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Why Shielded CAR T Therapy Is Our Best Chance to Cure Cancer

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Immune therapies have rewritten the game when it comes to cancer treatment, earning the “fifth pillar” label alongside more tried and true treatments like radiation, surgery and chemotherapy. And no immunotherapy has generated the same excitement as CAR T-cell therapy, first approved in 2017 by the Food and Drug Administration to treat a form of acute lymphoblastic leukemia. At the time, FDA Commissioner Scott Gottlieb called approval “a new frontier in medical innovation”, and it seemed like the possibilities for CAR T were nearly endless.

Flash-forward almost six years, and six therapies They have been approved for blood cancers including lymphoma, leukemia and multiple myeloma. There’s no doubt that when CAR T works, it works incredibly well. But why it doesn’t work for the majority of patients or types of cancer has researchers baffled.

“We have patients who several years ago would have had no options and thanks to this new therapy they are now in long-term remission.” Jakub Svoboda, an oncologist at the University of Pennsylvania, told The Daily Beast. “But with all of this, what I see in my clinic is that the number of patients who benefit greatly from this treatment is still well below 50%” as a third-line treatment for a type of lymphoma, said he added.

CAR T therapies have also not been extended to treat solid tumors, which constitute the majority of cancers. Immunotherapy has been unable to break down the physical barriers, idiosyncratic tumor cells, and suppressive microenvironment that characterize these cancers. But a new generation of CAR T therapies is emerging, equipped with highly effective small molecules that scientists hope will solve their low success rate for blood cancers and solid tumors. Known as “armored CAR T”, these infusions have been fortified with additional layers of protection and cancer-fighting proteins. Early research shows that the armored flavor of CAR T might have what it takes to make immunotherapy go the extra mile.

“We make these cells and send them on this really tough adventure through different terrains and different problems, so we have to give them a set of tools,” Wendell Limresearcher in cellular and molecular pharmacology at the University of California, San Francisco, told the Daily Beast.

In short, immunotherapy can boost or restore the body’s immune system by decrease in cancer cell defenses, prime immune system T cells to destroy tumors, or, in the case of CAR T-cell therapy, genetically modifying a patient’s T cells. To do this, scientists isolate a patient’s T cells from their blood and insert a gene for a chimeric antigen receptor, a type of synthetic protein specially designed to bind to another protein found on the surface of cancer cells. of this patient. Then, when these modified T cells are injected back into a patient, the immune fighters will recognize and destroy the tumor cells when the patient’s normal T cells have failed.

At least that’s the idea. But when CAR T isn’t working, a few factors may be at play. One, Lim said, is the tumor microenvironment, the set of chemicals and structures found in solid cancers that naturally suppress immune system pushback. from the body. Tumor heterogeneity is also a factor – depending on the type and stage of cancer, tumor cells may not express the protein that CAR T cell receptors were designed to recognize, blocking the ability of CAR T cells to attack the cancer Finally, there are physical barriers on the outside of a solid tumor that may even prevent T cells from entering inside to destroy the cancer.

The armored CAR T is intended to overcome these difficulties. With this form of therapy, not only are T cells engineered to express the surface protein of a tumor cell, but they also receive a powerful load often in the form of small proteins called cytokines. If deployed alone, these molecules can be toxic, but pairing them with T cells designed to deliver them at the tumor site and nowhere else represents a promising new strategy.

Svodoba is help run a clinical trial using shielded CAR T cell therapy to treat patients with non-Hodgkin’s lymphoma for whom previous CAR T therapy has failed. Last month he presented the conclusions that the first seven patients treated with this therapy all responded and were alive eight months after receiving it. Svoboda said another important finding was that the toxicities experienced by patients — a concern with cytokines — were comparable to those of traditional CAR T therapy.

Lim’s team is also working on a shielded CAR-T therapy, with the potential to use it to treat solid tumors. In one article published in Science the dec. 16, he and his colleagues engineered T cells to deliver a cytokine directly into tumors of mice with pancreatic cancer and melanoma. In the study, they wrote that these cancers are “almost completely resistant” to traditional CAR T treatment, but the release of a cytokine allowed the modified T cells to outgrow the tumor microenvironment, effectively solving one of the problems that set the therapy back. . .

“The way to think about the future of CAR T-cell therapies is to develop reliable tools that solve certain problems and couple them into a single package,” Lim said. Researchers hope to begin patient trials of a shielded CAR T therapy within the next two years.

Getting these treatments to the clinic will not be a quick process – further trials will be needed to ensure that the shielded CAR T can be effective while reducing toxicity as much as possible. Personalized immunotherapy can also take time to produce — timelines that cancer patients don’t always have — and are often expensive. Still, Svodoba said efforts are underway to make the therapies more accessible, and the cost may be worth it if the shielded CAR T can be effective over the long term.

“If an infusion of an expensive product can lead to long-term remission or cure, investing in this type of product makes a lot of sense to me.”

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