Attaching “backpacks” carrying immune-stimulating molecules to T-cells effectively enhances their activity, a study found.
The approach can be used in any kind of tumor-fighting T-cell, including engineered cells, and has caused melanoma tumors to completely disappear in more than 50 percent of mice tested.
The study, “Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery,” was published in the journal Nature Biotechnology.
Using a patient’s own immune cells to fight cancer is an approach that has shown promising results in blood cancers like lymphoma and leukemia. But their effectiveness in solid tumors is still far from desired.
Researchers have tried to boost this response by injecting cytokines — molecules that mediate and regulate immune and inflammatory response — along with the T-cells. But the problem with that approach is that cytokines stimulate all T-cells they encounter, not just tumor-fighting T-cells, causing the immune system to be overactive.
Investigators at the Massachusetts Institute of Technology (MIT) have come up with a way to go around this problem. They created a kind of cytokine “backpack” that is attached to T-cells, making sure that only T-cells in the vicinity of the backpack would be activated.
The first backpack was described in 2010, and existed in lipid spheres called liposomes. However, liposomes could carry only small amounts of cytokines and began releasing the molecules as soon as T-cells entered the body.
Now, researchers have developed an improved version of the backpack, which consists of a nanoparticle gel carrying the cytokine IL-15. Using this new technology, IL-15 is released only when the T-cell binds to a tumor cell, which concentrates anti-cancer activity on tumor tissue alone
Also, the team’s nanogel carries 100 times more IL-15 than previously tested nanoparticles can, making the therapy much more potent.
“That allowed us to link T cell activation to the drug release rate,” Darrell Irvine, PhD, an associate director of MIT’s Koch Institute for Integrative Cancer Research and senior author of the study, said in a press release. “The nanogels are preferentially dissolving when the T cells are in sites where they see tumor antigen: in the tumor and in the tumor-draining lymph nodes. The drug is most efficiently being released at the sites where you want it and not in some healthy tissue where it might cause trouble.”
Researchers already have tested the approach in animal models of melanoma and glioblastoma. The nanogel was attached to genetically engineered T-cells called chimeric antigen receptor (CAR) T-cells.
After multiple injections, nearly 60 percent of the mice had no signs of the tumor.
Importantly, the IL-15 nanoparticles were significantly more effective at activating T-cells than free IL-15. And, researchers could give the mice eight times as much IL-15 without side effects.
“We found you could greatly improve the efficacy of the T cell therapy with backpacked drugs that help the donor T cells survive and function more effectively. Even more importantly, we achieved that without any of the toxicity that you see with systemic injection of the drugs,” said Irvine.
A company created by Irvine and colleagues, called Torque Therapeutics, is planning to begin clinical trials of this approach this summer.
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