Abstract 320: Inhibition of adenosine A2A receptor (A2AR) by CPI-444 enhances CD8+ T cell killing of a HER-2/neu expressing murine tumor
Authors: Blake A. Scott, Todd Armstrong, Elizabeth M. Jaffee
Journal: Cancer Research (2016)

Abstract Immunotherapies such as checkpoint inhibitors that block immune suppressive mechanisms are transforming the way some cancers are treated. The identification of additional mechanisms that suppress immune cell function is stimulating the search for other immune modulating agents that are additive or synergistic with current immune checkpoint inhibitors or are capable of overcoming mechanisms of resistance and tolerance. 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. To test this, neu-expressing mammary tumor bearing HER-2/neu transgenic (Neu-N) mice were treated with low dose cyclophosphamide (Cy) to deplete Tregs followed one day later with a granulocyte-macrophage colony-stimulating factor (GM-CSF) and neu-expressing whole cell vaccine (GVAX). Mice were treated with the A2AR inhibitor, CPI-444, by oral gavage daily for twelve days. Mice also received adoptively transferred high-avidity naïve neu-specific CD8+ T cells intravenously one day after vaccination. Mice were monitored for tumor progression, and tumor-infiltrating lymphocytes (TIL) were harvested from additional mice at multiple time points and analyzed for T cell activation by flow cytometry. Inflammatory changes in the tumor microenvironment were assessed by immunohistochemistry. We found that T cells adoptively transferred to mice together with Cy, a neu-targeted vaccine and CPI-444 are more effective at reducing established tumors and delaying tumor progression when compared with mice treated with Cy, vaccine, adoptively transferred T cells and vehicle control. Of particular note, mice receiving the same treatment but with CPI-444 in lieu of vehicle had a significant mean difference in tumor area of 6.446mm2 (P&amp;lt;0.05) when compared to the vaccine and vehicle control cohort. When compared to the tumor alone cohort, mice receiving the full therapeutic regimen had a significant mean difference in tumor area of 13.59mm2 (P&amp;lt;0.001). Mechanistic studies are underway to assess the activity of the adoptively transferred T cells in the TIL. These studies may provide the rationale to test an A2AR inhibitor in combination with adoptively transferred T cells and/or vaccines in patients with cancer. Citation Format: Blake A. Scott, Todd Armstrong, Elizabeth M. Jaffee. Inhibition of adenosine A2A receptor (A2AR) by CPI-444 enhances CD8+ T cell killing of a HER-2/neu expressing murine tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 320.