Investigators from Brigham and Women’s Hospital reported the results of a Phase I clinical trial evaluating a novel engineered oncolytic herpes virus (oHSV) in patients with high-grade recurrent glioblastoma (rGBM). The candidate, designated CAN-3110 can infect cancer cells and stimulate an anti-tumor immune response. Findings from the first in human study, involving 41 patients, demonstrated the safety and preliminary efficacy of the novel gene therapy. The results also showed that treatment resulted in prolonged survival among a subgroup of recurrent GBM patients who were immunologically “familiar” with the virus and had pre-exiting viral antibodies.

“GBM has an aggressive effect in part because of a milieu of immunosuppressive factors surrounding the tumor, which enable the tumor’s growth by preventing the immune system from entering and attacking it,” said E. Antonio Chiocca, MD, PhD, chair of the BWH Department of Neurosurgery. “This study showed that with a virus we designed, we can reshape this ‘immune desert’ into a pro-inflammatory environment.” Chiocca is corresponding author of the investigators’ published report in Nature, titled “Clinical trial links oncolytic immunoactivation to survival in glioblastoma.” In their report the team concluded, “These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumor microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy.”

Glioblastoma is an aggressive form of high-grade glioma (HGG) brain cancer that is notoriously resistant to treatment. Recurrent HGG (rHGG), including rGBM are associated with survival of less than 10 months, the authors wrote.

Immunotherapies that are designed to mobilize the body’s immune defenses against cancer have not been effective for GBM, in part because the tumor microenvironment (TME) is largely impenetrable to assaults from the body’s immune system. This immunosuppressive TME defines these tumors as “lymphocyte depleted,” the investigators stated. “For rGBMs and several other highly immunosuppressive solid cancers, there is a need to find treatment modalities that can convert the TME into one that is more amenable to immunotherapy and immune activation.”

For the reported Phase I trial, Chiocca and colleagues examined the safety of the oncolytic virus CAN-3110, which was designed and taken through preclinical testing by researchers at BWH, a founding member of the Mass General Brigham healthcare system. The cancer-attacking oncolytic herpes simplex virus is the same type of virus used in a therapy approved for the treatment of metastatic melanoma.

Unlike other clinical oHSVs, CAN-3100 includes the ICP34.5 gene, which is often excluded from clinical oHSV candidates because it causes human disease in unmodified forms of the virus. However, the researchers hypothesized that this gene may be necessary to trigger a robust, proinflammatory response necessary for attacking the tumor. For their clinical candidate they designed a version of oHSV1 that contains the ICP34.5 gene but is also genetically programmed not to attack healthy brain cells. “To take advantage of ICP34.5’s functions that enhance viral replication/persistence and minimize neurotoxicity, CAN-3110 (former designation, rQNestin34.5v.2) was engineered to express a copy of the viral ICP34.5 gene under transcriptional control of the promoter for nestin, restricting viral replication and virulence to HGG/GBM cells,” the team explained.

Overall, the trial demonstrated the safety of CAN-3110 in 41 patients with high-grade gliomas, including 32 with recurrent GBM. The most serious adverse events were seizures in two participants. Notably, GBM participants who had pre-existing antibodies to HSV1 virus (66% of the patients) had a median overall survival of 14.2 months, compared to 7.8. months for seronegative patients. In patients with pre-existing antibodies, the researchers saw markers of several changes in the tumor microenvironment associated with immune activation. They hypothesized that the presence of HSV1 antibodies resulted in a rapid immune response to the virus, which brought more immune cells to the tumor and increased the levels of inflammation in the tumor microenvironment.

The authors also observed an increase in diversity of the T cell repertoire after CAN-3110 treatment, suggesting that the virus induces a broad immune response, perhaps by eliminating tumor cells resulting in the release of cancer antigens. The immunological changes observed after treatment were also shown to be associated with improved survival. “In summary, single-timepoint intralesional injection of rHGG/rGBM with CAN-3110 enriches the tumor microenvironment with TILs [tumor infiltrating lymphocytes], inducing defined changes in peripheral and tumor T cell repertoires and tumor transcriptomic signatures,” the team commented in their discussion. “These findings therefore provide human immunological and biological evidence supporting intralesional oncolytic modalities to convert the immunosuppressive TME characteristic of many solid cancers into a TME that is more favorable to immunologic rejection of the tumor.”

Going forward, the researchers plan to complete prospective studies to further investigate the effectiveness of the oncolytic virus in patients who do and do not have antibodies to HSV1. Having demonstrated the safety of one viral injection, they are proceeding to test the safety and efficacy of up to six injections over four months, which, like multiple rounds of vaccination, may increase the effectiveness of the therapy. “We are now set to determine whether multiple-timepoint injections lead to further improvements in this therapy,” the authors confirmed.

“Almost no immunotherapies for GBM have been able to increase immune infiltration to these tumors, but the virus studied here provoked a very reactive immune response with infiltration of tumor-killing T-cells,” Chiocca said. “That’s hard to do with GBM, so our findings are exciting and give us hope for our next steps.”

Brigham and Women’s Hospital own the patents related to oHSV and CAN-3110, with Chiocca as a co-inventor. The patents have been licensed to Candel Therapeutics.

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