linoserpaturev (CAN-3110)

P1, N=62, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Jan 2027 --> Jan 2028 | Trial primary completion date: Jan 2026 --> Jan 2027

For instance, CAN-3110, a Nestin-promoter-driven herpes simplex virus-1 (HSV-1), demonstrated a median overall survival of 14.9 months in patients with recurrent GBM, with HSV-1 seropositive patients achieving more prolonged survival (14.2 versus 7.8 months in seronegative patients). This review aims to synthesize the current evidence on clinical outcomes in patients with recurrent GBM receiving oncolytic virotherapy, with a specific focus on safety profiles, therapeutic efficacy, and survival outcomes.

A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures...Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.

Here, we identify that immunosuppressive eADO signaling in the TME is a major barrier to oHSV therapy and CD73 blockade prevents tumor immune escape. The combination of oHSV with CD73 blockade supports the development of an antitumor immune memory response in solid tumors. This study supports clinical development of this combination strategy.

Clinically, the Notch ligand JAG1 was upregulated in recurrent high-grade glioma patients treated with the oHSV CAN-3110 and correlated with poor prognosis. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic efficacy of OD-0J1.

P1, N=62, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2026 --> Jan 2027 | Trial primary completion date: Jun 2025 --> Jan 2026

P1, N=62, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2025 --> Jun 2026 | Trial primary completion date: Dec 2024 --> Jun 2025

This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

P1 | N=62 | NCT03152318 | "BostonGene...today announced the online publication...in Nature...Utilization of immunotherapy for GBM has been challenging due to the scarcity of infiltrating antitumor lymphocytes caused by a highly immunosuppressive or 'lymphocyte-depleted' tumor microenvironment (TME)....The results demonstrated a single injection of CAN-3110 activated an antitumor immune response in GBM, inducing defined changes in T cell repertoires and tumor transcriptomic signatures. These findings are evidence that intralesional onolytic viruses can convert the immunosuppressive GBM TME to an immunoactivated state that is more responsive to immunotherapy."

Combined with a lack of observed dose-limiting toxicities and a median post-treatment survival of 14.2 months (95% CI: 9.5-15.7) in IDHwt rGBM patients with positive HSV1 serology, these data provide evidence that intralesional CAN-3110 treatment can instigate immune activation in a traditionally immunologically cold tumor and that this immune activation may influence survival time—particularly when patients have had prior exposure to HSV1. (clinicaltrials.gov NCT03152318)

Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)...These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

P1, N=62, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2024