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CRISPR technology makes significant headway in cancer treatment

Researchers have taken an important step towards a long-desired goal: using the gene-editing technology CRISPR to treat cancer. The results of their trial showed it’s possible to use CRISPR to train a patient’s immune system to get better at targeting cancer – 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.

Time reports that for the study, the 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.

The scientists genetically sequenced each patient’s blood cells and tumours to determine which unique sequences on their cancers to target, using this information to isolate the immune cells from patients’ blood whose T cell receptors matched the cancer mutations.

They boosted this population of cancer-recognising 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 recognises 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,” said 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 recognising 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 one study showed that the therapy was safe. The study was not designed to test the effectiveness of the CRISPR therapy, so the results are not wholly indicative of the power of the therapy. But in this first trial, reported in Nature, the treatment helped five of the 16 patients to stabilise 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 tumours.”

The theory behind the treatment is to enhance the body’s existing ability to direct immune cells to recognise cancer. While some of these T cells are present in tumours, they often are not in high enough quantities to make an impact on the tumour. Ribas’ and Mandl’s teams decided to stack the deck in favour of the immune system by doing a thorough investigation of the proteins unique to a patient’s cancer cells that were not found on their normal cells.

It is a highly personalised 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.

CRISPR was then used 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 recognised proteins on their cancer. It was necessary to remove the existing code, said Ribas, to ensure 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 the body might not recognise.

“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,” said 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 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.

That’s an encouraging first step, and PACT plans to continue refining the treatment. Mandl said that such a highly personalised approach, in which the CRISPR product was designed in a bespoke way to target each patient’s cancer, would 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 tumours 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 shared by more people, to develop a therapy somewhere between the highly personalised 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 shared by many people and find the best fit for patients among these: an approach that’s still customised, but not as labour intensive as a made-to-order treatment.

For now, the results show 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, Ribas said, but would 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 recognise cancer regardless of whether it’s a blood cancer or a solid tumour. As long as it has mutations that make it different from normal cells, we can potentially make a therapy to treat it.”

Dr Manel Juan, head of the immunology service at Clinic Hospital in Barcelona, said it was “extraordinary work” and “undoubtedly one of the most advanced in the field”.

He added: “It opens the door to using this personalised (approach) in many types of cancer and potentially in many other diseases," reports BBC News.

Professor Waseem Qasim, who has given life-saving designer immune systems at Great Ormond Street Hospital, said it was a “powerful early demonstration of what might be possible with newer techniques”.

Dr Astero Klampatsa, from the Institute of Cancer Research, London, said the study was “important” but warned that the “time, labour and expense involved" were “huge”.

Study details

Non-viral precision T cell receptor replacement for personalised cell therapy

Susan Foy, Kyle Jacoby, Daniela Bota, Theresa Hunter, Zheng Pan, Eric Stawiski, Yan Ma, William Lu, Songming Peng, Clifford Wang, Benjamin Yuen, Olivier Dalmas, Katharine Heeringa, Barbara Sennino, Andy Conroy, Michael Bethune, Ines Mende, William White, Monica Kukreja, Swetha Gunturu, Emily Humphrey, Adeel Hussaini, Duo An, Adam Litterman, Stefanie Mandl.

Published in Nature on 19 November 2022


The T cell receptor (TCR) provides the fine specificity of T cells to recognise mutations in cancer cells 1-3. We developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out the two endogenous TCR genes, TCRα (TRAC) and TCRβ (TRBC), and insert in the TRAC locus the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient’s own circulating T cells using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with refractory solid cancers received up to three distinct neoTCR-transgenic cell products, each expressing a patient-specific neoTCR, in a cell dose-escalation, first-in-human phase 1 clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome, and one grade 3 encephalitis. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion at frequencies higher than the native TCRs pre-infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs recognising mutational neoantigens, the simultaneous knock-out of the endogenous TCR and knock-in of the neoTCRs using single-step, non-viral precision genome editing, the manufacturing of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients’ tumours.


Nature abstract – Non-viral precision T cell receptor replacement for personalized cell therapy (Open access)


Time article – CRISPR For Cancer Takes a Big Step Forward (Open access)


BBC article – 'Leap forward' in tailored cancer medicine' (Open access)


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University of California loses second gene-editing patent case


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New T-cell therapy has potential to kill most human cancer types – animal study


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