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Sunday, 9 February 2020

CANCER. Clinical trial suggests CRISPR genetic editing may be viable treatment

In addition to conventional cancer treatments like chemotherapy and radiotherapy, doctors are looking for new ways to fight the disease. One area of ​​research is particularly concerned with the genetic editing of immune cells to make them more efficient and less vulnerable to fighting cancer cells. The CRISPR genetic editing tool is one of the mechanisms used, and in a recent clinical trial, researchers showed that its use presented no danger or side effect.

Immune cells edited by the CRISPR gene were injected into three people with advanced cancer without any serious side effects, the first such test in the United States. It is also the first CRISPR cancer trial in the world to publish its results. Rather encouraging, they will open the way to many other trials. The study was published in the journal Science .

"This is an important step," said Waseem Qasim at the UCL Great Ormond Street Institute of Child Health in the United Kingdom, who is conducting a similar trial there. The purpose of the American test was only to assess safety. All three participants had tumors that had not responded to other treatments and had only received one dose of genetically modified cells.

Improve the effectiveness of genetic modification treatments

Many cancers involving blood cells are now treated by removing immune cells from individuals, adding a gene that directs them against cancer cells, and replacing them in the body. But this treatment does not work for everyone. And for some, it works at first, but then they relapse.

The hope is that using genetic editing to suppress genes in addition to adding the targeting gene will make this approach even more effective. For example, immune cells have a safety switch, called PD-1, that other cells can activate to say "don't hurt me." Many cancers exploit this to avoid immune attacks.

Diagram illustrating the genetic modification of T lymphocyte by CRISPR. Credits: Edward A. Stadtmauer et al. 2020

In this trial, the team removed the immune cells from three people who had tumors with the same protein on their surface. A virus has been used to add a gene so that immune cells target this protein. Then, three genes, including PD-1, were deleted using CRISPR. After six weeks, the cells were replaced in individuals, where they survived for at least 9 months.

CRISPR: a genetic edition without danger or side effect

There were two major security concerns. First, CRISPR can cause unintended changes in genomes that could turn healthy cells into cancer cells. Deleting three genes means cutting around each one in three places in the genome, for example, and the wrong ends can be joined. It happened in some cells, but there was no sign of cancer.

The other concern was that the persistent traces of the CRISPR protein used for gene editing could trigger an immune reaction, since it is a bacterial protein. But there was no sign of that.

The trial, however, will not continue because its gene editing technology (from 2016) is already out of date, says Carl June of the University of Pennsylvania. In particular, a new form of CRISPR called basic edition can be used to inactivate genes without cutting DNA, which should further reduce the risk of cancer.

Towards the development of optimized anti-cancer genetic engineering

There are also many other ways to modify immune cells to make them more efficient, says Stadtmauer. "The possibilities are limitless according to our imagination and our scientific orientation".  In particular, Stadtmauer wants to create "ready to use" cells that could be injected into any patient, rather than modifying each patient's own cells. This would speed up treatments and significantly reduce costs.

The Qasim team has already saved lives in an ongoing trial at Great Ormond Street Hospital using standard cells created by an old form of gene editing called TALEN. But these cells must be administered as part of a drastic treatment, which is followed by a bone marrow transplant which kills the edited cells. Stadtmauer wants to create cells that can survive in the body indefinitely.

The risk of modified cells becoming cancerous or starting to attack healthy cells would be higher if they survive longer. But it is also possible to add a self-destruct mechanism triggered by a specific drug to kill them if necessary. There have been a number of immune cell trials published by CRISPR for the treatment of cancer in China, but no results have yet been published.


CRISPR-engineered T cells in patients with refractory cancer

Edward A. Stadtmauer, Joseph A. Fraietta, Megan M. Davis, Adam D. Cohen, Kristy L. Weber, Eric Lancaster, Patricia A. Mangan, Irina Kulikovskaya, Minnal Gupta, Fang Chen, Lifeng Tian, Vanessa E. Gonzalez, Jun Xu, In-young Jung, J. Joseph Melenhorst, Gabriela Plesa, Joanne Shea, Tina Matlawski, Amanda Cervini, Avery L. Gaymon, Stephanie Desjardins, Anne Lamontagne, January Salas-Mckee, Andrew Fesnak, Donald L. Siegel, Bruce L. Levine, Julie K. Jadlowsky, Regina M. Young, Anne Chew, Wei-Ting Hwang, Elizabeth O. Hexner, Beatriz M. Carreno, Christopher L. Nobles, Frederic D. Bushman4, Kevin R. Parker, Yanyan Qi, Ansuman T. Satpathy, Howard Y. Chang, Yangbing Zhao, Simon F. Lacey, Carl H. June

Science  06 Feb 2020:

DOI: 10.1126/science.aba7365

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