2023-10-20 17:52:48
Immunotherapies against glioblastoma struggle to be effective due to the highly immunosuppressive microenvironment of this type of tumor. In a new effort, researchers modified an oncolytic virus so that it only infects cancer cells. The latter succeeded in inducing an anti-tumor immune response and improving survival in a subgroup of patients with recurrent glioblastoma. This new strategy perhaps offers hope of better treating this particularly aggressive cancer.
High-grade gliomas (HGG) are tumors affecting the central nervous system and exhibiting highly malignant morphological and genetic features. Among these tumors is glioblastoma (GBM), affecting approximately 200,000 people per year worldwide. Being the most aggressive form of HGG, GBM has the lowest survival rate (less than 10 months after diagnosis) and tends to quickly recur after surgical resection and chemotherapy (recurrent GBM).
Although the biomolecular mechanisms reflecting the evolution of HGG are well established, this has not yet resulted in sufficiently effective therapeutic strategies to counter them. Among the strategies explored is immunotherapy (a combination of gene therapy and cell therapy), but the effectiveness of which is hampered by the extremely immunosuppressive microenvironment reigning within these tumors. This characteristic also earns them the qualification of “lymphocyte-depleted” tumors. To overcome this obstacle, research is now focusing on ways to activate immunity within their environment.
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In this sense, researchers from Brigham and Women’s Hospital (BWH) have designed a new oncolytic virus that can infiltrate HGG and GBM. Their study, published in the journal Natureshowed “that with this virus, we can transform this immune desert into a pro-inflammatory environment”, explains in a communiqué E. Antonio Chiocca, from the Department of Neurosurgery at BWH. This new immunotherapy appears promising by demonstrating an increase in survival in preliminary clinical trials.
An overall survival rate of 14.2 months on average
As their name suggests, oncolytic viruses aim to induce oncolysis (destruction of cancer cells) by modifying the tumor environment. They do this by stimulating pro-inflammatory pathways, activating both local immune cells and those newly recruited through exposure to viral and tumor antigens. This strategy is being tested for melanoma and for rGBM, as well as other forms of HGG. However, “the immunological profiling of rGBM treated with oncolytic viruses in sufficient numbers to correlate with a therapeutic outcome is lacking,” explain the BWH researchers in their article.
As part of the new study, a preliminary clinical trial was conducted to evaluate the safety of an oncolytic virus called CAN-3110. It is a modified herpes simplex virus type 1 (oHSV), previously used to treat metastatic melanoma. But unlike other oHSVs, CAN-3110 includes the ICP34 gene, usually deleted due to its involvement in the proliferation and pathogenicity of herpes simplex (HSV-1). Additionally, it induces neurotoxicity in mice. However, BWH researchers believe it is essential for triggering an immune response robust enough to attack cancer cells. To take advantage of this aspect, the new oHSV was designed to express a copy of the gene under transcriptional control, thus limiting its replication and preserving healthy brain cells.
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The trial enrolled 41 HGG patients, 32 of whom had rGBM. The results revealed that the most serious side effects occurred in the form of seizures and affected two participants. After treatment with CAN-3110, an increase in T cell diversity was observed in all volunteers. This would mean that the virus induces a broad-spectrum immune response potentially capable of recognizing tumor antigens. These changes were also associated with improved survival. “ Almost no GBM immunotherapy has been able to increase immune infiltration of these tumors, but the virus studied here caused a highly reactive immune response with infiltration of tumor-killing T lymphocytes », Chiocca explained.
Furthermore, the presence of pre-existing antibodies against HSV-1 improved the median overall survival in rGBM patients, increasing it to 14.2 months instead of 7.8 months. These antibodies have notably been associated with several markers of changes linked to immune activation in the tumor microenvironment. This suggests that their prior presence results in a rapid immune response leading to high levels of infiltrated cells and inflammation.
These results were obtained with a single dose of treatment. As a next step, the researchers plan to increase the dosage with 6 injections spread over 4 months. Like vaccine boosters, this could increase the effectiveness of the therapy. On the other hand, details regarding the effectiveness and differences between patients with HSV-1 antibodies and those without will also be further explored.
Source : Nature
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