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Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and
Mohammed G Ghonime1, Josh Jackson2, Amish Shah2
1The Research Institute at Nationwide Children's Hospital-Center for Childhood Cancer and Blood Disorders, Columbus, OH, USA.
Abstract:
Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV) is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.
Insights
Oncolytic virotherapy using C134, a novel oncolytic herpes simplex virus-1, shows promise against malignant gliomas. This therapy leverages viral replication and immune responses to improve survival and establish long-term anti-tumor memory.
Area of Science:
- Neuro-oncology
- Virology
- Immunology
Background:
- Malignant gliomas are aggressive primary brain tumors with poor prognoses, necessitating novel therapeutic approaches.
- Oncolytic virotherapy (OV) offers a dual mechanism of action, combining direct viral tumor cell killing with immune-mediated responses.
- C134, a next-generation oncolytic herpes simplex virus-1 (oHSV-1), exhibits enhanced intratumoral replication and safety in the central nervous system (CNS) via induced interferon signaling.
Purpose of the Study:
- To evaluate the efficacy of C134 in an immunocompetent malignant glioma model with intact interferon signaling.
- To compare the anti-tumor effects of C134 with first-generation viruses in a restricted replication environment.
- To elucidate the role of T cell responses and the potential for durable anti-tumor memory induction by C134.
Main Methods:
- Utilized immunocompetent and immunodeficient mouse models of malignant glioma.
- Administered C134 and first-generation oHSV-1 intratumorally.
- Assessed viral replication, anti-tumor immune responses (T cell mediated), animal survival, and re-challenge experiments to evaluate memory responses.
Main Results:
- Both C134 and first-generation viruses induced T cell-mediated anti-tumor effects and improved survival, despite similar in vivo replication.
- C134 demonstrated subtle differences in median survival compared to first-generation viruses.
- T cell responses were critical for C134's anti-tumor activity, and OV therapy generated durable, circulating anti-tumor memory.
- Repeated intratumoral administration of C134 enhanced anti-tumor effects and established superior anti-tumor memory compared to tumor antigen exposure alone.
Conclusions:
- Oncolytic virotherapy with C134 elicits significant anti-tumor immunity and improves survival in malignant glioma models.
- The T cell response is integral to the efficacy of C134, highlighting the immunotherapeutic potential of OV.
- OV therapy, particularly with repeated administration, can induce durable and protective anti-tumor memory, offering a promising strategy for long-term cancer control.
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