A drug sold as Cometriq®, Cabozantinib, has demonstrated efficacy against invasive prostate cancer in mice. The drug is already used to treat people afflicted with some types of thyroid kidney cancer (as described in the video below). When mice modeling invasive prostate cancer were treated with the drug, tumor cells secreted molecules that recruited neutrophils to get into the tumor, where they triggered a response by the immune system that eradicated the tumor cells.
The work was reported in Cancer Discovery, and the authors noted that it is the first report of a drug that inhibits tyrosine kinase acting to stimulate anti-tumor immunity that removes cancer. This could be a new avenue for cancer therapeutics. The drug causes prostate cancer cells to release chemical factors, CXCL12 and HMBG1. In response to those signals, neutrophils infiltrate the tumor and mount an attack on cancer cells. In the treated mice, invasive cancers were almost completely cleared within only 72 hours.
"We saw dramatic anti-tumor responses," said the lead author and investigator of the work, medical oncologist and physician-scientist Akash Patnaik, MD, PhD, Assistant Professor of Medicine, Director of the Developmental Therapeutics Laboratory and Attending Physician at the Genitourinary Oncology Program of the University of Chicago Medicine. "We used a difficult-to-treat, aggressive prostate cancer mouse model. We were very surprised to see complete eradication of the most invasive, poorly differentiated tumors within days."
"The results of this study were really unexpected," commented co-author Lewis Cantley, PhD, Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City.
Cabozantinib, was approved by the FDA in 2012 for use against metastatic medullary thyroid cancer and given approval in 2015 to treat advanced renal cell carcinoma. The COMET-1 trial recently tried the drug in men with metastatic prostate cancer, but the results weren't encouraging. While some men were helped, others showed no response at all. "Why some of these patients responded and others did not was unclear," Cantley said.
Patnaik and colleagues started testing the drug in the lab after seeing positive results in patients with advanced prostate cancer patients in the Phase II trial. There, after exposure to cabozantinib, there was a dramatic reduction in the tumors carried by a mouse model for prostate cancer. When the researchers turned to prostate cancer cells growing in the laboratory, they again saw very little result. They wondered what could explain the differential effects. They found that the drug was not having a direct effect, it needed the infrastructure of an organism.
"The drug was not actually killing the tumor cells," Cantley explained. "Instead, it was inducing them to release factors that stimulated an attack by the innate immune system."
Confirming their findings, if the production of the CXCL12 and HMGB1signals was blocked tumor cells, the drug did not have any effect on tumor cells in the mice.. When the researchers blocked production of these signals, the drug was no longer effective. The neutrophils that would normally attracted by the CXCL12 and HMBG1 never mounted an attack.
"Our findings could also explain why some patients in the COMET-1 trial did not benefit from the drug," Patnaik said. "This Phase-III trial included patients who had already received aggressive chemotherapy, which may have compromised their immune systems."
There is additional research to elucidate exactly how cabozantinib exerts its effect, but "this paper raises the possibility that a new class of drugs could be developed to treat cancers by stimulating attack by neutrophils," Cantley said.
While immunotherapies had been in development for awhile, they primarily focus on drugs targeting immune checkpoint blockades. Those drugs, like ipilimumab, nivolumab and pembrolizumab, give the adaptive immune system the power to attack tumors. But this work instead highlights how neutrophils can be utilized in the fight against cancer.
"Neutrophils can be just as potent as T cells," Patnaik explained. His next goal is to combine them with other immunotherapies.
"Based on our results showing that cabozantinib can activate innate immunity and overcome an immunosuppressive tumor microenvironment, we are planning clinical trials to test the combination of cabozantinib and T cell checkpoint immunotherapy in specific subtypes of advanced kidney and prostate cancer. Our goal is to enhance long-term anti-cancer responses from activating both innate and adaptive immunotherapy," concluded Patnaik.
Learn more about neutrophils, highlighted in the video above.