New drugs, called “Checkpoint Inhibitors,” improve the immune system’s ability to fight cancer by helping maintain the presence and activity of immune cells that target cancer, cytotoxic T lymphocytes (CTLs)1. Many patients fail to respond to Checkpoint Inhibitor therapy, which suggests that tumors utilize additional mechanisms to evade the immune system. Research suggests that some tumors evade the immune system by recruiting myeloid-derived suppressor cells (MDSCs). MDSCs produce reactive nitrogen species (RNS) that alter the receptors on the surface of the tumor to “cloak” it from CTLs2. Omaveloxolone and other Nrf2 activators inhibit MDSC activity, suppress RNS, and restore anti-tumor immune responses in preclinical studies. Nrf2 activators also have direct anticancer effects in vitro and in animals. Reata is conducting our Phase 1b/2 REVEAL trial using omaveloxolone in combination with Checkpoint Inhibitors in patients with melanoma. We expect data from the 1b portion of the trial in the second half of 2017.
New drugs such as Yervoy®, Opdivo®, and Keytruda®, called “Checkpoint Inhibitors,” have emerged as novel treatments of melanoma and non-small cell lung cancers. They improve the immune system’s ability to fight cancer by helping maintain the presence and activity of cytotoxic T lymphocytes (CTLs), immune cells that target cancer. While Checkpoint Inhibitors result in improved outcomes compared to previous therapies, patient response rates to treatment remain relatively low1.
A significant body of evidence has shown that certain immature white blood cells, known as myeloid derived suppressor cells (MDSCs), are present in tumors and play a critical role in suppressing the ability of CTLs to detect and destroy cancer cells. MDSCs have the ability to generate reactive nitrogen species (RNS) such as nitrotyrosine that bind to and change the conformation of marker proteins on the surface of cancer cells. This can create an RNS “cloak” around tumor cells that allows them to be unidentifiable to CTLs, even if CTL activity is facilitated by Checkpoint Inhibitors2. This hypothesis has been supported by several clinical studies associating poor survival with high MDSC activity, and higher MDSC levels in patients are correlated with lack of clinical response to Checkpoint Inhibitors.
Preclinical studies conducted by leading immuno-oncology researchers have shown that Nrf2 activators, including omaveloxolone, suppress the activity of MDSCs, reduce levels of RNS in tumors, and restore anti-tumor immunity3,4,5. Nrf2 activator treatment improved immune cell infiltration of tumors and enhanced the anti-tumor effects of a cancer vaccine6. Omaveloxolone synergized with an anti-PD-1 (the target of Opdivo® and Keytruda®) antibody to promote immune rejection and regression of tumors7. Overexpression of RNS has been implicated as a potential contributing factor in MDSC-mediated immune evasion, and it is correlated with poor clinical outcomes in cancer patients8. In clinical studies, treatment with Nrf2 activators reduced levels of RNS in tumor biopsies from cancer patients5.
MDSCs are present and active in a broad range of tumor types. Accordingly, an agent that suppresses MDSC activity has the potential for wide use in combination with other cancer immunotherapies.
In addition to their inhibitory effects on MDSC, the direct anti-cancer effects of Nrf2 activators have been extensively documented in non-clinical studies9,10.
- Nrf2 activators inhibit cancer cell proliferation in vitro and in vivo, and promote apoptosis of tumor cells by reducing the expression of Bcl-XL and other anti-apoptotic proteins.
- Nrf2 activators reduce the expression of proteins that promote tissue invasion and metastasis, and are potent inhibitors of tumor-related angiogenesis.
- Nrf2 activators increase the effectiveness of other cancer therapies, including standard chemotherapy agents, targeted therapies, and radiation.
- Nrf2 activators prevent carcinogenesis and inhibit early tumor formation and growth. These effects have potential clinical relevance for the prevention of post-therapy recurrence and suppression of micrometastases.
- de Coaña et al. Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med. 2015 Aug;21(8):482-91.
- Corzo et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol. 2009 May 1;182(9):5693-701.
- Nagaraj et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010; 16(6): 1812-23.
- Lu et al. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest. 2011; 121(10):4015-29.
- Reata Pharmaceuticals, Inc., internal data.
- Liao et al. Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model. Cancer Res. 2011; 71(17):5688-96.
- Reata Pharmaceuticals, Inc., internal data.
- Ekmekcioglu et al. Tumor iNOS predicts poor survival for stage III melanoma patients. Int J Cancer. 2006; 119(4): 861-6.
- Liby and Sporn. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev. 2012;64(4):972-1003.
- Probst et al. RTA 408, a novel synthetic triterpenoid with broad anti-cancer and anti-inflammatory activity. PLoS One. 10(4): e0122942.
- Pardoll, DM. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012;12(4):252-64.