An experimental immune therapy can re-educate macrophages to tear down the scaffolding that surrounds and protects pancreatic cancer from chemotherapy. Typically, macrophages are implicated with helping tumors to grow, but this preclinical study, done in mice, suggests how they can be reprogrammed by manipulating the immune system.1
The key steps to redirecting macrophages to attack the microenvironment around the tumor were defined by this study. It was led by Gregory L. Beatty, MD, PhD, an assistant professor of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania and the Abramson Cancer Center in Philadelphia.
“We’ve unraveled some of the complex, bidirectional messaging between a tumor and its microenvironment. We’ve learned how antibodies that target a cell surface molecule called CD40 work with the immune system to tear back that wall,” said Beatty. “Additionally, our findings identify a novel role for CD40 antibodies: as a ‘lead-in’ therapy to enhance the efficacy of chemotherapy and possibly other biological treatments for pancreatic cancer.”
After the immune system is treated with CD40 antibodies, chemokine ligand 2 (CCL2) and interferon gamma (IFN-γ) cooperate to redirect macrophages to attack cancer. CCL2 facilitates the infiltration of macrophages into tumors. IFN-γ induces the release of enzymes that can degrade the fibrotic scaffolding so tumors are no longer protected from chemotherapy.
The study also found that the fibrotic scaffolding of tumors remained degraded after CD40 treatment for approximately 1 week, so that window of time may be the most effective time for chemotherapy treatment with gemcitabine.
The timing of delivery of a CD40 agonist and chemotherapy is critical, the authors said. Mice treated with gemcitabine 2 days after receiving CD40 antibodies were found to poorly tolerate chemotherapy and had significant weight loss, with 30% mortality. However, when chemotherapy was administered 5 days after CD40, it was both well-tolerated and produced promising clinical activity marked by tumor cell death and shrinkage.
“Together, we believe that this data supports further investigation of therapeutics that redirect monocytes and macrophages, rather than depleting them. Macrophages can be very potent killers of cancer. Since keeping them out of tumors is a challenge, why not harness their recruitment? This may be the Achilles heel of pancreatic cancer,” Beatty said.
“Now that we better understand this biology, we are hopeful that our findings will spark further clinical interest and a path forward to test this treatment approach in patients.”
1. Long KB, Gladney WL, Tooker GM, et al. IFN-gamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma [published online ahead of print February 19, 2016]. Cancer Discov. doi:10.1158/2159-8290.CD-15-1032.