T-Cells of the immune System attacking growing Cancer cells

Harnessing the body’s own ability to seek and destroy cancer cells has been one of the most promising methods of treating cancer of the blood, like leukemia. The technology reprograms a type of immune cells, called T-cells, and then puts them back into the patient where they can do their job. This method, which produces chimeric antigen receptor (CAR) T cells, has not worked so well for solid tumors. But, now engineers at Stanford University report in the 8 April 2022 issue of Science Advances that they have created a gel that can be injected adjacent to—or even far away from—a tumor and destroy it entirely.

“A lot of the CAR-T cell field is focusing on how to make better cells, but there is much less focus on how to make the cells more effective once in the body,” said Eric Appel, assistant professor of materials science and engineering at Stanford and senior author of the paper.

Currently, costly intravenous (IV) infusions are the main mode of administration for CAR-T cells. The reprogrammed cells enter the bloodstream and flow through the entire body. This does not work well for treating solid tumors, which are often dense, exist in specific locations, and have many defense mechanisms for hiding from or destroying immune cells.

Abigail Grosskopf, a PhD candidate in chemical engineering and lead author of the study, likens it to a war between the tumor and the modified immune cells. “The CAR-T cells have a hard time infiltrating to attack the tumor,” Grosskopf said.

Grosskopf said she and her colleagues were inspired by approaches used in tissue engineering and regenerative medicine that use hydrogels to improve cell transplantation for regenerative medicine applications. “We wondered if we could use a similar approach for therapeutic cell delivery applications since they often suffer from challenges associated with expansion of the cells outside of the body,” she explained.

In the current study, the researchers added CAR-T cells and specialized signaling proteins (cytokines) to an engineered, self-assembling, and injectable Polymer-Nanoparticle (PNP) hydrogel. This water-filled gel has characteristics in common with biological tissues. They injected the CAR-T gel next to tumors in mice, which provided a temporary environment inside the body where the immune cells could multiply and activate in preparation to fight the cancerous cells. The gel acted like a tiny factory, pumping out activated CAR-T cells to continuously attack the tumor over time, leaving the mice tumor free within 14 days, while CAR-T cell therapy alone only left 40 percent of the mice tumor-free. The same success was seen when the gel was injected far from the tumor: all mice were cured within 30 days, while only 80 percent of mice receiving CAR-T cells without gel were cured within 60 days.

The PNP hydrogels used in this study have been used in the past to improve the potency of vaccines, control delivery of antibodies in treating HIV and COVID, and to prevent scar tissue growth between organs after surgery. “The formula of PNP hydrogel we used in this study was optimized for the co-delivery of CAR-T cells and cytokines so that the hydrogel could best act as a factory for generating high numbers of activated CAR-T cells in the body,” Grosskopf said.

The hydrogel-based treatment promises to bring down the cost of CAR-T cell therapy because fewer cells need to be made outside the body, the gel is made up of only two simple components, and can be injected rather than delivered by IV. “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.”

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