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Simple Solution Supercharges T-Cell Production

By using a softer material as a scaffold, biomedical engineers Lance Kam and Helen Lu of Columbia University can generate a dramatically higher amount of functional T cells from blood taken from leukemia patients.

T cells are used in cell therapy to activate the immune system. Clinicians remove them from patients and reprogram them to attack specific types of cancers. The modified T cells are then expanded into larger populations and injected back into patients to help their immune system fight off the cancer.

While immunotherapy has the potential to become the safest, most effective treatment for cancer patients, less than half of patients see successful results. To find a solution, Kam, who specializes in growing T cells, and Lu, who develops scaffolds for bone and dental regeneration, took an unusual approach to the problem.

“One day Lance came to us with a very interesting hypothesis that a softer material may promote T cell production better than rigid materials,” Lu says. “He asked for help with designing a nanofiber mesh that would support the T cells.”

The current gold-standard model for expanding T cells involves growing them on hard plastic beads populated with proteins that help the T cells express the chimeric antigen receptor (CAR). CAR helps the T cells recognize and fight tumor-causing cells.

With healthy T cells, the process can turn 50 million T cells into about a billion cells that exhibit CAR. Clinicians then administer those modified cells to the patient to help them naturally fight off the disease without chemotherapy or radiation.

But if a patient is already receiving these other means of treatment, their cells may be too weakened by the combination of therapy and disease to function properly or grow robustly. About one-third of patients considered for T cell expansion do not have enough viable cells to be enrolled.

“We recognized that a softer material with a larger surface area than the rigid plastic beads might be a more useful and stronger catalyst for T cell expansion, especially for weaker cells,” Kam says. “Down the hall, Helen had been working on and perfecting a microfiber platform that I thought might be perfect for this, so we sat down and started talking.”

Aided by a $1.125-million Department of Defense Translational Research Grant, Lu and her team had been able to optimize their bioengineered nanofiber mesh to repair rotator cuffs by integrating tendons with bone.

She and Kam adapted the mesh to grow T cells, and found that the more flexible material allowed the T cells to expand beyond the geometries imposed by the rigid plastic beads. The soft mesh also successfully expands weakened or exhausted cells from patients previously treated for leukemia. In fact, the researchers could grow eight times as many functional T cells in a single step as the gold-standard bead-based process.

“It’s all about the design,” Kam says. “The mesh has to be optimized for the most effective results. That’s why it is so crucial to work with the right people who know their materials.”

Although the mesh has proven successful for T cell expansion outside of the body, Kam has not yet tested the cells in a living patient to show efficacy. Preliminary results on models look promising, and Kam believes the new technique will work well for patients with acute and chronic leukemia, as well as easy-to-access tumors, such as melanoma or pancreatic cancer.

It is also possible that the model may prove successful for patients with metastasized cancer. Rather than administer it directly to a tumor, clinicians could inject it into the circulatory or lymphatic system to fight circulating tumor cells (CTCs) after they detach from a tumor and begin to move through the body.

“We’re hoping that with this method, we can catch the disease before it ever spreads,” Kam says.

The next step for Kam is to test the efficacy of the mesh-grown T cells in animal trials. From there, he hopes to get swift FDA approval for human trials and beyond.

“If we can save the lives of 33 percent more people with this simple alteration to the model, that would send a powerful message about the current clinical standard,” Lu says. “It would change the way we think about cancer treatment.”



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