Genetic Engineering & Biotechnology News

OCT15 2017

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26 | OCTOBER 15, 2017 | | Genetic Engineering & Biotechnology News limitations, and best uses of each. GEN spoke to several re- searchers—who participated in a recent Cambridge Health- tech conference on preclinical animal models in oncology— on advances in engineered animal models used to study novel cancer immunotherapies. Paula Miliani de Marval, Ph.D., research associate di- rector at Charles River Laboratories, has seen exponential growth in the demand for syngeneic mouse models, which are immunocompetent animals implanted with tumors of mouse origin. Compared with xenograft models created us- ing immunodeficient mice, syngeneic mice provide a full pic- ture of how the mouse immune system affects and interacts with a tumor. As the focus of cancer therapy has been shifting from di- rectly treating the tumor to harnessing the immune system to attack the tumor, Charles River has followed this trend— by developing super-immunocompromised mice (Figure 1). While these models have some limitations, with not all hu- man immune cells being fully represented, "they can be used effectively to study how the immune system responds to im- mune checkpoint inhibition," says Dr. Miliani de Marval, to do proof-of-concept studies, immune target validation, and determine if the expected responses occur. Illustrating the value of these models in immuno-oncolo- gy, Dr. Miliani de Marval described a recent study of combi- nation checkpoint inhibitors to treat solid tumors. The study involved a NCG Il2-γ knockout mouse model—created by sequential CRISPR/Cas9 editing of the Prkdc and Il2rg loci in the NOD/Nju mouse—and hu- man RKO colorectal carcinoma xenograft, which has high PD-L1 expression. The model was used to evaluate the efficacy of the monoclo- nal antibody-based drugs pembroli- zumab (anti-PD-1) and ipilimumab (anti-CTLA-4) when administered alone or in combination. The anti- bodies each demonstrated efficacy as monotherapies, but, surprisingly, combination therapy did not have any additive effect. The results were replicated in a triple-negative breast cancer model. Ongoing research aims to achieve a broader range and normal balance of immune-cell representation in transgenic humanized models. The goal is to recreate accurately the tu- mor and immune microenvironment in much the same way it is in syngeneic mouse models. Engineering Large-Animal Models Surrogen, a wholly-owned subsidiary of Recombinetics, develops swine models of human diseases using gene-editing technologies including TALEN- and CRISPR-based tech- niques. Large animals are often used in preclinical studies to assess the safety of drug candidates. Pigs, in particular, have demonstrated effectiveness as efficient biomedical models for evaluating drug efficacy, according to Adrienne Watson, Ph.D., senior research scientist at Surrogen. One of the main cancer types being targeted at Surrogen is brain tumors, for which the first line of treatment is usually surgery to remove as much of the tumor as possible. The brain and other organs of pigs are anatomically (in size) and physi- ologically more similar to humans than are those of smaller animal models such as mice. Using pigs makes it possible to perform the types of surgeries and imaging studies that cancer patients might typically undergo. Furthermore, swine share vast genetic and metabolic similarities to humans, making nearly any genetic disease feasible to model in this animal. "The pig can be more predictive of how a drug will act in patients and accelerate the timeline of bringing a drug through preclinical development and to the clinic," says Dr. Watson. In developing a new model animal, Surrogen reviews exten- sive genetic datasets and scientific literature to identify the ex- act mutations associated with a specific type of human cancer in large groups of patients. The company then engineers those exact mutations into the swine genome. Using genome-editing tools, targeted mutations are made in fetal swine fibroblasts. Piglets carrying a particular mutation—for example, associ- ated with neurofibromatosis type 1 (NF1)—are then produced through somatic cell nuclear transfer. Cancer Immunotherapy Spurs Work on Better Animal Models Translational Medicine Feature Continued from page 1 Insights Molecular Diagnostics Indivumed and Helomics said they will analyze hu- man cancer biospecimens and annotated clinical data from consenting patients worldwide, in a col- laboration designed to enable basic and translation- al research through the development of biomarkers. The collaboration will combine Indivumed's global cancer database, biobank, and research laboratory with Helomics' advanced clinical labora- tory diagnostic tests, proprietary D-CHIP™ (Dynamic Clinical Health Insight Platform) bioinformatics platform launched in April 2017, and custom project services for customers. Helomics is an integrated clinical contract research organization based in Pittsburgh, PA, where the company maintains its CLIA-certified clinical and research laboratories. The company's Helomics Biomarker Panel consists of tests designed for any solid tumor type—though the tumor types most frequently tested through the panel, according to Helomics, are gynecologic cancers, lung cancer, breast cancer, colon cancer, and pancreatic cancer. Indivumed is an ISO-certified global oncology research company based in Hamburg, Germany. The company's cancer database, which covers 22 differ- ent cancer types, combines clinical information from more than 320 validated clinical data points for each patient—including long-term outcome information with raw biological data (including protein, phospho- protein, and DNA/RNA expression). n Individumed, Helomics Launch Cancer Biomarker Collaboration Figure 1. The use of super- immunocompromised mouse models enables the expression of human immune cells in mice engrafted with human tumors. Those models can be used to study the effectiveness of novel immunotherapeutic strategies to treat cancer, such as monoclonal antibody-based immune checkpoint inhibition. Charles River

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