On November 3, 2015 Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) reported 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) (Free SITC Whitepaper) annual meeting in Maryland, November 4-8, 2015 (Press release, Threshold Pharmaceuticals, NOV 3, 2015, View Source [SID:1234507918]). Evofosfamide is Threshold’s investigational hypoxia-activated prodrug, which is currently the subject of two fully-enrolled Phase 3 clinical trials for which Threshold expects to announce top-line data around the end of 2015. Schedule your 30 min Free 1stOncology Demo! "This is an exciting time for the field of cancer immunotherapy, and continued progress will depend on a better understanding of the tumor microenvironment and finding novel combination therapies that are more effective than immunotherapy alone," said Michael A. Curran, Ph.D., Assistant Professor at the University of Texas M.D. Anderson Cancer Center and senior author on the scientific poster.
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"Our research shows that hypoxia in the tumor microenvironment forms a barrier to T cell infiltration and fosters immunotherapy resistance in prostate cancer and other solid tumors," Curran said. "We found that evofosfamide-driven disruption of hypoxic zones sensitizes highly resistant prostate cancer models to treatment with immune checkpoint inhibitors anti-CTLA-4 and anti-PD-1."
Research conducted in 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.
"This combination of hypoxia disruption and T cell checkpoint blockade has potential to render some of the most therapeutically resistant cancers sensitive to immunotherapy," Curran said.
"Combining with immunotherapy is an exciting possibility that fits well with our development strategy to maximize the potential therapeutic applications of evofosfamide," said Tillman Pearce, M.D., Chief Medical Officer at Threshold. "The data from Dr. Curran’s research suggests that combining evofosfamide with immune checkpoint inhibitors warrants further investigation."
The poster titled "Tumor hypoxia drives immune suppression and immunotherapy resistance" by Midan Ai et al. will be presented on Saturday, November 7, 2015, from 12:45 PM – 2:00 PM. The abstract is now available at View Source or by clicking here.
About Evofosfamide
Evofosfamide (previously known as TH-302) is an investigational hypoxia-activated prodrug that is thought to be activated under severe hypoxic tumor conditions, a feature of many solid tumors. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood vessel supply. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic. Evofosfamide is currently in two Phase 3 trials, both of which are fully recruited: one in combination with doxorubicin versus doxorubicin alone in patients with locally advanced unresectable or metastatic soft tissue sarcoma (STS) (the TH-CR-406 trial), and the other in combination with gemcitabine versus gemcitabine and placebo in patients with locally advanced unresectable or metastatic pancreatic cancer (the MAESTRO trial). Top-line data for both trials are expected around the end of 2015. Both Phase 3 trials are being conducted under Special Protocol Assessment (SPA) agreements with the FDA. The FDA and the European Commission have granted evofosfamide Orphan Drug designation for the treatment of STS and pancreatic cancer. The FDA has also granted Fast Track designation for evofosfamide for both STS and pancreatic cancer. Evofosfamide is also being investigated in a Phase 2 trial designed to support registration for the treatment of non-squamous non-small cell lung cancer, and in earlier-stage clinical trials of other solid tumors and hematological malignancies.
Threshold has a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany, which includes an option for Threshold to co-commercialize in the U.S.