The success of the CRISPR cancer trial paves the way for personalized treatments

The success of the CRISPR cancer trial paves the way for personalized treatments

Molecular model of the CRISPR-CAS9 gene editing complex in red, yellow and blue

The CRISPR-Cas9 complex (blue and yellow) can precisely cut DNA (red).Credit: Alfred Pasieka/Science Photo Library

A small clinical trial has shown that researchers can use CRISPR gene editing to alter immune cells so that they recognize mutated proteins specific to a person’s tumors. These cells can then be safely released into the body to find and destroy their target.

It is the first attempt to combine two hot areas in cancer research: gene editing to create personalized treatments and engineering immune cells called T cells to better target tumors. The approach was tested on 16 people with solid tumors, including breast and colon.

“It’s probably the most complicated therapy ever tried in the clinic,” says study co-author Antoni Ribas, a cancer researcher and physician at the University of California, Los Angeles. “We’re trying to make an army out of the patient’s T cells.”

The results were published in Nature1 and presented at the Society for Cancer Immunotherapy meeting in Boston, Massachusetts on November 10.

Custom treatments

Ribas and his colleagues began by sequencing DNA from blood samples and tumor biopsies to look for mutations found in the tumor but not in the blood. This was to be done for each person in the trial. “Mutations are different in every cancer,” says Ribas. “And while there are some common mutations, they are a minority.”

The researchers then used algorithms to predict which of the mutations were likely to be able to trigger a response from T cells, a type of white blood cell that patrols the body for errant cells. “If [T cells] they see something that doesn’t look normal, they kill it,” says Stephanie Mandl, chief scientific officer at PACT Pharma in South San Francisco, Calif., and lead author of the study. “But in the patients we see in the cancer clinic, at some point the immune system loses the battle and the tumor grows.”

After a series of analyzes to confirm their findings, validate their predictions, and design proteins called T-cell receptors capable of recognizing tumor mutations, the researchers took blood samples from each participant and used CRISPR genome editing to insert the receptors into their T. cells. Each participant then had to take drugs to reduce the number of immune cells they produced, and the engineered cells were infused.

“This is an extremely complicated manufacturing process,” says Joseph Fraietta, who designs T-cell cancer therapies at the University of Pennsylvania in Philadelphia. In some cases, the whole process took more than a year.

Each of the 16 participants received engineered T cells with up to three different targets. Afterwards, the edited cells were found circulating in their blood and were present in higher concentrations than untreated cells near the tumor. One month after treatment, five participants had stable disease, meaning their tumors had not grown. Only two people had side effects that were probably due to the activity of the regulated T cells.

Although the effectiveness of the treatment was low, the researchers used relatively low doses of T cells to determine the safety of the approach, Ribas says. “We just need to hit it harder next time,” he says.

And as researchers develop ways to speed up the development of therapies, the engineered cells will spend less time growing outside the body and could be more active when given by infusion. “Technology is going to get better and better,” says Fraietta.

A solid start

Engineered T cells – called CAR T cells – are approved to treat some cancers of the blood and lymph, but solid tumors pose a particular challenge. CAR T cells are only effective against proteins that are expressed on the surface of tumor cells. Such proteins can be found in many types of blood and lymph cancers, meaning there is no need to design new T-cell receptors for every person with cancer.

But common surface proteins were not found in solid tumors, Fraietta says. And solid tumors provide physical barriers to T cells, which must circulate through the blood, travel to the tumor, and then infiltrate it to kill the cancer cells. Tumor cells also sometimes suppress the immune response, both by releasing immune-suppressing chemical signals and by using local stores of nutrients to fuel their rapid growth.

“The environment around a tumor is like a sewer,” says Fraietta. “The T cells become less functional as soon as they get there.”

With this initial proof of concept in hand, Mandl and her colleagues hope to be able to engineer T cells to not only recognize cancer mutations, but also to be more active near tumors. Mandl says there are several potential ways to boost T cells, for example by removing receptors that respond to immunosuppressive signals, or adjusting their metabolism so that they can more easily find an energy source in the tumor environment.

Such elaborate designs may be feasible thanks to recent technological advances in using CRISPR to edit T cells, says Avery Posey, who studies cell and gene therapies for cancer treatment at the University of Pennsylvania in Philadelphia. “It’s become incredibly efficient,” he says. “We’re going to see very sophisticated means of engineering immune cells in the next decade.”

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