1068P - Adenosine A2A receptor antagonist, CPI-444, blocks adenosine-mediated T cell suppression and exhibits anti-tumor activity alone and in combination...

Date 09 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Cancer Immunology and Immunotherapy
Presenter Stephen Willingham
Citation Annals of Oncology (2016) 27 (6): 359-378. 10.1093/annonc/mdw378
Authors S. Willingham1, P. Ho1, R. Leone2, C. Choy1, J. Powell2, I. McCaffery1, R. Miller3
  • 1Translational Sciences, Corvus Pharmaceuticals, 94010 - Burlingame/US
  • 2Dept Of Oncology, Johns Hopkins University, 21287 - Baltimore/US
  • 3Clinical Development, Corvus Pharmaceuticals, 94010 - Burlingame/US

Abstract

Background

Elevated extracellular adenosine in the tumor microenvironment generates an immunosuppressive niche that promotes tumor growth and metastasis. Adenosine signaling via A2A receptor (A2AR) on immune cells suppresses anti-tumor immunity and may also limit efficacy of immunotherapies such as anti-PD-L1 and anti-PD-1 antibodies.

Methods

CPI-444 is a potent, oral, selective A2AR antagonist that has been well tolerated in Ph 1 and 2 studies in non-oncology indications. The efficacy of CPI-444 ± Anti-PD-L1 or Anti-PD-1 was evaluated in MC38 and CT26 syngeneic mouse tumor models.

Results

In MC38, daily treatment of mice with CPI-444 (1, 10, 100 mg/kg) led to dose-dependent inhibition of tumor growth, leading to tumor elimination in 9/30 mice. Combining CPI-444 with anti-PD-L1 treatment in MC38 synergistically inhibited tumor growth and eliminated tumors in 90% of treated mice. In an additional model, CT26, 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. When cured mice were later re-challenged with MC38 cells, tumor growth was fully inhibited, indicating that CPI-444 induced systemic anti-tumor immune memory. CD8+ T cell depletion abrogated the efficacy of CPI-444 ± anti-PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. Anti-tumor efficacy of CPI-444 ± anti-PD-L1 was associated with increased CD8+ cell infiltration and activation in MC38 tumor tissues. Additionally, levels of immune checkpoints were modulated by treatment with CPI-444, including GITR, OX40, and LAG3 on tumor infiltrating lymphocytes and circulating T cells, suggesting a broad role for adenosine mediated immunosuppression.

Conclusions

Based on these results and others, we have initiated a Phase 1b clinical trial to examine safety, tolerability, biomarkers, and preliminary efficacy of CPI-444 as a single agent and in combination the investigational anti-PD-L1 antibody, Atezolizumab, in patients with solid tumors.

Clinical trial identification

NCT02655822

Legal entity responsible for the study

Corvus Pharmaceuticals

Funding

Corvus Pharmaceuticals

Disclosure

S. Willingham, P. Ho, C. Choy, I. McCaffery, R. Miller: Employee and stock holder of Corvus Pharmaceuticals. R. Leone, J. Powell: Grant support and stock from Corvus Pharmaceuticals.