Genetic Engineering & Biotechnology News

NOV1 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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26 | NOVEMBER 1, 2018 | Genetic Engineering & Biotechnology News | IHC-based biomarker content from whole-slide images of patient biopsies. By combining traditional IHC methods and stains with digital pathology approaches it can provide more precise data that can better predict contextual relationships between biomarker expression and treatment outcomes," says Dr. Krueger. "The software identifies every single cell in the tissue and its location," he continues. "It uses AI to identify each cell as a tumor cell or a leukocyte, using the morphological charac- teristics of each cell from the hematoxylin counterstain typi- cal of an IHC slide to classify what type of cell it is. Deter- mination of what specific type of leukocyte a cell is requires an IHC biomarker stain, such as CD8 (for T cells) or CD68 (for macrophages)." When this combination of morphologi- cal and staining characteristics is used, each tumor cell and each TIL is identified in its location in the tumor biopsy, and the TILs are reported as being infiltrative in the tumor epi- thelium or in the tumor-associated stroma. Currently, pathologists can only estimate the number of TILs in a tumor biopsy through an error-prone, labori- ous procedure requiring a survey of several high-powered fields across the slide and counting the TILs in the tumor epithelium and adjacent stroma separately. "This tedious ex- ercise requires more than a half hour, and ultimately yields report qualitative values such as high, medium, or low," Dr. Krueger complains. "Our technology allows [users] to access quantitative val- ues for these endpoints, which are determined by cell-by-cell analysis, and because the areas measured include the whole tis- sue, they are not susceptible to the errors caused by variability and heterogeneity in the tissue." Furthermore, this rich data profile can be used to create more comprehensive endpoints, such as ratios of different types of TILs, proximity to each other or tumor cells, and organizational patterns that truly capture the immune phenotype of the tissue, says Dr. Krueger. Biomarkers for Cystic Fibrosis Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane con- ductance regulator (CFTR). This protein, a protein kinase A (PKA)-activated epithelial anion channel, participates in salt and fluid transport in multiple organs. The protein functions at the cell surface and contributes to the regulation of ab- sorption and secretion of salt and water in tissues including the lung, sweat glands, pancreas, and gastrointestinal tract. Most CF mutations either reduce the number of CFTR channels at the cell surface, due to synthesis or processing mutations, or impair channel function through gating or conductance mutations, or both. Approximately 4–5% of patients with CF have the G551D mutation on at least one allele, resulting in a dysfunctional ion gating function. In vitro models of CF using transfected cells carrying CF-associated gene defects have greatly advanced drug dis- covery, notes Fred Van Goor, Ph.D., head of CF research at Vertex Pharmaceuticals. These models recapitulate disease markers found in patients' cells. Ivacaftor (Kalydeco ® ; Vertex), a small molecule treat- ment for CF, acts as a CFTR "potentiator" indicated for the treatment of CF in patients six years and older who have a G551D mutation in the CFTR gene, in which the amino acid glycine (G) in position 551 is replaced with aspartic acid with the effect of producing a defect in the CFTR ion gating function. The orally available small molecule drug works by keep- ing the CFTR gate open longer at the cell surface, facilitating the transport of salt and water through cells to improve hy- dration and mucus clearance. In 2012, ivacaftor was initially approved in patients two years and older with at least one mutation in their CF gene that is responsive the drug. In 2017, the FDA expanded approval of ivacaftor for the treatment of additional mutations, a decision, Dr. Van Goor says, not based on clinical studies but on the in vitro studies using biomarkers that established improvement in the pro- tein's ion channel function in cell lines carrying other muta- tions. The compound is currently approved in the United States for the treatment of 38 types of CF mutations in pa- tients two years and older. In a press release, the FDA said, "The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 muta- tions, to 33. The agency based its decision, in part, on the re- sults of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data." Vertex tested a combination of its VX-152/tezacaftor/iva- caftor combination therapy in Phase III trials. Both VX-152 and tezacaftor are correctors of CFTR, small molecules that can enhance movement of the protein into its functional posi- tion in the cell membrane. 1 The drug is intended to help treat the almost 90% of people with CF carrying F508del, resulting in proteins that do not fold into their proper shape and are tar- geted for degradation before making it to the cell membrane. Ongoing triple-combination therapy trials in Phase III development include VX-659 and BX-445, two next-gener- ation correctors. The decision to advance VX-659 and VX- 445 into Phase III development was based on initial Phase II data, including new data from ongoing Phase II studies that showed mean absolute improvements in percent pre- dicted forced expiratory volume in one second (ppFEV1) of up to 13.3 and 13.8 percentage points from baseline through four weeks of treatment for the triple-combination regimens with VX-659 (400 mg QD) or VX-445 (200 mg QD), respectively. The triple combination of these drugs has the potential to benefit a broad range of people with CF with two copies of the F508del mutation (homozygous), and with one copy of F508del mutation and one copy of another mutation that affects CFTR function (heterozygous). Preclinical testing of the triple combination of VX-152/ tezacaftor/ivacaftor human bronchial epithelial (HBE) cells showed an increase in the chloride transport, as well as in cilia beat frequency, when compared to the lumacaftor/ ivacaftor combination, suggesting an improvement in the CFTR function. Dr. Van Goor tells GEN, "CF is a lifelong disease. What we really want to accomplish is to stop the decline in lung function over time due to multiple exacerbations. The disease affects multiple body organs, including the pancreas, and more re- cently, we have progressed the use of our therapies to younger and younger patients. "With the triple combinations in late-stage trials, we use two correctors and a potentiator—correctors to get the pro- At Flagship Biosciences, the power of artificial intelligence has been harnessed by the Computational Tissue Analysis (cTA) platform, which delivers comprehensive tissue profiling for predictive diagnostic applications. Here, cTA was used to analyze a whole-slide image (left), assist in the CDx scoring of a PD-L1 assay (Ventana's SP263), and generate "markup" representations (middle and right). The platform allows for direct cell counting and scoring. Translational Medicine Precision Biomarkers and Medicines Go Global Continued from page 1

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