On October 3, 2018 Corvus Pharmaceuticals, Inc. (NASDAQ: CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of precisely targeted oncology therapies, reported the publication of results of preclinical studies of CPI-444 demonstrating that it induces dose dependent anti-tumor responses as a monotherapy and in combination with anti-PD-1, anti-PD-L1 and anti-CTLA-4 therapies (Press release, Corvus Pharmaceuticals, OCT 3, 2018, View Source [SID1234529768]). The article, which is titled "A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti–PD-(L)1 and Anti–CTLA-4 in Preclinical Models," is featured on the cover of and in the October issue of the journal Cancer Immunology Research, which is an official journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). The article can be accessed here.
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CPI-444, Corvus’ lead product candidate, is a selective and potent inhibitor of the adenosine A2A receptor. It is currently being evaluated in clinical trials in patients with various solid tumors as a single agent and in combination with Genentech’s atezolizumab, an anti-PD-L1 antibody.
"Our carefully conducted pre-clinical studies of CPI-444 demonstrated robust, dose-dependent inhibition of cancer growth as monotherapy, and synergistic efficacy with checkpoint inhibitors, in multiple tumor models," said Stephen Willingham Ph.D., a senior scientist at Corvus and lead author of the article. "These studies indicate that CPI-444 is associated with T-cell activation, which is believed to be its main mechanism of increased cancer killing activity."
Dr. Willingham added, "In these studies we used two different models to characterize the intratumor levels of adenosine, confirming they should be easily blocked by CPI-444. We believe this is the first publication to accurately measure intratumor levels of extracellular adenosine, which is important for evaluating the potential efficacy of therapeutics aimed at this pathway."
Key takeaways from the pre-clinical studies covered in the article include:
CPI-444 is a selective and potent inhibitor of the adenosine A2A receptor and provides dose dependent inhibition of tumor growth as a monotherapy in multiple tumor models
CPI-444 is synergistic with checkpoint inhibitors (anti-PD-1, anti-PD-L1 and anti-CTLA-4), demonstrating the elimination of tumors in up to 90% of treated mice and the restoration of immune responses in mice with tumors that are resistant to anti-PD-L1 or anti-CTLA-4 monotherapy
In monotherapy and combination-therapy, CPI-444 inhibited tumor growth and enabled long-term anti-tumor immune memory
CD8+ T-cells were shown to be required for a response with CPI-444 , demonstrating a role for CD8+ T-cells in mediating primary and secondary immune responses
Intratumor adenosine levels as measured in two models were shown to be approximately 100-150 nanomolar, which is a level that is completely blocked by CPI-444
"These extensive pre-clinical studies formed the basis for our ongoing Phase 1/1b trial in renal cell cancer and Phase 1b/2 trial in non-small cell lung cancer, in each case, with CPI-444, which has now been investigated in over 250 cancer patients," said Richard A, Miller M.D., an oncologist; co-founder, president and chief executive officer of Corvus; and a senior author of the article. "We are delighted that the quality of this research led to this article being featured on the cover of the journal. We will provide an update on our ongoing human clinical studies at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in November."
ABOUT CPI-444
CPI-444 is a small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine in the tumor microenvironment to the A2A receptor. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2A receptor present on immune cells and block their activity. CD39 and CD73 are enzymes on the surface of tumor cells and immune cells. These enzymes work in concert to convert ATP to adenosine. In vitro and preclinical studies have shown that dual blockade of CD73 and the A2A receptor may be synergistic.