Targeting Macrophages Boosts Pancreatic Cancer Therapy

In a phase Ib safety trial, a new approach to treating pancreatic cancer prevented recruitment of immunosuppressive macrophages to tumors and enhanced the effectiveness of a standard adjuvant chemotherapy regimen. The results were published last month in Lancet Oncology.

Pancreatic tumors are notoriously hard to treat, in part because they secrete the chemokine CCL2. CCL2 recruits CCR2-positive monocytes from the bone marrow to the tumor, where they differentiate into immunosuppressive macrophages. Preclinical studies have shown that blocking recruitment of CCR2-positive monocytes with CCR2 or CCL2 inhibitors improves tumor response to chemotherapy.

In the single-center, open-label, dose-finding study, researchers added the small molecule CCR2 inhibitor PF-04136309 (Pfizer) to FOLFIRINOX (a four-drug chemotherapy combination) in 39 patients with borderline resectable and locally advanced pancreatic cancer; eight patients received FOLFIRINOX alone. The endpoints were safety and tumor response.

The drug was well tolerated and even at the highest dose produced no additional toxicity over FOLFIRINOX alone. Of 33 patients who had their tumors imaged before and after treatment, 48% experienced significant tumor shrinkage, double the historical response rate of FOLFIRINOX alone.

Some of the responses were remarkable, allowing patients who would not have been candidates for surgery to undergo potentially curative resection, says principal investigator David Linehan, MD, a surgeon at the University of Rochester Medical Center in Rochester, NY. “I've been taking care of pancreatic cancer patients for 20 years and I have rarely seen these kinds of dramatic responses before,” says Linehan.

As part of the trial, the investigators obtained bone marrow, peripheral blood, and tumor samples from patients before and after treatment. They found that PF-04136309 prevented CCR2-positive inflammatory monocytes from leaving the bone marrow and decreased the number of macrophages in tumors. In patients who responded to the treatment, the number of monocytes in tumors was significantly lower than among the nonresponders.

PF-04136309 also appeared to increase endogenous antitumor immune responses, based on cytokine measurements in tumor samples. “Prior to treatment, the tumors had cytokine profiles associated with immune suppression,” says Linehan. “Afterward there was upregulation of more cytokines associated with immune activation,” as well as evidence of an influx of immune T cells.

“This compound gives us a new way to ask whether the limited response to chemotherapy seen in most patients with pancreatic cancer can be improved by breaking down some of the barriers that may be preventing it from working,” says Gregory Beatty, MD, PhD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, who was not involved with the study.

As a follow up to this first study, Linehan has begun a multicenter, randomized phase II trial for metastatic pancreatic cancer that will combine PF-04136309 with a more commonly used chemotherapeutic regimen, nab-paclitaxel plus gemcitabine. The endpoint will be progression-free survival. –Pat McCaffrey