Glioblastoma (GBM), a highly aggressive brain cancer, has long posed a formidable challenge in the realm of cancer treatment.
Patients with recurrent GBM typically face a grim prognosis, with survival rates of less than 10 months. Traditional immunotherapies, which harness the body’s immune system to combat cancer, have proven ineffective against GBM.
A major obstacle has been the tumor’s ability to create an immunosuppressive environment that shields it from immune attacks.
A groundbreaking study led by investigators from Brigham and Women’s Hospital, a key member of the Mass General Brigham healthcare system, has introduced a novel gene therapy approach that seeks to transform this immunosuppressive environment into one conducive to an anti-tumor immune response.
This innovative therapy involves an engineered oncolytic virus capable of infecting cancer cells and stimulating the body’s immune system to fight the cancer.
The results of this pioneering research, published in the journal Nature, demonstrate both the safety and preliminary efficacy of this gene therapy approach, particularly in patients with recurrent GBM who already possessed immunity against the virus.
Converting an “Immune Desert” into an Immune-Active Environment
GBM’s aggressiveness is partly attributed to the presence of immunosuppressive factors surrounding the tumor. These factors obstruct immune system access to the tumor and hinder its ability to launch an attack.
Dr. E. Antonio Chiocca, the corresponding author of the study and Chair of the BWH Department of Neurosurgery, explained the importance of reshaping this environment:
“This study showed that with a virus we designed, we can reshape this ‘immune desert’ into a pro-inflammatory environment.”
The Oncolytic Virus – CAN-3110
The trial centered on an oncolytic virus named CAN-3110, which had been designed and subjected to preclinical testing by researchers at Brigham and Women’s Hospital.
This virus, classified as an oncolytic herpes simplex virus (oHSV), shares its viral type with an approved therapy for metastatic melanoma.
What sets CAN-3110 apart is the inclusion of the ICP34.5 gene, typically omitted from clinical oHSVs due to its potential to cause human disease in unmodified forms of the virus.
However, the researchers theorized that this gene could be instrumental in triggering a robust, pro-inflammatory response necessary for attacking the tumor.
They engineered a version of oHSV1 that contained the ICP34.5 gene but was genetically programmed not to harm healthy brain cells.
Promising Results and Safety Profile
The phase I clinical trial examined the safety of CAN-3110 in 41 patients with high-grade gliomas, including 32 individuals with recurrent GBM.
The trial demonstrated the virus’s safety profile, with the most severe adverse events being seizures in two participants.
Notably, recurrent GBM patients who had pre-existing antibodies against the HSV1 virus (66% of the patients) exhibited a median overall survival of 14.2 months.
The presence of HSV1 antibodies appeared to trigger a rapid immune response to the virus, attracting more immune cells to the tumor and elevating inflammation levels in the tumor environment.
Following CAN-3110 treatment, the researchers observed increased diversity in the T cell repertoire, suggesting that the virus induced a broad immune response, possibly by eliminating tumor cells and releasing cancer antigens.
These immunological changes correlated with improved survival rates.
Future Research and Hopeful Outlook
The study underscores the potential of gene therapy in addressing formidable medical challenges.
Mass General Brigham’s Gene and Cell Therapy Institute is at the forefront of translating scientific discoveries into pioneering clinical trials that may lead to life-changing treatments.
Looking ahead, the research team plans to conduct prospective studies to further assess the effectiveness of the oncolytic virus in patients with and without antibodies to HSV1.
They aim to investigate the safety and efficacy of up to six viral injections over four months, akin to multiple rounds of vaccination, which may enhance therapy effectiveness.
Dr. Chiocca expressed optimism about the findings, saying, “Almost no immunotherapies for GBM have been able to increase immune infiltration into these tumors, but the virus studied here provoked a very reactive immune response with infiltration of tumor-killing T-cells.
That’s hard to do with GBM, so our findings are exciting and give us hope for our next steps.”
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The research findings can be found in Nature.
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