New delivery method improves CAR T cell ‘attack power’ against tumors

A cutting-edge cancer treatment that excites researchers today involves harvesting and reprogramming a patient’s T-cells – a special set of immune cells – then introducing them back into the body, ready to detect and destroy cancer cells. Although effective for common blood cancers like leukemia, this method is rarely successful in treating solid tumors.

Now, engineers at Stanford University have developed a delivery method that enhances the “attack power” of engineered immune cells, called chimeric antigen receptor (CAR) T cells. Researchers add CAR-T cells and specialized signaling proteins to a hydrogel — a water-filled gel that shares characteristics with biological tissue — and inject the substance next to a tumor. According to a new study published on April 8 in Scientists progress. The gel acts like a leaky sustain pen that pumps activated CAR-T cells to continuously attack the tumor over time.

Much of the CAR-T cell field focuses on how to make better cells themselves, but much less focuses on how to make cells more efficient once in the body. So what we’re doing is totally complementary to any efforts to design better cells.”


Eric Appel, assistant professor of materials science and engineering at Stanford and senior author of the paper

Gelled together

Currently, intravenous (IV) infusions are the primary mode of administration of CAR-T cells. In this method, the cells enter the bloodstream and pass through the whole body. But the approach isn’t ideal for treating solid tumors, which are often dense, exist in specific locations, and have defenses to hide and fend off immune cells.

“It’s kind of like a battlefield full of terrible things trying to fight these T-cells,” said Abigail Grosskopf, a chemical engineering doctoral student and lead author of the study. “So CAR-T cells have a hard time infiltrating to attack this tumor.”

To activate CAR-T cells enough to eradicate a tumor, the cells must undergo prolonged exposure to a high concentration of specialized signaling proteins. Called cytokines, these proteins signal modified immune cells to replicate quickly and prepare to destroy the tumor. However, if administered systemically by intravenous infusion, the amount of cytokines needed to mount an effective attack would be toxic to other parts of the body.

Instead, Grosskopf and his colleagues created a gel that can temporarily house cytokines and CAR-T cells near the tumor. Immune cells grow and proliferate there, inside the body, and are continually released to bombard the cancerous growth.

The gel is made of water and two ingredients: a cellulose-based polymer, a material found in plants, and biodegradable nanoparticles. When combined, the two components bond together like molecular Velcro – they want to stay together but can easily be pulled apart.

“This material can be injected through small needles,” Grosskopf said. “Yet after being injected, the ‘Velcro’ finds itself again and reforms into a sturdy gel structure.”

The mesh-like configuration of the gel is woven enough to prevent tiny cytokines from slipping out. At the same time, the framework’s connections are weak enough for the CAR-T cells to break them and break free when they are ready to kill the cancer cells.

Treating tumors in mice

After determining the best gel formula to deliver the cancer treatment, the research team put their method to the test in mice with tumors.

Grosskopf found that all experimental animals injected with a gel containing both CAR-T cells and cytokines became cancer-free after 12 days. She and her colleagues also tried delivering only CAR-T cells into the gel, but tumors disappeared more slowly or not at all in some mice. Treatments given by intravenous infusion or saline solution rather than gel were even less effective on tumours.

Additionally, the gel did not induce adverse inflammatory reactions in mice and it was completely degraded in the body within weeks.

The team also tried injecting the treatment gel farther from the tumor – on the opposite side of the mouse’s body to the cancerous growth. To everyone’s surprise, all of the animals’ tumors still disappeared, even though it took about twice as long as when the treatment was added next to the tumor.

“What we were evaluating are mostly tumors next to which you can inject yourself. But unfortunately we still can’t reach all the tissues in the body,” Appel said. “This ability to inject away from tumors really opens the door to possibly treating a number of solid tumors.”

Appel says his lab’s next set of experiments will further explore the gel delivery method’s ability to treat distant tumors.

Overall, this research offers a simple and effective way to improve a promising cancer treatment.

“I think one of the great things about our gels is how easy they are to make: you mix two things and inject them,” Grosskopf said. “We need to do more preclinical work, but I think there’s a lot of promise.”

Source:

Journal reference:

Grosskopf, AK, et al. (2022) Delivery of CAR-T cells in a transient injectable stimulating hydrogel niche improves treatment of solid tumors. Scientific advances. doi.org/10.1126/sciadv.abn8264.

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