Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

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.

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

“…Convincing evidence has revealed that the tumour tissue environment consists of heterogeneous components, such as tumour cells, fibroblasts, and immune cells [43–46]. The interactions between these cells define the microenvironment of tumour cells and are involved in the growth and metastasis of tumours [47].…”

Combination Therapy Using Ruxolitinib and Oncolytic HSV Renders Resistant MPNSTs Susceptible to Virotherapy

“…Tumor cells with relative low passage numbers (<12 passages) were used in the study before returning for a "low" passage form of the cell line to minimize genetic drift in our studies. Viruses have been previously described (22), but in brief; HSV-1 (F) strain and R3616, the Dg 1 34.5 recombinant, were kindly provided by Dr. Bernard Roizman (University of Chicago, Chicago, IL; ref. 23).…”

“…DNA was extracted by DNeasy blood and tissue kit (Qiagen) per the manufacturer's instructions. Virus recovery was measured by Taq-Man quantitative PCR (22). Briefly, extracted DNA samples were incubated with the following HSV-specific primers and probes for HSV polymerase (sequences kindly provided by Dr. Fred Lakeman University of Alabama at Birmingham, Birmingham, Alabama): PolF (forward), 5 0 -ACC GCC GAA CTG AGC AGA C-3 0 ; and PolR (reverse), 5 0 -TGA GCT TGT AAT ACA CCG TCA GGT-3 0 .…”

Oncolytic Virotherapy in Glioma Tumors

“…Following a different strategy, HSV-1 C134 was developed as a chimeric virus that includes not only the deletion of γ 1 34.5 loci but also the expression of human cytomegalovirus (HCMV) IRS1 gene. This insertion increases viral replication and lytic effect when administered intrathecally in a murine GBM tumor model inducing antitumor T cell mediated immune responses, which elicit long systemic immune-memory enhancing survival [ 32 , 33 ].…”