Stanford University engineers have developed a method that enhances chimeric antigen receptor (CAR)-T cell delivery for solid tumors in mice. The researchers added CAR-T cells and specialized signaling proteins to a hydrogel and injected the substance next to a tumor. This gel provides a temporary environment inside the body where the immune cells multiply and activate in preparation to fight cancerous cells.

The findings are published in the journal Science Advances in a paper titled, “Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors.”

“Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically,” the researchers wrote.

“A lot of the CAR-T cell field is focusing on how to make better cells themselves, but there is much less focus on how to make the cells more effective once in the body,” explained Eric Appel, PhD, assistant professor of materials science and engineering at Stanford and senior author of the paper. “So what we’re doing is totally complementary to all of the efforts to engineer better cells.”

“Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors,” the researchers wrote. “The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells.”

“It’s kind of like a battle territory that’s filled with terrible things trying to fight off these T cells,” said Abigail Grosskopf, a PhD candidate in chemical engineering and lead author of the study. “So the CAR-T cells have a hard time infiltrating to attack that tumor.”

The researchers created a gel that can temporarily house cytokines and CAR-T cells near the tumor to overcome the toxicity of cytokines if delivered systemically through an IV drip.

The gel is made of water and two ingredients: a polymer made from cellulose, a material found in plants and biodegradable nanoparticles.

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

After determining the best gel formula to deliver the cancer treatment, the research team put its method to the test in mice with tumors. The researchers observed that all experimental animals injected with gel containing both CAR-T cells and cytokines became cancer-free after 12 days.

Additionally, the gel did not induce adverse inflammatory reactions in the mice.

“What we were evaluating is primarily tumors that you can inject next to. But we unfortunately still can’t get to all tissues in the body,” Appel said. “This ability to inject far away from the tumors really opens the door to possibly treat any number of solid tumors.”

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

“Overall, this interesting class of hydrogels addresses an unmet need for effective CAR-T cell delivery approaches that can enable the effective treatment of solid tumors.”

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