Chemokines and their receptors influence many hallmark processes in cancer. C-C Chemokine receptor 4 (CCR4) and its ligands are highly expressed in many types of human tumors, and are often associated with poor prognosis. CCR4 antagonism has been demonstrated to reduce tumor growth in various mouse tumor models. Here we have assessed a small molecule inhibitior of CCR4 as a therapeutic agent to potentiate the effects of anti-CTLA-4 in the CT26 and KCM tumor models.
The subcutaneous CT26 colon cancer model and the orthotopic KCM pancreatic cancer model were used to assess the effects of CCX6239, a CCR4 inhibitor, in combination with anti-CTLA-4 antibody. Mice implanted with CT26 cells were randomized into study groups on day 7 based on the pre-treatment tumor sizes. KCM cells were implanted directly into the pancreas. Dosing of CCX6239 and anti-CTLA-4 began on day 7. CCX6239 was dosed orally twice daily at 30mg/kg, and anti-CTLA-4 was dosed intraperitoneally on days 7, 11, and 15 at 100μg/mouse.
Combined treatment with anti-CTLA-4 and CCR4 inhibitor significantly decreased tumor size and increased the proportion of long-term survivors in the CT26 model. Mice with tumor regression exhibited a high proportion of CD8 T cells that recognized a CT26-specific neoantigen, and these mice were resistant to re-inoculation with CT26 cells (without further dosing of either drug), while another type of tumor grew well in the same mice. In the KCM model, anti-CTLA-4 alone provided substantial tumor growth inhibition, which was further enhanced by CCX6239. Interestingly, CCX6239 alone also significantly reduced tumor burden in this model.
A specific CCR4 inhibitor reduces tumor growth either alone or in combiniation with anti-CTLA-4 in two preclinical models, suggesting CCR4 is a potential new target for cancer treatment.
ChemoCentryx Inc.
ChemoCentryx Inc.
C. Li, J.J. Campbell, L.S. Ertl, Z. Miao, V. Chhina, A. Kumamoto, S. Yau, T. Dang, P. Zhang, T.J. Schall, R. Singh: Full time employee and stock holder of ChemoCentryx Inc.