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February 7, 2020 03:30 am

First Clinical Trial of Gene Editing To Help Target Cancer

An anonymous reader quotes a report from Ars Technica: Today, scientists are releasing the results of a clinical trial designed to test the safety of gene editing as a way of fighting cancer. The results are promising, in that a version of the CRISPR gene-editing system that's already a few years out of date appears to be safe when used to direct immune cells to attack cancer. But the cancers that it was meant to treat simply evolved ways of slipping past immune surveillance. For the clinical trial, this gene-editing system has been combined with recently developed immune therapies that target cancer. There is a class of immune T cells that kill cells recognized as foreign, either because they come from a different person (such as after an organ transplant) or because they are infected with a bacteria or virus. These cells can also recognize and attack cancer but often don't, in part because cancer cells are so similar to healthy ones. People have engineered versions of the T cells' recognition system that specifically target cancer cells, and placed these back into patients, helping the immune system attack the cancer, sometimes with spectacular results. As part of the clinical trial, gene editing was used to improve the efficiency of the cancer-targeting T cells. This was done in two different ways. The first was to target a gene that normally functions to tone down the immune system (called PDCD1). There has been evidence generated in mice that using antibodies that block the protein made from this gene will increase the immune system's attack on cancers. For this work, the researchers targeted the CRISPR system to delete part of the gene itself, inactivating it. This poses a potential risk, as a failure to tone down the immune response can lead to problematic conditions such as autoimmune diseases. The other way gene editing was used was to knock out the T cell's normal system for recognizing foreign cells, called the T cell receptor (TCR). The TCR is composed of two related proteins that form a binary receptor complex. Engineered versions of this protein are the ones used to get cells to recognize and kill cancer. Normally, these engineered versions of the TCR are simply inserted into an immune cell, where both they and the cell's normal TCR genes are also active. The result is four different TCR parts active at the same time, resulting in a variety of hybrid TCRs. At best, these are ineffective and will reduce the total amount of active TCR in a cell. At worst, they'll cause the T cell to attack healthy cells. For the trial, the researchers generated CRISPR constructs that targeted the cell's normal TCR genes. When successfully deleted, this would ensure that the only TCR on the cell's surface would recognize cancer cells. The researchers ended up working with a total of three patients that had cancers recognized by a known version of the TCR genes. "While the rates of successful editing were high, the procedure is nowhere near 100 percent effective, and rates of editing varied from nearly half down to 15 percent, depending on the gene," the report says. It adds: "There were no serious adverse affects of the T cell infusions, no sign of a problematic immune response, and the cells persisted in the patients up to nine months after the transfusions, indicating they were tolerated well. [...] The response to the tumor, however, was limited. Two patients appeared to stabilize, while the third showed a response in some tissues but not in others. Ultimately, however, the disease began to progress again, and one of the patients has since died."

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