Genetic Engineering & Biotechnology News

JUL 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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Page 14 of 33 | Genetic Engineering & Biotechnology News | JULY 2018 | 13 therapy in the clinic that was tested in CAN- script. The results from the CANscript testing were correlated to patient clinical response using a machine learning algorithm, produc- ing an "M-Score," which predicts positive versus negative response. To date, more than 4000 patient samples have been evaluated by CANscript. A subset of the clinical assay performance has been published, showing 90% clinical correlation. Preservation of the Tumor-Immune Contexture, Ex Vivo In this example, utilizing tissue from head and neck squamous cell carcinoma and breast cancer patients, we characterized the tumor-immune contexture during the course of culture in the presence or absence of PD-1 checkpoint blockade. To study the role of T-cell repertoires under different environmental and immunotherapy pressures, lymphocyte infiltration was char- acterized. Fluorescently labeled PBMCs were incorporated in CANscript and then studied using flow cytometric analysis. T-cell and immune subsets were quan- tified from vehicle and pembrolizumab- treated breast tumor CANscript, post-co- culture with PBMCs, at 24 h, 48 h, or 72 h to profile infiltration of Treg cells defined by CD4+CD25+CD127Lo, cytotoxic CD8+CD3+ T cells, and CD56+ Natural Killer cells. Using technologies such as multi-spectral imaging and cytokine multiplexing, we can develop a more comprehensive understand- ing of the tumor microenvironment as lym- phocytes dynamically traffic. Capuring Nonuniform Infiltration In this study, we determined that immune checkpoint blockade induced unique pat- terns of migration and infiltration of effector T cells (Teffs) and regulatory T cells (Tregs) in hot versus cold tumors. Furthermore, it was determined that, in some instances, cold tumors can be driven toward a hot pheno- type characterized by trafficking of active immune lymphocytes following treatment, which corresponded to differential ratio of Teffs to Tregs compared to baseline. The dynamic, spontaneous migration of tumor-infiltrating lymphocytes (TILs) is a key factor for immune-dependent tumor rejec- tion. However, little is known about the role of immunotherapy or other anticancer agents as they modulate TILs. Not only were we able to capture the dynamism of the tumor microenvironment, the range of behavior in T-regulatory versus T-effector cells indicates patient-specific response to PD-1 blockade. CANscript enables a platform to study the antitumor effect of different therapies along with stochastic lymphocyte infiltration at the individual patient level. By integrating an algo- rithm-driven predictive clinical assessment (M- Score), CANscript can contribute to a unique understanding of the role dynamic TILs play during the clinical response to therapy. These data demonstrate that high inter- patient variability in immune modulation, alterations to the tumor microenvironment under drug pressure, and predicted clinical response to immunomodulators requires a multidimensional approach to understand the effect of drugs on a per-patient basis. Taken together, these data exhibit the utility of CANscript as a platform to char- acterize response to immunotherapy in a spatial context, providing insight into the migratory patterns of immune-cell subsets at the individual patient level. Such an advance in our preclinical meth- ods to study immunomodulators may help guide treatment decisions for clinicians while simultaneously functioning as a plat- form to study and discover mechanisms of clinical efficacy for emerging drug combina- tions. BRING SMALL CONCENTRATIONS AND LARGE FRAGMENTS INTO FOCUS. Make QC more efficient for the analysis of precious genomic samples with the FEMTO Pulse ® from Advanced Analytical Technologies, Inc. You can quickly evaluate high molecular weight DNA for long read sequencing, and detect low-concentration samples down to the single cell. With incredibly comprehensive QC, you can focus your research in ways you never thought possible. Explore the unprecedented sensitivity and precision of the FEMTO Pulse . FEMTO Pulse ® Automated Pulsed-Field CE Instrument Aaron Goldman, Ph.D. (agoldman@, is director, R&D, Immuno-Oncology, at Mitra Biotech. Website: Drug Discovery Figure 3. Predicted responders and nonresponders to pembrolizumab are profiled for lymphocyte infiltration. A: Two patient samples are profiled, which are predicted to respond to treatment (M-score = 26) or not to respond (M-score = 16). B: Tumor samples are examined for expression of CD4 and CD8 to stratify T-lymphocyte activity (CD4 + high/CD8 + low suggests a more favorable "hot" tumor microenvironment). C: Prelabeled total lymphocytes (CD45 + ) are evaluated by CANscript™ in 24-, 48-, and 72-hour cultures. B A C

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