Pinpointing patients

Researchers identify immune biomarker showing which HCC patients would benefit most from sorafenib

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BUFFALO, N.Y.—Taking a step closer toward individualized cancer treatment, immunology researchers at the Roswell Park Comprehensive Cancer Center have uncovered a biomarker that could explain why some patients with advanced hepatocellular carcinoma (HCC) respond better than others to sorafenib, a common chemotherapy treatment for liver cancer. If this research holds up, the analysis of immune responses among patients receiving sorafenib could lead to more individualized treatment options and ultimately better overall outcomes for liver cancer patients diagnosed with the disease.
Dr. Yasmin Thanavala, a Roswell Park Department of Immunology scientist, got the ball rolling by leading the study, which was published online in JCI Insight and highlighted in the journal’s JCI This Month digest for September 2019.
Knowing which HCC patients are most likely to respond to sorafenib eliminates failed treatment and unnecessary expense for patients with little time left, Thanavala says. In fact, most of the subjects have passed away since the study was conducted between November 2013 and May 2017.
HCC is the most common primary liver cancer and the second leading cause of cancer-related death worldwide. HCC arises from liver cirrhosis, with chronic infection by hepatitis B or C viruses as the leading cause, followed by other etiologies of cirrhosis, such as alcohol consumption and fatty liver disease associated with metabolic defect. Treatment options for advanced HCC are limited, rendering it a serious therapeutic challenge.
Although the mainstay oral chemotherapy treatment for patients with advanced HCC is sorafenib, side effects from this drug may cause many patients to miss doses or discontinue treatment. These side effects include hand and foot syndrome (palmar-plantar erythrodysesthesia), diarrhea, fatigue and rash, according to Thanavala.
In the United States, there are approximately 33,000 new cases of HCC each year, with 27,000 expected to die from the disease annually.
The Roswell Park researchers—which included Dr. Renuka Iyer, section chief for gastrointestinal oncology—collected blood samples from 30 patients before treatment and at two time points during treatment with sorafenib, according to the journal. They observed elevated levels of a subset of CD8+ cytotoxic T-cells producing interferon type II, an important immune protein that destroys tumor cells and significantly reduces risk of death over time. Similarly, CD8+ cells showed an increase in granzyme B, an important enzyme that helps drive cell death.
Additional findings showed that patients with a high ratio of CD4+ T-effector/T-regulatory cells prior to treatment showed significant improvement in both progression-free and overall survival, the authors reported. Decreased numbers of two important immune checkpoint proteins expressed on T cells—PD-1 and CTLA-1—suggest that a combination treatment of sorafenib with checkpoint inhibitors such as nivolumab and pembrolizumab could produce positive results in the future.
“Studying biomarkers that correlate with progression-free or overall survival can help reduce exposure to therapies that have an impact on a patient’s quality of life and survival,” Thanavala comments. “Utilizing this information, our evidence supports the rationale that patients could benefit from a regimen of sorafenib and immunotherapy, which could help with antitumor immunity and improve the magnitude and strength of antitumor responses.”
The study will continue, although in “a different direction,” she says, noting that “My lab is still developing ideas as to what questions we need to explore next. We will need donations to generate additional preliminary data and then seek grant funding.
“Our ultimate goal is to be able to choose the HCC patients most likely to benefit from sorafenib,” she adds.
According to Thanavala, although sorafenib treatment results in improved progression-free survival and overall survival, treatment-associated toxicities are frequent, requiring dose interruptions and dose reductions for the majority of the patients. In addition, conventional clinicopathological diagnostic tools have proved inadequate to identify patients who will benefit from therapy.
The study also suggests that treatment with sorafenib may delay tumor growth and metastases in patients with HCC, not only by inhibiting angiogenesis, but also by suppressing immunosuppressive cell subsets; this seems to reveal the central role of CD8+ T cells in this targeted therapy for liver cancer.
“Importantly, our results provide the scientific rationale for combining sorafenib with checkpoint inhibitors,” the journal article states. “Such a regimen should be capable of both targeting tumor angiogenesis and down-regulating suppressor cell phenotypes, an ‘off-target’ effect of sorafenib on the immune system.”

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