CAN-2409 combo therapy shows survival benefits in brain cancer
Therapy was tested on 41 patients with high-grade glioma in Phase 1b study
CAN-2409 (aglatimagene besadenovec), Candel Therapeutics‘ investigational immunotherapy, was safe and demonstrated potential survival benefits in patients with high-grade glioma, an aggressive type of brain cancer.
That’s according to results of a Phase 1b clinical trial that evaluated CAN-2409’s safety and efficacy in combination with nivolumab (sold as Opdivo and Opdualag) and standard of care therapy.
“The results from this mechanistic clinical trial confirm and extend previous observations in clinical trials that have shown clinical and immunological activity of CAN-2409 across different solid tumors,” Paul Peter Tak, MD, PhD, president and CEO of Candel, said in a company press release. The results, “A multi-institutional phase 1 clinical trial exploring upfront multimodal standard of care and combined immunotherapies for newly diagnosed glioblastoma,” were published in Neuro-Oncology.
Gliomas are a type of brain tumor that start in the glial cells, which support and protect nerve cells in the brain. They can be low-grade, that is, slow-growing, or high-grade, aggressive and fast-growing. High-grade gliomas, such as glioblastomas, are the most severe form. They grow quickly, invade nearby brain tissue, and are difficult to treat, often requiring a combination of surgery, radiation, and chemotherapy.
Poor survival rates for high-grade gliomas are associated with their highly immunosuppressive environment and the absence within the tumor of T-cells, a subset of immune cells that play a role in identifying and eliminating cancer cells. CAN-2409 is intended to trigger targeted and more durable anti-tumor immune responses. It uses a modified virus to deliver a gene that provides instructions to make herpes simplex virus thymidine kinase (HSV-tk), an enzyme, directly into tumors. Patients are then given an oral antiviral therapy called valacyclovir that the HSV-tk enzyme converts into a toxic molecule that kills cancer cells, but leaves surrounding healthy cells unharmed.
This targeted cell death triggers the immune system by releasing tumor-specific proteins and pro-inflammatory signals, helping it recognize cancer cells and directing T-cells to attack and eliminate them.
Testing combination therapy
The Phase 1b study (NCT03576612) enrolled 41 newly diagnosed patients before tumor resection, with 35 completing the full treatment regimen, which included CAN-2409 plus its prodrug valacyclovir, nivolumab, a checkpoint inhibitor that helps the immune system fight cancer, and standard of care therapy (neurosurgery, radiotherapy, and the chemotherapy drug temozolomide).
Patients had their tumors surgically removed and tumor and blood samples were evaluated for genetic and immunological biomarkers before and during treatment. After surgery, CAN-2409 was injected into the resection cavity wall and valacyclovir was given one to three days later and continued for 14 days. Around day eight, radiation therapy was started and lasted for six weeks. Nivolumab was administered every two weeks for up to a year. MRI scans were performed every two months to monitor disease progression.
The combination therapy was well tolerated, with no severe toxicity directly attributed to CAN-2409 and no significant increase of overall toxicity when combined with other treatments.
Outcomes of CAN-2409 treatment
The patients had a median survival of 15.1 months. However, six patients with MGMT promoter methylation who underwent complete tumor removal showed better outcomes, achieving a median overall survival of 30.6 months, longer than the typical 24-month survival for this group. MGMT promoter methylation is a change in the DNA of the MGMT gene that helps determine how well a tumor will respond to certain treatments. When the MGMT promoter is methylated, the gene is turned off, making cancer cells more sensitive to chemotherapy drugs like temozolomide and enhancing treatment efficacy.
A biomarker analysis found that improved outcomes were tied to higher initial levels of immune-supporting cells, such as B-cells, dendritic cells, and memory CD4+ T cells within tumors. Those with higher levels of immunosuppressive monocytes had worse outcomes.
Patients with longer survival also showed stronger and more diverse immune responses, as indicated by a richer set of T-cell receptors, which are crucial for recognizing and attacking cancer cells. This increase in T-cell receptor diversity was observed early in treatment, specifically after CAN-2409, but before starting nivolumab. This suggests CAN-2409 can help release substances from the tumor that trigger the immune system, boosting the ability to fight the tumor, both at the site and throughout the body, according to the company.
The combination therapy revealed a broad immune response overall, including increased subtypes of T-cells that are critical for initiating and sustaining anti-tumor responses, and a reduction of immune cells that can help the tumor escape immune responses.
“We are excited by the promising results from this Phase 1b clinical trial,” said Candel CSO Francesca Barone, MD, PhD. “Our data demonstrates that CAN-2409 has the potential to broaden the T-cell receptor repertoire and foster a more diverse immune response, which has previously been shown in several publications to be associated with improved clinical outcome in high-grade glioma and other solid tumors.”
CAN-2409 is also being evaluated in other types of solid tumors, including in a Phase 2 trial in pancreatic cancer.
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