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First clinical trial of gene editing to help target cancer, Ars Technica

First clinical trial of gene editing to help target cancer, Ars Technica
    

      Needs more editing –

             

The safety results are promising, the cancer outcomes less so.

      

      

The ability to edit genes has raised the prospect of treating genetic conditions and arming the body to better handle infectious diseases and cancers. But for that potential to be realized, we need to deal with
a variety of safety issues , as well as work out the ethics of when the technology is appropriate to use. 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 The results are promising, in that a version of the CRISPR gene-editing system that’s already a few years out of date appears to be safe when used to direct immune cells to attack cancer.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. Editing genes to fight cancer While there have been a number of gene-editing systems developed, CRISPR / CAS9 is currently the most flexible and efficient. It creates cuts in specific DNA sequences, directed to the sequence by a short piece of RNA. The normal cellular process of repairing these cuts often results in small deletions, which can knock out any genes affected. Alternately, if a replacement sequence is made available, the repair can incorporate the replacement, thus altering the targeted sequence. Either of these, however, can sometimes cause problems by cutting at related sequences or when the repair process accidentally creates large rearrangements.
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.
Of mice and TCR
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. About what you’d expect
It’s important to emphasize that the patients chosen for initial safety testing are very far along in disease progression, making it difficult for anything to reverse their progression. That’s integral to the risk calculation of being involved in testing of what may be a first-of-its-kind therapy. A cartoon diagram of three strands of DNA interacting. And, in terms of safety, things seem quite promising. 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. Testing of these cells suggested that many of them had been converted into memory cells, which are able to respond quickly following new stimulation.
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. In examining the cancer cells from these patients, the researchers found something that you might expect: the protein recognized by the TCR used in these experiments had seen its levels reduced. This allowed the cancer to escape detection by the immune system — especially an immune system that had been reprogrammed to recognize this protein. It’s a standard evolutionary response to this sort of pressure and has been seen in cancers in other contexts.

A cartoon diagram of three strands of DNA interacting. Science, . DOI: . 1866 / science.aba () (About DOIs

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