Clinical OMICS

SEP-OCT 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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38 Clinical OMICs September/October 2018 www.clinicalomics.com immunosuppressive," and that they "propose a model in which these exosomes act like drones to fight against T cells in circulation, even before the T cells get near to the tumor." Indeed, PD-L1 has been found in blood samples derived from melanoma patients. While primarily focused on meta- static melanoma, the team found that breast and lung cancer also release the PD-L1-carrying exosomes. Currently, tumor PD-L1 levels are used as a predictive biomarker for clinical responses to anti-PD-1 therapy. The higher the percentage of cells expressimg PD-L1, in general, the more likely the patient is to respond to immune check- point inhibition. Gulley said that "this work opens the door to an import- ant question as to whether circulating PD-L1+ exosomes could be a clinical predictor if they are correlated to patient outcomes." He added that it raises the attractive possibility of developing "a liquid biopsy that could may tell you the patient's PD-L1 level in a blood-based test." Gulley said that this work is very promising, but "needs to be looked at in large, clinically annotated datasets to understand the true impact of this." Tasuku Honjo's, M.D., Ph.D., lab at Kyoto University first brought programmed cell death protein 1 (PD-1) into focus in 1992, with the paper "Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death" in EMBO J. Since then, PD-1 has been at the heart of cancer research as a primary target for one of the most successful innovations in cancer therapy— the checkpoint inhibitor drugs. Currently, there are two FDA-approved PD-1 inhibitors (Pembrolizumab [Keytruda; Merck & Co.] and Nivolumab [Opdivo; Bristol-Myers Squibb]) and three FDA-approved PD-L1 inhibitors (Atezolizumab [Tecentriq; Genentech], Avelumab [Bavencio; EMD Serono], and Durvalumab [Imfinzi; AstraZeneca]). A sixth FDA approval is expected in the next few months from Regeneron and their part- ners at Sanofi. These drugs are designed to block the PD-1/PD-L1 interaction and have shown great promise in treat- ing tumors. However, the patient response rate is low. Guo said, "Immuno- therapies are life-saving for many patients with meta- static melanoma, but about 70% of these patients don't respond." In addition, "these treatments are costly and have toxic side effects so it would be very help- ful to know which patients are going to respond." He added that this is why "identification of a biomarker in the bloodstream could potentially help make early predictions about which patients will respond." The UPenn researchers found that the exosomal PD-L1 has the same membrane topology as cell surface PD-L1 and that exosomal PD-L1 binds to PD-1 in a concentration-depen- dent manner, an interaction that can be disrupted by PD-L1 blocking antibodies. This research offers a paradigm-shift- ing picture of how cancers take a systemic approach to sup- pressing the immune system. According to Gulley, this work will "change how many people think about PD-L1 only being important in the tumor microenvironment. [It] offers a lot of opportunities to interrogate clinical datasets." He added that the researchers know a lot of information about some patients and that both academic and pharma companies will probably act quickly to figure out how clinically relevant this is. To erase any doubts, Gulley said with enthusiasm that he will be sharing this work with his team of researchers as soon as possible. He hopes that this will lead to rapid insights. (continued from previous page) University of Pennsylvania researchers Wei Guo, Ph.D., and Xiaowei Xu, M.D., Ph.D., showed that exosomes con- taining PD-L1 were found far from the tumor microenvironment, opening the door to developing methods to predict immunotherapy response. Hazmat2, WikiMedia Commons

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