Sorafenib has beneficial immunomodulatory effects in hepatocellular carcinoma

Reuters Health Information: Sorafenib has beneficial immunomodulatory effects in hepatocellular carcinoma

Sorafenib has beneficial immunomodulatory effects in hepatocellular carcinoma

Last Updated: 2016-07-29

By Will Boggs MD

NEW YORK (Reuters Health) - Sorafenib, an oral antiangiogenic agent, also has beneficial immunomodulatory effects that correlate with survival in patients with hepatocellular carcinoma (HCC), researchers report.

"Sorafenib therapy resulted in the reduction of several immunosuppressive phenotypes including the expression of the inhibitory checkpoint molecule called PD-1," Dr. Yasmin Thanavala from Roswell Park Cancer Institute in Buffalo, New York, told Reuters Health by email. "Importantly from a patient benefit standpoint, several of the responses were associated with increased overall survival."

T cells express PD-1 after chronic antigenic stimulation, and upregulation of PD-L1 by neoplastic cells allows them to escape the antitumor effector T cell responses. Recent efforts in cancer immunotherapy have focused on inhibiting the immune checkpoint pathways responsible for T cell paralysis.

Dr. Thanavala's team investigated the frequency of PD-1+ T cells, Tregs, and myeloid derived suppressor cells (MDSC) in 19 patients with advanced HCC before and after sorafenib treatment.

Following sorafenib treatment, there were decreases in the frequency and absolute numbers of PD-1+ T cells and in the frequency and absolute numbers of Tregs. The frequency and absolute number of MDSC did not change, however, they report in a paper online July 21 in JCI Insight.

Patients with greater declines in circulating PD-1+ T cells achieved significantly better overall survival compared with patients with lesser declines.

Moreover, patients who had higher baseline numbers of PD-1+ T cells achieved significant improvement in overall survival compared with patients with lower baseline numbers of these cells.

The numbers of Treg cells before treatment and the reduction in absolute numbers of Tregs after sorafenib treatment also correlated strongly with overall survival.

"Our studies suggest that administration of sorafenib in combination with immunotherapeutic approaches (such as anti-PD-1 treatment) may enhance the therapeutic efficacy of immune-based strategies in patients with advanced-stage HCC," Dr. Thanavala said. "While PD-1 therapy is not currently approved for patients with hepatocellular cancer, however, when/if it is, offering this combination to patients with HCC may translate to increased survival benefit than either treatment alone."

"The measurement of the phenotype and functional activity of T cells before treatment and their modulation following sorafenib therapy could serve as a prognostic biomarker to help predict treatment outcome and identify HCC patients who may benefit from this treatment alone or as a combination therapy regimen," Dr. Thanavala added. "Offering novel, newly approved treatments along with 'gold standard' therapy may translate to improved clinical outcome."

Dr. Dan G. Duda from Harvard Medical School in Boston told Reuters Health by email, "The study is an interesting one, but inherently correlative in nature. I think that what needs to be understood are the direct immunomodulatory effects of sorafenib (on lymphocytes) versus the indirect effects through changes within the HCC environment."

The study had no commercial funding, and the authors reported no conflicts of interest.


JCI Insight 2016

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