sResearchers have taken an important step forward toward a long-sought goal: the use of gene-editing technology CRISPR to treat cancer.
in A study published in temper natureIn this study, the scientists recruited 16 people who had already received standard treatment for their cancer (including colon, head and neck, lung, skin, and more) but whose cancers had returned. They wanted to use gene-editing therapy in a new way, providing patients with an army of immune cells that have been genetically modified to specifically fight individual cancers.
The scientists sequenced the genetics of each patient’s blood cells and tumors in order to determine the unique sequences on which cancers to target. They used this information to isolate immune cells from the blood of patients whose T-cell receptors are compatible with cancerous mutations. They boosted this group of cancer-recognizing cells by making more copies of them. In this group of patients’ cells in the lab, they used molecular clues to guide them CRISPR To remove the genetic sequences of a specific T-cell receptor, which recognizes foreign proteins, and replace them with a gene that can bind to and attack cancer cells. Before returning these CRISPR-modified cells to patients, the researchers treated the patients with chemotherapy in order to deplete most of their existing immune cells; Then, the new genetically modified cells were able to multiply and expand until they eventually detected and attacked the cancer cells they were designed to recognize.
“We’re reprogramming a patient’s immune system to target their own cancer,” says Stephanie Mandel, chief scientific officer of PACT Pharma, who helped develop and manufacture the treatment based on research from Dr. Anthony Ribas’ lab at UCLA. Angelis. “It is a live medicine, so you can give a single dose and get perfect protection for life [from the cancer]. “
Whereas previous CRISPR-based strategies for cancer have involved removing genes from 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 will ultimately help the patient avoid recurrence. like that.
Ribas, one of the study’s senior authors, co-founded PACT to take the treatment from the lab to patients, and this phase I study showed the treatment was safe. The study was not designed to test the effectiveness of the CRISPR treatment, so the results do not fully demonstrate the treatment’s strength. But in this first trial, the treatment helped five of 16 patients stabilize their disease so that it wouldn’t progress, while 11 showed no benefit.
Although the results did not conclusively show that the CRISPR treatment worksAnd the Ribas and his team are confident that the process can be improved to benefit more patients. “We have to make this more robust,” he says. “We now know that we can take cells and redirect them to cancerous mutations, so we need to arm them and give them more weapons to fight cancer, and a greater ability to survive once they have 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 are often not in large enough quantities to have an effect on the tumor. Ribas and Mandel’s team decided to stack deck in favor of the immune system by thoroughly investigating proteins that were unique to a patient’s cancer cells that were not found in their normal cells. It’s a highly personalized approach to cancer treatment and involves combing through thousands of mutations, then filtering the list down to nearly 200 mutations that were specific to each cancer patient.
The researchers then used CRISPR technology to cut 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 proteins on the cancer. It was necessary to remove the existing code, Ribas says, to ensure that the new genetic code did not create a safety issue. The T-cell receptor consists of two protein chains, and if one of the protein chains from the patient’s original codon is fused with the chain from the newly introduced strand, it may result in a new receptor that may not be recognized by the body.
“The CRISPR-editing approach worked well, and the evidence we used only cut the genome in one place, where we removed one gene and inserted the other,” Ribas says. The study was conducted on two patients first, at a low dose [of the edited cells that were infused]The team worked on a higher dose once the treatment seemed safe. In the first patient, only 1% of the patient’s T cells showed signs of modification and containment of the cancer target gene, but in the last two patients, who received a higher dose of the CRISPR product, 40% of their T cells became visible. Redirect them to attack cancer.
This is an encouraging first step, and PACT plans to continue improving treatment. Such a highly personalized approach, in which a CRISPR product is tailored to target each patient’s cancer, would not be feasible at large scale, Mandel says. In this trial, it took an average of 5.5 months from the time patients’ and tumors’ cells were genetically sequenced to find the correct CRISPR-targeting sequence. “We need to improve the response time, the efficiency of the whole process, and it can be done,” Mandel says.
PACT plans to focus on finding cancer-specific targets on T cells that more people will share in order to develop a treatment that falls somewhere between the highly personalized process scientists used in the current trial and a one-size-fits-all process. strategy. The hope is to find a set of common goals that many people share and to find what works best for patients among these: an approach that is still customized, but not as labor intensive as a tailored treatment.
For now, the results show that it is possible to use CRISPR technology to train a patient’s immune system to better target cancer. It is the first step in eventually enabling people to become their own cancer-fighting factories, generating immune cells to attack any malignant growth before it can be detected. This is within the realm of possibilities, Ribas says, but it will take more studies and tweaks to the system he and his team tested.
“This is arguably the most complex treatment given to humans,” he says. But our goal is to redirect the immune system to recognize cancer regardless of whether it’s leukemia or a solid tumor. As long as it has mutations that make it different from normal cells, we can perform a treatment to address it.”
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