CAN-2409 transduces tumor cells with the thymidine kinase gene, sensitizes these cells to valacyclovir, and stimulates patients’ immune response.
Combination treatment of CAN-2409 plus valacyclovir plus nivolumab and standard of care seems to improve survival in patients with newly diagnosed, high-grade glioma intended for gross total resection (GTR).1
These data, from 35 evaluable participants in a phase 1 study (NCT03576612), were presented in a late-breaking oral abstract at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts, by Patrick Wen, MD, professor, neurology, Harvard Medical School, and director, Center for Neuro-Oncology, Dana-Farber Cancer Institute.1
“The development of effective immunotherapy forbrain tumors has been limited by the suppressed tumor microenvironment. There is a paucity of T-cell infiltration in these tumors and enhancement of immunosuppressive macrophages and microglia. These tumors make immunosuppressive factors like IL10 and TGFβ. The majority of these patients undergo radiotherapy and temozolomide chemotherapy, producing a profound and long-lasting lymphopenia, and most of these patients are also on corticosteroids,” Wen said during his presentation.1
The phase 1 trial was launched in a collaboration with the Adult Brain Tumor Consortium, Bristol-Myers Squibb, and Candel Therapeutics.Forty-oneparticipants were enrolled to receive an injection of 2.5x1011 vp of CAN-2409 during resection surgery, followed by temozolomide and nivolumab after around 2 and 3 weeks, respectively.Participants had a median age of 62 years, all but 1 had glioblastoma, and 73% of patients actually achieved a GTR.
Around 2/3 of participants were found to have unmethylated MGMT promoters and temozolomide was discontinued while the 1/3 with methylated MGMT promoters continued temozolomide treatment, first with radiation and then with nivolumab. The study’s primary endpoint was safety while secondary endpoints included overall survival (OS), progression free survival, radiologic changes, and immunological biomarkers.
The treatment regimen was generally well-tolerated and consistent with standard-of-care resection, with no dose-limiting toxicities. The most common adverse events (AEs) included fatigue (n = 16; 39%), nausea (n = 12; 29%), and alanine transaminase elevations (n = 10; 24%). More serious, grade 3-4 AEs included neutrophil decreases, acute kidney injury, and hypertension (n = 2 each; 5%). Nine participants discontinued the study based off AEs associated with temozolomide and nivolumab treatments, underlying disease symptoms, or unrelated medical events.
Overall, study participants had an OS of 15.1 months. Patients with methylated MGMT promoters who achieved GTR had a median OS of 30.6 months (n = 10) while those who did not achieve a GTR had a median OS of 12.6 months (n = 5). Patients with unmethylated MGMT promoters who achieved GTR had a median OS of 13.2 months (n = 16) while those who did not achieve GTR had a median OS of 15.9 months (n = 4).
Immune profiling performed in collaboration with CIMAC-CIDC revealed that CAN-2409 elicited a strong systemic activation of effector immune response, and, in combination with nivolumab, expanded activated CD4/CD8 T cells and decreased exhaustion.
“We are encouraged to see strong systemic immune activation after a single administration of CAN-2409 to the resection bed during neurosurgical removal of the tumor combined with nivolumab treatment in one of the most treatment-resistant cancers, high-grade glioma, which is characterized by a highly immunosuppressive microenvironment,” Paul Peter Tak, MD, PhD, FMedSci, president and chief executive officer, Candel Therapeutics, said in a statement.2 “The data support the potential therapeutic synergies between CAN-2409 in combination with immune checkpoint inhibitors across various solid tumors.”