Pancreatic tumours containing immunosuppressive M2 tumour associated macrophages (TAMs) have a poor prognosis . TAMs are derived from circulating inflammatory monocytes both of which express the CCR2 chemokine receptor. Pancreatic tumours are known to express CCL2 – the CCR2 ligand. In mouse models of pancreatic cancer it has been found that inhibition of CCR2 inhibits M2 TAM infiltration into the tumour microenvironment . M2 TAMs are one of the reasons immune checkpoint inhibitor antibodies are not effective as a single agent therapy for pancreatic cancer. Combinations of checkpoint inhibitors with CCR2 inhibitors are therefore of future interest if single agent CCR2 inhibition proves safe and effective in pancreatic cancer clinical trials.
A phase I clinical trial with a CCR2 inhibitor in combination with the chemotherapy FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer demonstrated that CCR2 inhibition prevented inflammatory monocyte migration from the bone marrow and decreased the number of TAMs in the tumour microenvironment . It also demonstrated that combination with FOLFIRINOX was safe and tolerable.
The following pancreatic cancer clinical trials for agents targeting CCR2 are active:
- Kurahara, Hiroshi, Hiroyuki Shinchi, Yuko Mataki, Kousei Maemura, Hidetoshi Noma, Fumitake Kubo, Masahiko Sakoda, Shinichi Ueno, Shoji Natsugoe, and Sonshin Takao. ‘Significance of M2-Polarized Tumor-Associated Macrophage in Pancreatic Cancer’. The Journal of Surgical Research 167, no. 2 (15 May 2011): e211–19. PMID: 19765725.
- Sanford DE, Belt BA, Panni RZ, Mayer A, Deshpande AD, Carpenter D, Mitchem JB, Plambeck-Suess SM, Worley LA, Goetz BD, Wang-Gillam A, Eberlein TJ, Denardo DG, Goedegebuure SP, Linehan DC. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013 Jul 1;19(13):3404-15. doi: 10.1158/1078-0432.CCR-13-0525. PubMed PMID: 23653148.
- Nywening TM, Wang-Gillam A, Sanford DE, Belt BA, Panni RZ, Cusworth BM, Toriola AT, Nieman RK, Worley LA, Yano M, Fowler KJ, Lockhart AC, Suresh R, Tan BR, Lim KH, Fields RC, Strasberg SM, Hawkins WG, DeNardo DG, Goedegebuure SP, Linehan DC. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016 May;17(5):651-62. Doi: 10.1016/S1470-2045(16)00078-4. PubMed PMID: 27055731.