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CRISPR For Cancer Takes a Big Step Forward

flyynews by flyynews
November 11, 2022
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CRISPR For Cancer Takes a Big Step Forward
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Researchers have made an important step forward toward a long-desired goal: using the gene-editing technology CRISPR to treat cancer.

In a study published in Nature, scientists recruited 16 people who had already received standard treatment for their cancer (which included colon, head and neck, lung, skin, and more) but whose cancers had returned. They wanted to use the gene-editing therapy in a new way and infuse patients with an army of immune cells that had been genetically modified to specifically fight their individual cancers.

Scientists genetically sequenced each patient’s blood cells and tumors in order to determine which unique sequences on their cancers to target. They used this information to isolate the immune cells from patients’ blood whose T cell receptors matched the cancer mutations. They boosted this population of cancer-recognizing cells by making more copies of them. In this population of patient cells in the lab, they used molecular guides to instruct CRISPR to remove genetic sequences for a specific T cell receptor, which recognizes foreign proteins, and replace them with a gene that could bind to and attack cancer cells. Before introducing these CRISPR-edited cells back to patients, the researchers treated the patients with chemotherapy in order to deplete most of their existing immune cells; the new gene-edited cells were then able to populate and expand so that they eventually found and attacked the cancer cells they were designed to identify.

“We are reprogramming a patient’s immune system to target their own cancer,” says Stefanie Mandl, chief scientific officer of PACT Pharma, which helped to develop and manufacture the therapy based on research from Dr. Antoni Ribas’ lab at the University of California Los Angeles. “It’s a living drug, so you can give one dose and ideally have life-long protection [from the cancer].”

While previous CRISPR-based strategies for cancer have involved removing genes in cancer cells that help them grow, or that prevent the immune system from recognizing and attacking malignant cells, this approach introduces specific cancer-fighting immune cells that ultimately will help the patient avoid recurrences as well.

Ribas, one of the senior co-authors of the study, co-founded PACT to move the treatment from the lab to patients, and this first Phase I study showed that the therapy was safe. The study wasn’t designed to test the effectiveness of the CRISPR therapy, so the results aren’t wholly indicative of the power of the therapy. But in this first trial, the treatment helped five of the 16 patients to stabilize their disease so they did not progress, while 11 did not show benefit.

Even though the results didn’t conclusively show that the CRISPR therapy works, Ribas and his team are confident that the process can be refined to benefit more patients. “We have to make this more potent,” he says. “We now know we can take cells and redirect them to cancer mutations, so we need to arm them and give them more weapons to fight cancer, and more ability to survive once they are in the tumors.”

Read More: How Jennifer Doudna’s Life Has Changed Since Discovering CRISPR 10 Years Ago

The theory behind the treatment is to enhance the body’s existing ability to direct immune cells to recognize cancer. While some of these T cells are present in tumors, they often aren’t in high enough quantities to make an impact on the tumor. Ribas’ and Mandl’s teams decided to stack the deck in favor of the immune system by doing a thorough investigation of the proteins that were unique to a patient’s cancer cells that were not found on their normal cells. It’s a highly personalized approach to treating cancer and involved combing through thousands of mutations, then winnowing the list down to nearly 200 that were specific to each patient’s respective cancer.

The researchers then used CRISPR to cut out the genetic code for a receptor that appears on the patient’s T cells and replaced them with the code for a gene that recognized proteins on their cancer. It was necessary to remove the existing code, says Ribas, to ensure that the new genetic code did not create a safety problem. The T cell receptor is made up of two protein chains, and if one of the protein chains from the patient’s original code combined with the chain from the newly inserted one, that could create a new receptor that the body might not recognize.

“The CRISPR editing approach worked really well, and the guides we used cut the genome in just one place, where we removed the gene and inserted the other gene,” says Ribas. The study was done in a couple of patients first, at a low dose [of the edited cells that were infused], and the team worked up to a higher dose once the therapy appeared safe. In the first patient, only 1% of the patient’s T cells showed signs of being edited and containing the cancer-targeting gene, but in the last two patients, who received a higher dose of the CRISPR product, 40% of their T cells became redirected to attack their cancer.

Read More: CRISPR Gene Editing Is Being Tested in Human Patients, and the Results Could Revolutionize Health Care

That’s an encouraging first step, and PACT plans to continue refining the treatment. Mandl says that such a highly personalized approach, in which the CRISPR product was designed in a bespoke way to target each patient’s cancer, will not be feasible on a large scale. In this trial, it took a median of 5.5 months from the time the patients’ cells and tumors were genetically sequenced to finding the right sequences to target for CRISPR. “We need to improve the turnaround time, and the efficiency of the whole process, and that can be done,” says Mandl.

PACT is planning to focus on finding cancer-specific targets on T cells that are shared by more people in order to develop a therapy that is somewhere between the highly personalized process the scientists used in the current trial and a one-size-fits-all strategy. The hope is to find a suite of shared targets that many people share and find the best fit for patients among these: an approach that’s still customized, but not as labor intensive as a made-to-order treatment.

For now, the results show that it’s possible to use CRISPR to train a patient’s immune system to get better at targeting cancer. It’s the first step in eventually making it possible for people to become their own cancer-fighting factories, generating immune cells to attack any malignant growths before they become detectable. That’s within the realm of possibility, says Ribas, but it will take more studies and tweaking of the system he and his team tested.

“This is arguably the most complicated therapy given to humans,” he says. “But our goal is to redirect the immune system to recognize cancer regardless of whether it’s a blood cancer or a solid tumor. As long as it has mutations that make it different from normal cells, we can potentially make a therapy to treat it.”

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