Genetic Engineering & Biotechnology News

MAY15 2017

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10 | MAY 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News Biobank Withdrawals in Support of Liquid Biopsies "Liquid biopsy, the evaluation of circulat- ing tumor cells (CTCs) or circulating DNA in blood samples taken from cancer patients, is currently the hottest segment within the biomarker field," exclaimed Dr. Bouche. "Street analysts predict sales could soon ex- ceed $10 billion from opportunities opened up by liquid biopsy technologies." Pharmaceutical and in vitro diagnostic (IVD) companies that are working on the same targets are also "competing" for the same biological sample types. Samples col- lected from patients treated by drugs target- ing the PD-1/PD-L1 pathways, now just be- coming available, are particularly difficult to find. "Lack of access to biospecimens is the main bottleneck for researchers," observed Dr. Bouche. Trans-Hit Biomarkers asserts that it offers unparalleled and fully transparent access to biospecimens, and that it has a proprietary network of over 100 clinical sites and aca- demic biobanks. Biospecimens are collected and curated from more than 400 hospitals all over the world, including North America, Europe, and Asia. In contrast, biospecimen brokerage firms whose core business is to provide off-the- shelf commoditized samples likely lack the depth of expertise and academic connections to meet liquid biopsy sample requirements, cautioned Dr. Bouche. Unprecedented demand for matched plas- ma and formalin-fixed, paraffin-embedded (FFPE) blocks spurred Trans-Hit BioMark- ers and its U.S. partner, MT Group, to initi- ate and sponsor a consortium in lung cancer. The consortium aims to collect 5,000 high- quality unique patient series of specimens (matched tissues and biofluids at diagnosis and relapse) within one year. The samples will be ethically collected from different ge- ographies, annotated with detailed clinical information, and screened for biomarkers of current interest (EGFR, KRAS, BRAF, ALK, MET, ROS, RET, and PD-L1). "Our initiative will accelerate the devel- opment of new biomarkers that are of stra- tegic interest for public health but are stuck in laboratories due to the scarcity of high- quality samples," concluded Dr. Bouche. Raw and Amplifiable DNA Mutational load (that is, number of mu- tations) is a predictive biomarker of response to checkpoint inhibitors such as Merck's pembrolizumab. The more mutations a tu- mor has, the more likely a response. Whole exome sequencing (WES) can help define the mutational landscape and correlate muta- tional load with the likelihood of responding to immunotherapy. "There's a lot of preanalytical work that needs to be streamlined and standardized before the mutational load assay can be validated," cautioned Dr. Qiu. For exam- ple, several parameters that are relevant to NGS-based tests—including the amount of DNA input for WES—are in need of stan- dardization. The lack of standardization is complicat- ing tests that extract nucleic acids from FFPE tissue. DNA/RNA extracted from FFPE tis- sue is typically highly degraded, fragmented, and cross-linked. Dr. Qiu has evaluated many different DNA/RNA extraction kits and quantifica- tion methods. This work led him to conclude that "10 different vendors might provide 10 different DNA input recommendations, ranging from 50 ng to 2 μg." Standardiza- tion is lacking, and quantification is inaccu- rate, because amounts include poor quality and unamplifiable DNA. "We investigated several more-accurate measurement methods called 'amplifiabil- ity of the DNA' to qualify the amplifiable copy of DNAs instead of the 'raw' DNA from FFPE extractions," explained Dr. Qiu. Input guidelines based on copies of amplifi- able or usable DNA can be more standard- ized and controllable than raw DNA input amounts. Biomarker Validation Continued from page 9 Drug Discovery Insights Discovery & Development Combinatorial chemistry is molecular pugilism, a sport that one follows in hopes of seeing lots of "hits." All too often, however, the contenders (small drug-like molecules) fail to lay a glove on the champion (a hard-to-drug protein). In such cases, bouts remain hit-free and seem to last forever. Fortunately, drug discovery bouts needn't occur sequentially. Instead, they may take place simultane- ously in tiny boxing rings known as a microwell. When many microwells are arrayed in high-throughput screens, they can give many, many contenders