strategies with different antitumor agents with a mechanistic rationale, (4) "armed" viruses expressing therapeutic transgenes, (5) use of GSC-derived models in oHSV evaluation, and (6) combinations of these. In this review, we will describe the current status of oHSV clinical trials for glioblastoma, and discuss recent research advances and future directions toward successful oHSV-based therapy of glioblastoma.
| S-EPMC4064532 | biostudies-literature
Project description:Despite intensive research efforts and therapeutic advances over the last few decades, the pediatric neural crest tumor, neuroblastoma, continues to be responsible for over 15% of pediatric cancer deaths. Novel therapeutic options are needed for this tumor. Recently, investigators have shown that mice with syngeneic murine gliomas treated with an engineered, neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ 1 34.5 gene, enabling replication in tumor cells but precluding infection of normal neural cells. We hypothesized that M002 would also be effective in the neural crest tumor, neuroblastoma. We showed that M002 infected, replicated, and decreased survival in neuroblastoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly decreased tumor growth, and that this effect was augmented with the addition of ionizing radiation. Importantly, survival could be increased by subsequent doses of radiation without re-dosing of the virus. Finally, these studies showed that the primary entry protein for oHSV, CD111 was expressed by numerous neuroblastoma cell lines and was also present in human neuroblastoma specimens. We concluded that M002 effectively targeted neuroblastoma and that this oHSV may have potential for use in children with unresponsive or relapsed neuroblastoma.
| S-EPMC3795073 | biostudies-literature
Project description:Oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are a new class of cancer therapeutic, which selectively replicate and kill cancer cells, while inducing an inflammatory microenvironment, immunovirotherapy. Recently, an oHSV (talimogene laherparepvec) has been approved for the treatment of advanced melanoma. Glioblastoma (GBM) is an almost always lethal primary tumor in the brain that is highly immunosuppressive, and posited to contain GBM stem-like cells (GSCs). Immune checkpoint blockade has revolutionized therapy for some cancers, but not GBM. We have used a syngeneic GSC-derived orthotopic GBM model (005) to develop immunotherapeutic strategies. Curative therapy required oHSV expressing IL-12 in combination with two checkpoint inhibitors, anti-PD-1 and anti-CTLA-4. This response required CD4+ and CD8+ T cells, and macrophages in a complex interplay.
| S-EPMC6275562 | biostudies-literature
Project description:Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution. Oncolytic viruses attack tumor cells in two ways: direct infection of tumor cells leading to cytolysis, and production of a debris field that stimulates an anti-tumor immune response. Our group has previously shown that M002, an oncolytic herpes simplex virus (oHSV), genetically engineered to express murine interleukin-12 (mIL-12), was effective at targeting and killing long term passage tumor cell lines. In the current study, we investigated M002 in three neuroblastoma patient-derived xenografts (PDXs). PDXs better recapitulate the human condition, and these studies were designed to gather robust data for translation to a clinical trial. We found that all three PDXs expressed viral entry receptors, and that the virus actively replicated in the cells. M002 caused significant tumor cell death in 2D culture and 3D bioprinted tumor models. Finally, the PDXs displayed variable susceptibility to M002, with a more profound effect on high-risk neuroblastoma PDXs compared to low-risk PDX. These findings validate the importance of incorporating PDXs for preclinical testing of oncolytic viral therapeutics and showcase a novel technique, 3D bioprinting, to test therapies in PDXs. Collectively, our data indicate that oHSVs effectively target high-risk neuroblastoma, and support the advancement of this therapy to the clinical setting.
| S-EPMC8834037 | biostudies-literature
Project description:Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors.
| S-EPMC3907427 | biostudies-literature