CRISPR for cancer takes a big step forward

CRISPR for cancer takes a big step forward

RResearchers have taken an important step towards a long-desired goal: to use CRISPR gene-editing technology to treat cancer.

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

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

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

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

Ribas, one of the study’s co-lead authors, co-founded PACT to bring the treatment from the lab to patients, and this first phase I study showed the therapy to be safe. The study was not designed to test the effectiveness of CRISPR therapy, so the results are not entirely indicative of the therapy’s potency. But in this first trial, the treatment helped five of the 16 patients stabilize their disease so that they did not progress, while 11 showed no benefit.

Even though the results did not conclusively show that CRISPR therapy works, Ribas and his team believe the process can be refined to benefit more patients. “We need to make this more powerful,” he says. “We now know that we can take cells and redirect them to cancerous mutations, so we need to weaponize them and give them more weapons to fight cancer, and more ability to survive once they’re in tumors. .”

Read more: How Jennifer Doudna’s life has changed since discovering CRISPR 10 years ago

The theory behind the treatment is to improve the body’s existing ability to direct immune cells to recognize cancer. Although some of these T cells are present in tumors, they are often not in sufficient quantity to impact the tumor. Ribas and Mandl’s teams decided to stack the deck in favor of the immune system by doing a thorough investigation of proteins that were unique to a patient’s cancer cells and not found on their normal cells. This is a highly personalized approach to treating cancer and involves combing through thousands of mutations and then narrowing 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 replace it with the code for a gene that recognizes their cancer proteins. It was necessary to remove the existing code, says Ribas, to ensure that the new genetic code does not create a security 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 combines with the chain from the one just inserted, it could create a new receptor that the body might not recognize.

“The CRISPR editing approach worked very well, and the guides we used cut the genome in one place, where we removed the gene and inserted the other gene,” says Ribas. The study was first carried out in a few patients, 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 editing 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 healthcare

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

PACT plans to focus on finding cancer-specific targets on T cells that are shared by more people in order to develop a therapy that falls somewhere between the highly personalized process used by scientists in the trial. current and unique solution. strategy. The hope is to find a set of shared goals that many people share and to find the best solution for patients among them: an approach that is still personalized, but not as laborious as a tailor-made treatment.

So far, the results show that it is possible to use CRISPR to train a patient’s immune system to better target cancer. It’s the first step in enabling people to become their own cancer-fighting factories, generating immune cells to attack any malignant growth before it becomes detectable. It’s within the realm of possibility, Ribas says, but it will take more study and tweaking of the system he and his team have been testing.

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

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