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A trio of promising studies
June 2016
by Mel J. Yeates  |  Email the author
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BURLINGAME, Calif.—Corvus Pharmaceuticals Inc. has announced the results of three preclinical studies of CPI-444, its lead oral checkpoint inhibitor. The studies demonstrated that CPI-444 was effective in stimulating various immune cells, generating antitumor immunity, suppressing tumor growth and delaying tumor progression in animal models of cancer. The data were presented in oral and poster sessions at the American Association for Cancer Research Annual Meeting 2016.
 
CPI-444 is an adenosine A2A receptor antagonist designed to disable a tumor’s ability to subvert attack by the immune system by inhibiting adenosine in the tumor microenvironment. Corvus is currently evaluating CPI-444 in a multicenter Phase 1/1b clinical trial in patients with various solid tumors. This successive expansion cohort trial is examining the activity of CPI-444 both as a single agent and in combination with atezolizumab (MPDL3280A), Genentech's investigational cancer immunotherapy.
 
“These preclinical studies demonstrate that CPI-444 enhances the immune response to various tumors in animal models of melanoma, breast and colon cancer. Enhancement of T cell function was also corroborated with adoptively transferred T cells and with tumor vaccines, indicating that this agent may have broad applications in immuno-oncology,” commented Dr. Richard A. Miller, Corvus co-founder, president and CEO. “These studies support our commitment to advancing the clinical development of CPI-444 as an immuno-oncology therapy for many types of cancer. Based on these study findings and others, we have begun enrolling patients in a Phase 1/1b clinical trial to evaluate the safety, tolerability and preliminary efficacy of CPI-444 as a single agent and in combination with an anti-PD-L1 in patients with solid tumors.”
 
"The Adenosine A2A Receptor Antagonist, CPI-444, Blocks Adenosine-Mediated T-Cell Suppression and Exhibits Anti-Tumor Activity Alone and in Combination with Anti-PD-1 and Anti-PD-L1" (abstract #2337) data from this preclinical study were presented in a poster session by Dr. Stephen Willingham, a senior scientist at Corvus. Results showed that CPI-444 restored T cell activation in vitro in T cells that were treated with immunosuppressive levels of adenosine. 
 
According to the study’s abstract, “Elevated levels of extracellular adenosine within the tumor microenvironment create an immunosuppressive niche that promotes tumor growth and metastasis. Adenosine signaling via the A2A receptor (A2AR) on immune cells suppresses antitumor immunity and limits the efficacy of immunotherapies such as anti-PD-L1 or anti-PD-1 monoclonal antibodies (mAbs).”
 
CPI-444 demonstrated single-agent antitumor activity and synergized with either anti-PD-1 or anti-PD-L1 in multiple animal tumor models, resulting in a significant number of cured animals. CPI-444 combined with anti-PD-L1 treatment resulted in increased CD8+ T cell infiltrates in tumors, indicating a heightened antitumor immune response. In tumor-bearing mice cured by treatment with CPI-444, long-term antitumor immunity was demonstrated by showing that all these mice were protected from tumor rechallenge.
 
The abstract continues, “The efficacy of CPI-444 was evaluated in MC38 and CT26 syngeneic mouse tumor models. In the MC38 model, daily treatment of mice with CPI-444 (1, 10, 100 mg/kg) led to a dose-dependent reduction in tumor growth, leading to full tumor elimination in 9/30 treated mice. New tumors failed to establish when the cured mice were rechallenged with MC38 cells, indicating that CPI-444 induced systemic antitumor immune memory. Combining CPI-444 with anti-PD-L1 mAb treatment in the MC38 model synergistically inhibited tumor growth and led to elimination of tumors in 9/10 treated mice.
 
“In the CT26 model, CPI-444 alone or anti-PD-1 alone led to non-significant reductions in tumor growth; however the combination of CPI-444 and anti-PD-1 led to a synergistic inhibition of tumor growth and prolonged survival compared to either agent alone. These results, and others, suggest that adenosine signaling may be an important resistance mechanism in tumors that incompletely respond to anti-PD-1/PD-L1 mAb therapy.”
 
A second abstract—“Inhibition of Adenosine A2A Receptor (A2AR) by CPI-444 Enhances CD8+ T-Cell Killing of a HER-2/neu Expressing Murine Tumor" (abstract #320)—reported that “Extracellular adenosine and its signaling through A2AR increases the activity of regulatory T cells (Tregs) and attenuates tumor-specific CD4+/CD8+ T cells. In this study we evaluated the role of a small-molecule inhibitor of A2AR in enhancing antitumor immunity against murine Her-2/neu (neu)-expressing breast cancer. We examined whether an A2AR inhibitor would enhance the activity of cancer specific CD8+ T cells when given with a T cell-inducing vaccine.”
 
Results showed that CPI-444 enhanced the activity of adoptively transferred, cancer-specific CD8+ T cells when administered with a T cell-inducing tumor vaccine.
 
Data from the third preclinical study reveal that “Present work in our lab demonstrates the ability of CPI-444 to enhance immunologic response in mice. First, A2aR blockade with CPI-444 (1 mg/kg) in the peri-vaccination period led to significant expansion of antigen-specific T cells over untreated controls,” according to the study abstract. “Interestingly, antigen-specific CTLs from CPI-444-treated mice showed significantly lower expression of inhibitory checkpoint receptors, including PD-1 and TIM-3. Second, in an MC38 tumor model, daily treatment with CPI-444 (100 mg/kg) led to tumor growth suppression and survival benefit compared with vehicle-treated controls. Notably, tumor infiltrating regulatory T cells had significantly lower CTLA-4 and FoxP3 expression in CPI-444 treated mice.”
 
In addition, “Treatment of animals with CPI-444 enhanced tumor immunity by lowering the expression of other inhibitory checkpoint receptors on tumor infiltrating immune cells (e.g., Lag 3, Tim 3 and PD-1). CPI-444 also enhanced the efficacy of adoptively transferred T cells, leading to suppressed tumor growth and increased survival compared with controls. CPI-444 increased the expansion of antigen-specific T cells in vitro and synergized with anti-PD-1 antibody treatment and glutamine metabolism inhibitors in animal models of colon tumors.”
 
As noted in the abstract, these data suggest that “CPI-444 may lower the threshold for effective anti-PD-1 therapy and achieve synergistic effects as combination therapy. Indeed, daily CPI-444 (100 mg/kg) treatment combined with anti-PD-1 treatment showed robust antitumor effect in the CT26 tumor model, with complete tumor rejection in 7/9 mice (vs. 2/10 mice in the anti-PD-1 alone group). Survival was markedly improved in mice receiving combination treatment versus either CPI-444 or anti-PD-1 alone.”
 
Code: E061614

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