Stanford University scientists have taken aim at a key problem holding back an exciting form of cancer immunotherapy, and demonstrated how a novel gel can help overcome it by acting as an injectable holding pen for killer immune cells. The breakthrough promises to expand the scope of the treatment to tackle solid tumors, and offer these cells a base in close proximity for sustained attacks on the cancer.
The type of treatment at the center of this study is known as CAR-T cell therapy, and it involves harvesting a subject's own immune T-cells and exposing them to specialized signaling proteins that reprogram them. These re-engineered cells are then better equipped to replicate and destroy cancer cells, and returning them to the body via intravenous infusion has proven effective at tackling blood cancers such as leukemia.
Once in the bloodstream, these CAR-T cells flow through the entire body, which makes them potent when dealing with widespread cancers but problematic when it comes to solid tumors. These dense growths tend to form in certain locations and have defense mechanisms that fend off attacks from the immune 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, lead author of the new study. “So the CAR-T cells have a hard time infiltrating to attack that tumor.”
Scientists exploring solutions to this problem have made some exciting breakthroughs in recent years. Promising techniques involve using ultrasound to activate T cells once at the site of a solid tumor and using vaccines to supercharge their cancer-fighting abilities, including ones created using mRNA technology.
The Stanford team has approached the problem by developing a special gel made from water and cellulose, which is loaded up with CAR-T cells and the signaling proteins. The scientists liken the two-ingredient gel to Velcro, in that the components can bind together strongly, but also be easily pulled apart.
“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.”
The mesh structure of gel is strong enough to contain the T cells, but once they have replicated and are ready to destroy the tumor, they are able to free themselves and go after their target. This was demonstrated in mice with solid tumors, where the gel was injected adjacent to the growth. These animals became cancer free after 12 days, with no adverse inflammatory reactions.
This technique returned better results than parallel experiments in which a gel carrying only CAR-T cells was injected, when treatments were administered via the conventional IV drip, and when the gel was injected farther away from the tumor. These tumors still vanished, but the process took around twice as long.
“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,” said Eric Appel, assistant professor of materials science and engineering at Stanford and senior author of the paper. “This ability to inject far away from the tumors really opens the door to possibly treat any number of solid tumors.”
With the ability to rear modified CAR-T cells and release them when they're ready to take on the cancer, the scientists liken the hydrogel to a "leaky holding pen." They say there is a need for more pre-clinical work before it enters regular use, and their next experiments will explore the gel's ability to take out tumors from greater distances.
“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,” said Appel. “So what we’re doing is totally complementary to all of the efforts to engineer better cells.”
The research was published in the journal Science Advances.
Source: Stanford University
