2023-10-18 17:00:05
A gene therapy using an engineered oncolytic virus has been shown to prolong survival in patients with one of the deadliest and most difficult-to-treat brain tumors, glioblastoma.
These are the first results of a clinical trial, the first according to its authors, carried out on 41 patients with recurrent glioblastoma, published in ‘Nature‘, which demonstrate the safety and preliminary efficacy of a novel gene therapy.
Glioblastoma, an aggressive brain cancer, is known for its resistance to treatment. The average survival of recurrent cases is just 10 months.
Immunotherapies, the treatment that has revolutionized cancer management and activate the body’s immune defenses against cancer, have not been effective in patients with glioblastoma. One of the reasons for this failure is because the environment surrounding the tumor is largely impenetrable by the immune system cells responsible for attacking the cancer.
The objective of this new therapy designed by the team at Hospital Brigham and Women’s de Boston (USA) is to modify this environment to allow the immune system to do its job.
As? This team designed a novel oncolytic virus which can infect cancer cells and stimulate an anti-tumor immune response.
The results, published now’Nature‘, they demonstrated the safety and efficacy preliminary of this innovative gene therapy approach in patients with high-grade gliomas, with prolonged survival in a subgroup of patients with recurrent glioblastoma who were immunologically ‘familiar’ with the virus.
“Glioblastoma has an aggressive effect in part due to a series of immunosuppressive factors that surround the tumor, which facilitate tumor growth by preventing the immune system from attacking it,” says researcher E. Antonio Chiocca. “The study shows that with a virus we designed, we can transform this ‘immune desert’ into a pro-inflammatory environment.”
This phase I trial, the first in humans, examined the safety of an oncolytic virus called CAN-3110, Candel Therapeutics.
The virus that attacks the cancer is an oncolytic herpes simplex virus (oHSV), the same type of virus used in an approved therapy for the treatment of metastatic melanoma. Unlike other clinical oHSVs, this therapy includes the ICP34.5 gene, which is often excluded from clinical oHSVs because it causes human disease in unmodified forms of the virus.
The study shows that with a virus we designed, we can transform this ‘immune desert’ into a pro-inflammatory environment
E. Antonio Chiocca
Brigham and Women’s Hospital
However, the researchers hypothesized that this gene might be necessary to trigger a potent, pro-inflammatory immune response needed to attack the tumor.
Therefore, they engineered a version of oHSV1 that contains the ICP34.5 gene, but is also genetically ‘programmed’ not to attack healthy brain cells.
Overall, the trial demonstrated the safety of CAN-3110 in 41 patients with high-grade gliomas, including 32 with recurrent glioblastoma. The most serious adverse events were seizures in two participants.
An important detail to note is that participants with glioblastoma who had pre-existing antibodies against HSV1 (66% of patients) had a median overall survival of 14.2 months. In patients with preexisting antibodies, the researchers observed markers of several changes in the tumor microenvironment associated with immune activation.
This, he explains in his work, raises the hypothesis that the presence of antibodies against HSV1 caused a more rapid immune response to the viruswhich attracted more immune cells to the tumor and increased levels of inflammation in the tumor microenvironment.
After treatment with CAN-3110, the researchers also observed an increase in the diversity of the T cell repertoire, suggesting that the virus induces a broad immune response, possibly by eliminating tumor cells and releasing cancer antigens. These immunological changes after treatment were also shown to be associated with improved survival.
Future gene therapy
Studies like this show the promise of gene therapy for treating untreatable conditions.
In the future, the researchers plan to conduct prospective studies to further investigate the efficacy of the oncolytic virus in patients with or without HSV1 antibodies.
After demonstrating the safety of one viral injection, they are moving forward to test the safety and effectiveness of up to six injections over four months, which, like multiple rounds of vaccination, can increase the effectiveness of the therapy.
«Almost no immunotherapy for glioblastoma has been able to increase immune infiltration in these tumors, but the virus studied here caused a very reactive immune response with the infiltration of T cells that kill the tumor,” adds Chiocca. “This is difficult to achieve in this type of tumor, so our findings are exciting and give us hope for our next steps.”
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