A study of Cometriq (cabozantinib) in mice with aggressive prostate cancer may explain why a previous clinical trial of the drug failed to treat human prostate cancer. Researchers demonstrated that Cometriq acts by engaging particular cells of the innate immune system — cells that wiped out aggressive tumors in mice in a matter of days.
Since many of the men in the earlier trial had been heavily pretreated with chemotherapy, their immune systems were likely compromised. Even so, the newer findings suggest that Cometriq may indeed help to treat aggressive prostate cancer.
The study, “Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Anti-Tumor Innate Immunity,” appeared in the journal Cancer Discovery and points to the possibility of using neutrophil cells in cancer immunotherapy.
Cometriq blocks a type of enzymes called tyrosine kinases. The enzyme is used by many tumor types, and the medicine is approved for certain types of thyroid or kidney cancer. An earlier Phase 3 clinical trial (NCT01605227), called COMET-1, showed that while the treatment was effective in some men with prostate cancer, others did not respond at all.
“Why some of these patients responded and others did not was unclear,” Lewis Cantley, PhD, and senior author of the study, said in a press release. Cantley is director of the Sandra and Edward Meyer Cancer Center at New York’s Weill Cornell Medicine.
To better understand this difference, University of Chicago Medical Center researchers went back to the lab and found that when they used Cometriq to treat mice harboring aggressive prostate cancer, the tumor disappeared within a few days. But treating cancer cells in a lab dish was surprisingly ineffective.
Further studies helped them understand what was going on. “The drug was not actually killing the tumor cells,” Cantley said. “Instead, it was inducing them to release factors that stimulated an attack by the innate immune system.”
Researchers observed how Cometriq triggered the release of two factors — immune mediators known as CXCL12 and HMGB1 — from prostate cancer cells. These molecules acted to attract neutrophils to the tumor. Neutrophils belong to the first-line immune defense, and have the capacity to swiftly kill virus-infected cells. This gathering of neutrophils almost completely wiped out aggressive prostate cancer within 48 to 72 hours.
“We saw dramatic anti-tumor responses,” said Akash Patnaik, MD, PhD, the study’s lead author and director of the developmental therapeutics laboratory at the University of Chicago Medical Center’s Genitourinary Oncology Program. “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.”
Added Cantley: “The results of this study were really unexpected.”
Researchers say this is the first time a drug acting to block tyrosine kinases is found to have activate innate immune responses that target tumors.
“Our findings could also explain why some patients in the COMET-1 trial did not benefit from the drug,” Patnaik said. “This Phase-3 trial included patients who had already received aggressive chemotherapy, which may have compromised their immune systems.”
T-cell based cancer immunotherapies have been successful in treating several cancer types. Patnaik envisions that neutrophils — which other researchers are exploring as a possible cancer treatment — could be used in combination with current T-cell cancer immunotherapies.
“Neutrophils can be just as potent as T-cells,” Patnaik said. “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.”
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