Among brain tumors, high-grade gliomas are the most frequently diagnosed and fatal. Most of the patients with high-grade glioma will have glioblastoma, a more aggressive form of the cancer. The global burden of high-grade gliomas, which have a median overall survival of less than 15 months, cannot be understated, especially given the lack of available treatments to date. The unmet need is even greater in patients with recurrent high-grade glioma, where the expected median overall survival is less than 6 to 9 months.
A leader in the development of therapies to treat this field of rare tumors, clinical-stage biopharmaceutical company Candel Therapeutics, Inc. CADL, is developing CAN-3110 – a first-in-class drug candidate – to help patients combat these deadly tumors.
Candel Therapeutics leverages the ability of viral gene constructs to activate cancer-killing mechanisms, exposing multiple tumor antigens and inhibiting the immunosuppressive tumor microenvironment. The company reports that this tactic has been shown to produce an individualized immune response specific to the patient and their cancer.
The company’s viral immunotherapy approach utilizes intratumoral administration of genetically engineered viruses to selectively induce tumor cell death. This elicits an innate and adaptive systemic immune response against the injected tumor and uninjected distant metastases. Best of all, local delivery enables Candel to achieve these results while aiming to minimize systemic toxicity.
The lead product candidate in Candel Therapeutics’ HSV platform, CAN-3110, is a replication-competent herpes simplex virus-1 (HSV-1) engineered to enhance the selective killing of cancer cells while sparing healthy neighboring cells. Designed with dual activity for oncolysis and immune activation in a single therapeutic, CAN-3110’s activity is designed to be conditional to the expression of Nestin in cancer cells.
CAN-3110 is being evaluated in a phase 1b investigator-sponsored clinical trial in patients with recurrent high-grade glioma. The results from this ongoing clinical trial were recently published in Nature.
Investigators discovered that the drug candidate was well tolerated with no dose-limiting toxicity reported, and CAN-3110 was associated with improved survival. Pre-existing anti-HSV-1 immunity increased infiltrating immune cells in the tumor microenvironment and expansion of the T cell repertoire after treatment were all associated with improved survival.
“Single-timepoint intralesional injection of rHGG with CAN-3110 enriches the tumor microenvironment with tumor infiltrating lymphocytes, inducing defined changes in peripheral and tumor T cell repertoires and tumor transcriptomic signatures,” investigators wrote in the report. “These changes are particularly evident in patients who are seropositive for HSV1 and are associated with improved survival in this otherwise therapy-refractory cancer. These findings therefore provide human immunological and biological evidence supporting the ability of CAN-3110 to convert the immunosuppressive one immunosuppressive tumor microenvironment characteristic of many solid cancers into a one that is more favorable to immunologic rejection of the tumor.”
In the CAN-3110 clinical trial, Candel Therapeutics reports that a near-doubling of the expected median overall survival was observed after a single CAN-3110 injection, compared to historical reports of less than 6 to 9 months in this therapy-resistant condition.
The company’s scientists and academic collaborators are currently evaluating the effects of multiple CAN-3110 injections in recurrent high-grade glioma, supported by the Break Through Cancer Foundation. Fresh off receiving FDA Fast Track Designation for the treatment of recurrent high-grade glioma, Candel Therapeutics plans to announce a data readout for the multiple injection cohort in CAN-3110’s phase 1 trial in 2H 2024. They expect initial results in the second half of 2024.
How Does CAN-3110 Work?
The off-the-shelf drug candidate is engineered for selective replication by placing ICP34.5 – the gene controlling HSV replication – under the control of the Nestin promoter. Nestin is highly expressed in high-grade glioma cells but absent in healthy adult brain cells, which could explain why dose-limiting toxicity was not observed in a study of a single injection of CAN-3110 into the brain tumor in patients with recurrent high-grade glioma.
Nestin expression has also been detected in aggressive tumors other than high-grade glioma, broadening the potential reach of CAN-3110 into other indications outside the brain – creating a future pipeline-in-a-product.
For more information on Candel Therapeutics, visit candeltx.com.
Featured photo by National Cancer Institute on Unsplash.
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