In oncologic disease, tumors can profoundly subvert inflammatory and effector immune responses. In the tumor cellular microenvironment, CCR2 bearing cells are thought to largely have an immunosuppressive behavior. These are the so-called myeloid derived suppressor cells, (MDSCs). These cells effectively help tumors hide from the body’s cytotoxic immune response to tumor cells. Inhibiting CCR2, and thus the MDSCs controlled by CCR2, could therefore lead to the liberation of the cytotoxic immune response against the tumor cells and improved patient survival. We have an ongoing clinical development program for the treatment of patients with advanced pancreatic cancer, a deadly cancer, with our drug candidate CCX872, our second inhibitor of the chemokine receptor known as CCR2.
We currently have an ongoing Phase Ib clinical trial of CCX872 in patients with advanced pancreatic cancer. The primary aim of this study is to evaluate whether orally administered CCX872 is safe and can improve the progression of disease in patients with nonresectable pancreatic cancer being treated with FOLFIRINOX, one of the current standard of care treatments for this disease. Clinical trial enrollment of 50 patients was completed in January 2016. In August 2016, we reported overall response rate (ORR) data, and we are continuing to treat patients for as long as they remain in a progression-free state.
In January 2018, data from the ongoing Phase Ib clinical trial of CCX872 in locally advanced/metastatic pancreatic patients were presented at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, demonstrating promising overall survival (OS) of all patients randomized of 29% at 18 months with CCX872 and FOLFIRINOX combination therapy. This compares favorably with previously published OS rates of 18.6% at 18 months using FOLFIRINOX alone to treat pancreatic cancer patients with metastatic disease.
The objective of using a CCR2 inhibitor such as CCX872 is to reduce the suppressive myeloid cell presence in the tumor and, in doing so, slow the progression of disease in these patients.
CCX872 has previously been evaluated in a Phase I clinical trial in healthy volunteers. The results showed that CCX872 was safe and well-tolerated, and suitable for chronic, or longer-term, dosing in patients. CCX872 was able to effectively block CCR2 in the circulation, and it had a predictable dose-linear pharmacokinetic profile.
We believe that CCX872 may represent a promising novel immunotherapeutic approach. Drugs that block CCR2 have shown evidence of activity in patients with pancreatic cancer as well as in a mouse orthotopic pancreatic cancer model.
Pancreatic cancer is the 12th most common cancer worldwide but the 4th leading cause of cancer-death in developed countries. In the United States in 2016, approximately 53,070 people were expected to develop pancreatic cancer, and 41,780 of those cases were expected to succumb to the disease.
Human pancreatic tumors are characterized by a highly immunosuppressive microenvironment. In the tumor cellular microenvironment, CCR2 bearing cells are thought to be largely of an immunosuppressive behavior; these are the so-called myeloid derived suppressor cells (MDSCs). These cells effectively help tumors hide from the body’s cytotoxic immune response to tumor cells. Inhibiting CCR2, and thus the myeloid derived suppressor cells controlled by CCR2, could therefore lead to the liberation of the cytotoxic immune response against the tumor cells, and improved patient survival.
Reduction of Liver Fibrosis by CCR2 Antagonist CCX872 in Murine Models of NASH
Zhenhua Miao, Dale Newland, Linda Ertl, Richard Parker, Jeff McMahon, Penglie Zhang, David Adams, Thomas Schall, Israel Charo. Presented at the American College of Gastroenterology (ACG) 2016 Annual Meeting, 2016.
Pharmacokinetic and pharmacodynamic profile of the novel, oral and selective CCR2 inhibitor CCX872-B in a Phase Ib pancreatic cancer trial, Aram Hezel, Ferry Eskens, Stefan Steifer, Marcus Noel, Andrea Wang-Gillam, Janet Diehl, Antonia Potarca, Bin Zhao, Heiyoun Jung, Lisa Lohr, Shichang Miao, Israel Charo, Pirow Bekker, Thomas J. Schall. Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2015.
Orally Administered CCR2 Selective Inhibitor CCX872-B Clinical Trial in Pancreatic Cancer. Ferry Eskens, Stefan Sleijfer, Sabrina Cheng, Antonia Potarca, Niky Zhao, Lisa Lohr, Shichang Miao, Israel Charo, Pirow Bekker, Thomas Schall. IBCD Meeting, 2015.
CCX872: Pharmacodynamic study of a potent and selective CCR2 antagonist in human volunteers and plans for phase Ib trial in patients with pancreatic cancer. Anne-Marie Duliege, Stefan Sleijfer, Ashley Bischof, Joanne Tan, Penglie Zhang, Lisa Seitz, Daniel Dairaghi, Pirow Bekker, Israel Charo, Thomas Schall. AACR meeting, April 2015. Abstract CT223.
Phase 1 Clinical Evaluation of the CCR2 Antagonist CCX872-B. Pirow Bekker, Trevor Charvat, Shichang Miao, Lisa Lohr, Timothy Sullivan, Zhenhua Miao, Jay Powers, Juan Jaen, Thomas J. Schall. Presented at the American Diabetes Association Meeting, Abstract 1126-P, 2013.
Targeting Tumor Infiltrating Myeloid Cells with Potent Small Molecule Chemokine Receptor Antagonists. Ashley Bischoff, Joanne Tan, Punna Sreenivas, Penglie Zhang, Israel Charo, Anne-Marie Duliege, Thomas Schall. Presented at the AACR-Tumor Immunology and Immunotherapy Meeting, 2014.
Monocytic CCR2+ Myeloid-Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T-cell Infiltration into the Tumor Microenvironment. Alexander M. Lesokhin, Tobias M. Hohl, Shigehisa Kitano, Czrina Cortez, Daniel Hirschhorn-Cymerman, Francesca Avogadri, Gabrielle A. Rizzuto, John J. Lazarus, Eric G. Pamer, Alan N. Houghton, Taha Merghoub, and Jedd D. Wolchok. Cancer Res February 15, 2012 72:876-886