This invention identifies that tumor-specific T cells are susceptible to immunotherapy induced IFN-gamma toxicity in low tumor burden circumstances, and provides a novel method for rescuing those tumor-reactive T cells and anti-tumor immunity through disruption of IFN-gamma signaling.
Previously, it has been unknown how tumor-reactive T cells are regulated during immunotherapy treatments. Particularly, combination therapies for T cell checkpoint inhibitors can paradoxically abate antitumor immunity depending on the stage of tumor progression. Investigators at UCSF found that IFN-gamma plays a crucial role in regulating tumor-specific T cells, most instrumentally in low tumor burden circumstances. They have shown that disruption of the IFN-gamma signaling pathway restores immunotherapy activity. Advantages of the novel outlined technology include: (1) Broadly applicability to all T cell immunotherapies (2) Pro-longed antitumor immunotherapy response (3) Rescue of tumor specific T cell activity in tissues with low tumor burden (4) Potential to significantly increase antitumor immunotherapy efficacy, particularly in treatment of melanoma (5) Improvement of robustness of certain immunotherapies
The combination of immune checkpoint inhibitors CTLA-4 and anti-PD-1 can compromise antitumor immunity in the low tumor burden state in both animal models and melanoma patients. Investigators at UCSF found that this treatment induced reduction of immune activity is due to IFN-gamma caused apoptosis. Most notably, activated tumor-specific T cells are most susceptible to apoptosis because of elevated expression of IFN-gamma receptors, and combination therapy induces significantly higher levels of IFN-gamma in low versus high tumor burden states. They demonstrated that deficiency in the IFN-gamma receptor restores the antitumor phenotype, and that tumor-bearing mice with a T cell IFN-gamma receptor knockout showed significant survival advantage over their wildtype counterparts when receiving combination therapy.
To develop and commercialize the technology to increase the efficacy of immunotherapy cancer treatments.
|Patent Cooperation Treaty||Published Application||WO2019060823||03/28/2019||2018-019|