Clinical OMICS

JAN-FEB 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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In the Lab 36 Clinical OMICs January/February 2018 www.clinicalomics.com Researchers at Cardiff University, Wales, have used CRISPR/Cas9 gene editing to engineer killer T cells that are up to a thousand times more sensitive to can- cer cell antigens than T cells engineered using more conventional approaches, and which allowed far better targeting of T cells to cancer cell lines and patient-de- rived leukemia cells. The new approach exploits the genome, editing technology to remove the T cells' endogenous T–cell receptors (TCRs), and simultaneously replace them with cancer antigen-specific TCRs. The researchers, led Professor Andrew Sewell and Mateusz Legut, Ph.D., hope the new method will enable the development of more effective anticancer immunothera- pies, and offer a new experimental sys- tem for identifying novel cancer targets. "The T cells we made using genome editing do not have any of their own T-cell receptors left, and therefore the only receptor they can use is the one spe- cific for cancer," Legut commented. "As a result, these cells can be a thousand times better at seeing and killing cancer than the cells prepared using the current methodology." Traditional approaches to engineer- ing T cells for cancer immunotherapy involve the transduction of cells with a chimeric antigen receptor (CAR) or a TCR for a specified antigen. The methods used effectively add the cancer antigen receptor to T cells that already express their own native receptors. But the pres- ence of these preexisting endogenous TCRs reduces the number of cancer-spe- cific TCRs that can be inserted into the T cells, and also creates the potential for generating hybrid TCRs that can trigger potentially fatal autoimmunity. "Up until now, T cells engineered to fight cancer had two kinds of receptors— the therapeutic one that was added in the lab, and their own naturally existing one," noted Legut. "Since there is only limited 'space' on a cell for receptors, cancer-specific ones need to compete with the cell's own receptors to perform their function. More often than not, the cell's own receptors win that competi- tion, and leave 'space' for only a very limited number of newly introduced, cancer-specific receptors, which means that T cells engineered with the current technology never reach their full poten- tial as cancer killers." Rather than just adding the new can- cer-specific TCRs to T cells, Cardiff researchers used CRISPR/Cas9 editing to simultaneously knockout the cells' endogenous αβ TCR, and replace it with a cancer antigen–specific γδ TCRs. "This approach enhanced the expression of the transduced TCR at the T cell surface and resulted in TCR transductants that dis- played substantially improved antigen sensitivity," they reported. CRISPR/Cas9 Creates Killer T Cells Highly Sensitive to Cancer Cell Antigen between people who suffer from AD and those who don't is not explained by known markers. The markers identified to date are not diagnostic, and not much is known about how they impact biolog- ical pathways implicated in AD. These issues have fueled the search for new variants and for further understanding of their biological impacts. It has also led to innovation in study design because AD is such a difficult disease to research, in part because it cannot be diagnosed until after death. Variants that either heighten risk or protect agains, described so far, include some in APP, APOE, PLD3, and TREM2. Given the amount of study that has already gone into this topic, it is expected that any further such variants will be relatively rare, but it is still important to map out as many as possible. Multiple large-scale AD sequencing projects are currently in the works, and papers announcing their results are expected soon, making this a time of great anticipation in AD research. "At the end of the day we are going to end up with several dozen genes that either increase risk or are protective," says Tanzi. "I would not be surprised if it ends up being as many as 100." Rudolph Tanzi, professor of neurology at Harvard University, and director of the Genetics and Aging Research Unit at Massachusetts General Hospital. (continued from previous page) Jack0m / Getty Images

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