CAN-3110

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

P1, N=62, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting

Conclusions Our findings show that the combination of HSV-1 rQNestin34.5v2 virotherapy with anti-TIGIT checkpoint blockade immunotherapy represents a promising strategy to overcome primary resistance to immune checkpoint inhibitors in GBM. Ethics Approval All animal experiments and procedures described in this study were approved by Brigham and Women's Institutional Animal Care and Use Committee.

These datademonstrate that mouse gliomas expressing IDH1 resemble human glioma cellsharboring IDH1 and are suitable models to study translational immunotherapiesfor low grade gliomas. Experiments to address the therapeutic andimmunostimulatory potential of intratumoral HSV-1 administration in primary andrecurrent IDH1-mutant gliomas are ongoing.

NOTCH induced immunosuppressive myeloid cell recruitment limited anti-tumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.

Despite positive functional modifications on CD4 + T cells, global lack of IL-27R signaling promoted tumor growth accompanied by increased circulating myeloid derived suppressor cells (MDSCs) in the GL261 model. Experiments to address the immunoregulatory role of IL-27R signaling during HSV-1 rQNestin34.5v2 virotherapy-induced glioma tissue destruction are ongoing.

Furthermore, the CT2A model was completely resistant to virus therapy, while in the GL261N4 model rQNestin34.5v1 treatment resulted in enhanced macrophage recruitment, impaired tumor progression, and long-term survival of a few animals. We conclude that prolonged intratumoral viral presence correlates with immune cell recruitment, and both are needed to enhance anti-tumor immunity.