CAR-T cells in the first line of cancer

CAR-T cells in the first line of cancer

CAR-T treatments are hard weapons in the fight against cancer. Here’s how they can succeed in many more patients

As CAR-T cells increase in price in the clinic, they are beginning to be used to treat patients with less complex blood cancers.

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This article was written by Scientific American Custom Media, an independent department of the journal’s editorial board.

Immunotherapies have replaced the cancer treatment paradigm thanks to their ability to induce long-term remission in blood cancer patients in whom other treatments have failed. Thanks to new treatments like CAR-T therapies, these patients are living longer after a single infusion. , with a higher quality of life, which would have been unthinkable before.  

“People are very excited because it offers hope that one day the cancer can be cured,” says Frank Zhang, president of Legend Biotech, which has effectively treated multiple myeloma patients with CAR-T therapy. “But now we need to succeed in more patients. “

As demand for CAR-T treatment increases and regulatory agencies approve wider use and on older treatment lines, brands will want to find tactics to produce more CAR-T remedies more quickly. Since existing CAR-T remedies are personalized remedies derived from a patient’s own cell experience, their creation is a time-consuming and highly regulated process. Zhang and others in the box favor tactics to speed up the delivery of CAR-T to patients.

Immunotreatments, like all cancer treatments, are more likely to be effective in the early stages of the disease, before the cancer spreads too much or grows too large, and while the cancer is more likely to lose its war against the immune system. It creates a dilemma. As experimental treatments progress through clinical trials, they are first tried in sicker patients, i. e. , those whose cancer has come back after treatment with more established treatments and is therefore harder to beat.  

This dilemma can be overcome through clinical trials, which can give regulators confidence that the new cure is more effective than an established cure. For example, in April, after a phase 3 clinical trial, the FDA approved Legend’s CAR-T remedy. for multiple myeloma, ciltacabtagene autoleucel (Carvykti), to treat patients whose cancer had returned after the first few cycles of treatment.

Current CAR-T therapies, known as autologous therapies, harness the strength of a cancer patient’s immune system. To produce them, immune cells called T cells must first be collected from the patient and grown in a production facility. These white blood cells form the basis of the body’s adaptive immune reaction to fight pathogens.  

Once isolated, those T cells will have to be modified to produce proteins on their surface called chimeric antigen receptors, or CARs. These CARs recognize and bind to express proteins (antigens) on the surface of cancer cells, allowing the modified T cells to bind. and destroy them. The modified CAR-T cells are then cultured until technicians can collect enough to be therapeutic. Finally, they will have to be infused back into the patient, where they act as a living drug capable of stimulating the ability of the immune system. to kill tumor cells.  

The entire procedure, from collecting the immune motifs to injecting the patient with the CAR-T mobiles, takes weeks. This delay limits the performance of mobile production facilities, restricting the number of patients they can treat. And that’s too long for some seriously ill patients. “Because their cancer progresses very quickly, many patients can’t wait,” Zhang says.

One way to bring CAR-T treatment to more patients is to build capacity by reducing the time it takes to process a batch of cells. Every step of the production chain can be optimized, says Ying Huang, CEO of Legend.

“We approach this from other angles,” Huang says. The company plans to test the robotic arms to upgrade repetitive manual steps, such as pipetting, to facilitate mobile design. “A robot can do this 24/7. They can’t get enough of the status there,” he says.

Another breakthrough may come from something as undeniable as a larger bioreactor to grow the viruses used to engineer the patient’s own T cells. Called lentiviruses, they are needed to transduce the healing chimeric antigen receptor on T cells.

Lentiviruses for CAR-T cell progression are historically grown in one- or five-liter vials. This may provide sufficient numbers for a CAR-T trial involving one hundred people. “But now we’re looking to treat a few thousand patients a year,” Huang says. Legend and Johnson

There are dozens of other potential tactics to allow CAR-T mobile treatments to treat more people, says Bruce Levine, who works on new mobile treatments at the University of Pennsylvania.  

The first is to analyze the quality of a patient’s T cells to know which ones will respond to treatment. The higher the percentage of T cells with these characteristics, the higher the quality of the product and the more likely we are to see a response,” he says.

Another solution is to find tactics to engineer T cells that don’t require lentiviruses. His lab, for example, uses lipid nanoparticles to move genes that improve the functionality of a patient’s T cells. “You get a very fast uptake of lipid nanoparticles targeting T cells, in the absence of targeting other cells,” he says.  

Allogeneic or commercially available CAR-T cells can treat more patients than existing CAR-T cells, as they would be manufactured ahead of time, stored, and then used if needed, in the same way as most other drugs.

But this technique presents one main hurdle, Zhang says. A patient’s immune formula can recognize cells as foreign and attack them. Therefore, allogeneic treatments will need to be designed to avoid detection and to be effective and safe.   

Zhang says it will take more time and studies to achieve the best allogeneic technique: “At the moment, if we use the patient’s own cells, the effectiveness is very good. To compete, any next drug will have to fulfill this functionality in one form or another.

Alisdair Macdonald

Learn more about CAR-T technologies on this Legend Biotech site.

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