their shot at the title in a more reasonable amount of time. Even so, hits have remained few and far between, lessening enthusiasm for combinatorial approaches. There is another combinatorial approach, however, that is generating excitement. It is less of a tournament and more of a free-for-all. It is called DNA-encoded library (DEL) technology. It enables much larger contests—all at once and all at the same place. Think of it as a drug discovery Donneybrook. It is less chaotic than it sounds. Each small molecule is attached to a DNA tag, a sort of barcode. The DNA tag not only uniquely identifies each contender, it facilitates the identification of low- profile performers. After these molecules are isolated, the DNA tag enables signal amplification via the polymerase chain reaction. Promising drug candidates, though rare, can be characterized by NGS. Even better, libraries of tagged candidates can be kept together in mixtures, teeming multitudes of millions or billions, rather than in separate compart- ments that require robotic management. DEL technology has started to catch on only recently, even though it was envisioned about 25 years ago, in a paper co-authored by Sydney Brenner and Richard Lerner, then at The Scripps Research Institute (TSRI). Curiously, in the ongoing flurry of partnership activity centered around DEL technology companies—which include Ensemble Therapeutics, HitGen, Nuevolution, Philochem, Vipergen, and X-Chem—one collaboration emphasizes how development in this space has come full circle. HitGen recently partnered with TSRI and its affiliate, the California Institute for Biomedical Research (Calibr), to identify new drug candidates. "We are excited to collaborate with TSRI-Calibr for these discovery efforts," said Jin Li, Ph.D., HitGen's chairman and CEO. "And we acknowledge the fundamental contributions of Brenner and Lerner in initiating DNA-encoded chemistry technology." n DNA Tags Let Combinatorial Chemistry Mix It Up Novel immunotherapies, such as therapeutic vaccinations and checkpoint inhibitors, have shown great potential in the fight against cancer, but are currently only effective for a subset of patients. Furthermore, as they work by stimulating the immune system, they can also trigger immune-related adverse events (irAEs), sometimes even leading to severe autoimmune diseases. Given these challenges, there is a need to identify bio- markers that can better predict and monitor treatment response, as well as detect the early signs and the course of irAEs. However, traditional oncological biomarkers like ge- netic mutations have so far failed to provide the answers, as they cannot be used to monitor the activity of the immune system. As such, novel biomarkers will be required. Autoantibodies are established biomarkers for the diag- nosis, prognosis, and patient stratification of autoimmune diseases. Given the effect of cancer immunotherapies on the immune system, as well as the fact that irAEs that have been observed when administering them, autoantibodies could also be effective biomarkers for use in immuno-oncology. However, to date, they have not been systematically ana- lyzed in cancer patients undergoing immunotherapies. "To fill this knowledge gap, Protagen recently an- nounced two research collaborations, one with the U.S. National Cancer Institute (NCI) and the other with the German National Center for Tumor Diseases (NCT)," said Georg Lautscham, Ph.D., chief business officer at Protagen. "Both programs will utilize Protagen's biomarker develop- ment engine, SeroTag ® , to identify new autoantibody bio- marker signatures capable of predicting therapy response and detecting irAEs in patients treated with checkpoint in- hibitors, therapeutic vaccines, or combination therapies. As Jessica Hassel, M.D., of the NCT, highlights, "At least half of patients with a metastasized melanoma see no long- term benefit when given current checkpoint inhibitors. Response rates can be increased via combination therapies, but this increases the risk of irAEs, which then occur in up to 60% of patients. To overcome these challenges, we must learn more about their immune status. Utilizing Protagen's SeroTag platform enables this insight." These important new collaborations stand to generate a wealth of information that will help support the effective future development, evaluation and clinical use of cancer immunotherapies. n Autoantibodies as Biomarkers for Cancer Immunotherapies

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