70P - Chemokine Receptor 2 (CCR2) Antagonism With a Small Molecule Enhances the Effectiveness of Checkpoint Inhibition by Altering the Tumor Microenviron...

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Cancer Immunology and Immunotherapy
Translational Research
Presenter James Campbell
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors J. Campbell1, C. Janson1, L. Ertl2, C. Li1, Z. Miao1, V. Chhina2, M. Vilalta1, A. Kumamoto2, T. Dang3, S. Liu3, S. Yao4, P. Zhang4, T.J. Schall5, R. Singh4
  • 1Biology, ChemoCentryx, Inc, 94043 - Mountain View/US
  • 2Comparative Medicine, ChemoCentryx, Inc, 94043 - Mountain View/US
  • 3Dmpk, ChemoCentryx, Inc, 94043 - Mountain View/US
  • 4Chemistry, ChemoCentryx, Inc, 94043 - Mountain View/US
  • 5Board, ChemoCentryx, Inc, 94043 - Mountain View/US



CT26 tumors are heavily infiltrated by tumor-specific CD8 T cells but nevertheless grow rapidly in Balb/c mice. These tumors are partially responsive to anti-PD-1 monoclonal antibody therapy, suggesting an active suppression of the tumor-specific cytotoxic T cells. As CCR2 is expressed by a potentially suppressive leukocyte subset within these these tumors, we aimed to test whether CCR2 blockade could enhance the anti-tumor effects of anti-PD-1.


Five days after subcutaneous CT26 implantation into the flanks of 9wk female Balb/c mice (2.5x105/mouse), the recipients were randomized based on tumor size and treatment was begun. Mice received anti-PD-1 by IP injection on days 7, 10, 17 and 21 (200μg/mouse), and received CCR2 antagonist CCX598 (30 or 60mg/kg) or vehicle by oral gavage every 24 hours until day 60.


We have found that the therapeutic effects of anti-PD-1 therapy are appreciably enhanced by specific blockade of chemokine receptor 2 (CCR2) via a small molecule antagonist. This combined anti-PD-1/CCR2i approach significantly decreases tumor size and increases the proportion of long-term survivors, with more than 50% of the mice (up to 73%) showing complete regression of a previously established tumor. The effects of this combined therapy are dependent on the presence of CD8+ T cells, as tumors do not respond to the therapy in CD8-depleted mice. The anti-CT26 tumor response is specific: long term survivors are resistant to re-inoculation with the CT26 tumor (even without further dosing of either drug) but are not resistant to the 4T1 breast tumor. CCR2 antagonism alters the tumor microenvironment by reducing the number of mMDSC per gram of tumor (a CCR2hi population phenotypically defined as CD11b+/Ly6G-/Ly6Chi). Reduction in tumor size is inversely proportional to the ratio of CD8 T cells to mMDSC.


These data are consistent with a hypothesis that CCR2 antagonism enhances anti-PD-1 therapy by preventing mMDSC from accumulating within the tumor, thus reducing their suppressive effects on cytotoxic T cells.

Clinical trial identification

Legal entity responsible for the study

ChemoCentryx, Inc.


ChemoCentryx, Inc.


J. Campbell, C. Janson, L. Ertl, C. Li, Z. Miao, V. Chhina, M. Vilalta, A. Kumamoto, T. Dang, S. Liu, S. Yao, P. Zhang, T.J. Schall, R. Singh: Full time employee of ChemoCentryx, Inc.