In First, Scientists Use CRISPR for Personalized Cancer Treatment

In First, Scientists Use CRISPR for Personalized Cancer Treatment

A small clinical trial has shown researchers that CRISPR gene editing can be used to alter immune cells to recognize mutations specific to cancerous cells. These cells can then be safely released into the body to destroy their target.

This is the first attempt at combining two hot areas of cancer research: gene editing to create personalized treatment options and engineering immune cells called cells T to target tumours. The approach was tested in 16 people with solid tumours, including in the breast and colon.

” “It is probably one of the most difficult therapies ever attempted in the clinic,” says Antoni Ribas, co-author of the study and a physician at the University of California Los Angeles. “We are trying to make an army from a patient’s T cells .”

The results were published inNatureand presented at the Society for Immunotherapy of Cancer meeting in Boston, Massachusetts on 10 November.

Tailored treatments

Ribas began by sequencing DNA from blood samples, and tumour biopsies. This was to identify mutations in the tumour that are not found in the blood. This was necessary for each participant in the trial. Ribas says that every cancer has its own mutations. “And even though there are some common mutations, they are still the minority .”

The researchers used algorithms to predict which mutations would trigger a response from T-cells, a type white blood cell that monitors the body for errant cells. Stephanie Mandl (chief scientific officer at PACT Pharma, South San Francisco, California) and lead author of the study, said that “If [T cells] detect something that is not normal, they kill them.” “But, in patients with cancer, the immune system lost the battle and the tumor grew .”

,” says Mandl.

After a series of analyses to confirm and validate their predictions, and to design proteins called T cell receptors capable of recognizing tumour mutations, researchers took blood samples from each participant. Then, they used CRISPR genome edit to insert the receptors in their T cells. After each participant was given medication to reduce their immune cells, the engineered cells were instilled into them.

” This is a very complicated manufacturing process,” says Joseph Fraietta who designs T-cell cancer therapies at University of Pennsylvania in Philadelphia. Sometimes, the entire process took over a year.

Each of the 16 participants received engineered T cells with up to three different targets. The edited cells were found in the bloodstream and in higher levels than non-edited cells close to tumours. Five participants had stable disease one month after treatment. This meant that their tumours hadn’t grown. Two people only experienced side effects likely related to the activity in the edited T cells.

Although the effectiveness of the treatment was low the researchers used small doses T cells to establish safety. Ribas said, “We just need it to hit it harder the next time.”

As researchers find ways to speed up therapies’ development, engineered cells will spend less time outside of the body and be more active when infusions take place. Fraietta says that technology will only get better.

A solid start

Engineered cells, also known as CAR T cells, have been approved for treatment of certain blood and lymph cancers. However, solid tumours pose a particular challenge. CAR T cells can only be used against proteins expressed on the tumour cells’ surfaces. These proteins are found in many types of lymph and blood cancers. Therefore, there is no need for T-cell receptors to be created for every person with cancer.

However, common surface proteins are not found in solid tumours, according to Fraietta. Solid tumours also prevent T cells from traveling through blood vessels to reach the tumour, where they can then infiltrate the tumour to kill cancer cells. Tumor cells can also suppress immune responses by either releasing immuno-suppressing chemical messages or using up local nutrients to fuel their rapid growth.

” The environment around a tumor is like a sewer,” Fraietta says. “T cells become less functional when they reach the site .

With this proof-of-concept, Mandl and her collaborators hope to engineer T cells to not only recognize cancer mutations but also to be more active around the tumour. Mandl suggests several ways to make T cells more resilient, such as removing receptors that are sensitive to immunosuppressive signals or changing their metabolism to allow them to find energy in the tumour environment.

Such elaborate designs may be possible thanks to technological advances in CRISPR to modify T cells. Avery Posey is a researcher at the University of Pennsylvania in Philadelphia who studies cell and gene therapies to treat cancer. He says, “It’s become extremely efficient.” “We’ll see very sophisticated means of engineering immune cells withi

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