Date: 2015-11-03
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the Society for Immunotherapy of Cancer (SITC) annual meeting in Maryland
Company: Threshold Pharmaceuticals (USA - CA)
Product: evofosfamide (TH-302) and immune checkpoint inhibitors
Action
mechanism: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. The product has been discovered by Threshold scientists. It is designed as a prodrug that is selectively activated under the extreme hypoxic conditions commonly found in tumors, but not typically in healthy tissues. Within regions of tumor hypoxia, TH-302 is converted to its active form, bromo isophoramide mustard (Br-IPM). Variants of IPM are clinically validated potent DNA alkylating agents, which kill tumor cells by causing DNA to crosslink thereby rendering cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”. Evofosfamide is currently in Phase 3 clinical trials in locally advanced or metastatic pancreatic cancer and advanced soft tissue sarcoma.
In February 2012, Merck KGaA signed a global agreement to co-develop and commercialize TH-302 with Threshold. Under the terms of the agreement, Merck KGaA received co-development rights, exclusive global commercialization rights with Threshold retaining an option to co-commercialize the therapeutic in the United States.
Disease:
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On November 3, 2015, Threshold Pharmaceuticals announced that preclinical data on the combination of evofosfamide with immune checkpoint inhibitors will be presented in a scientific poster at the Society for Immunotherapy of Cancer (SITC) annual meeting in Maryland , November 4-8, 2015 . Research conducted in Michael A. Curran's laboratory shows that hypoxic zones in prostate tumors resist infiltration by T cells, which are capable of attacking and killing tumor cells. In contrast, normoxic areas of the same tumor experience robust infiltration by T cells. In mouse models of prostate cancer, Curran and colleagues show that combination therapy with evofosfamide and anti-CTLA-4/anti-PD-1 treatment opens up the hypoxic zones to T cell infiltration.
Furthermore, evofosfamide helps sensitize otherwise immunotherapy-resistant prostate tumors to anti-CTLA-4/anti-PD-1 therapy in models of prostate cancer as evidenced by the smallest tumor burdens on average being observed with combination therapy. The poster is titled "Tumor hypoxia drives immune suppression and immunotherapy resistance" by Midan) Ai et al.
