Engineered nanostructures boost CAR T-cell potency and longevity for cancer therapy

Our immune system is designed to protect us by recognizing and attacking infected or abnormal cells. However, cancer cells often manage to “cheat” the immune system by pretending to be healthy cells and thus disabling immune cell attack mechanisms.

Recently, this limitation has been overcome by a breakthrough treatment that helps the immune system fight cancer more effectively. This therapy involves extracting a patient’s own T cells—the sentinels of our immune system—and reprogramming them in the lab to better recognize and destroy cancer cells.

During this process, the T cells are activated (like what happens in the body during, for instance, infection) and genetically modified to produce special receptors on their surface called chimeric antigen receptors (CARs), which recognize and target cancer cells of specific types.

After expanding their number, these reprogrammed cells—now called CAR T cells—are infused back into the patient, where they act like precision-guided missiles, seeking and destroying cancer cells that the natural immune system may overlook.

CAR T-cell therapy is considered a revolution in cancer treatment, offering several advantages over traditional chemotherapy. It provides precise targeting of specific cancer types, uses the patient’s own immune cells for personalized therapy, and has demonstrated remarkable success in treating blood cancers like leukemia and lymphoma that often resist conventional treatments. Yet, despite its promise, CAR T-cell immunotherapy still faces challenges that limit its widespread clinical adoption.

One key issue is that T cells often become exhausted during their lab-based reprogramming, resulting in short-lived effects once infused back into the patient. To address this, researchers at Ben-Gurion University of the Negev, led by Prof. Mark Schvartzman (Department of Materials Engineering) and Prof. Angel Porgador (Department of Immunology), have been studying why T cells remain active in the body during natural immune responses but quickly lose function when activated artificially in the lab.

They hypothesized that a major difference lay in the physical nature of the activating environment: in the lab, T cells are typically stimulated using stiff plastic beads coated with activating molecules, whereas in the body, T cells are stimulated by antigen-carrying, abnormal, or infected cells, which are typically soft and elastic, with complex surfaces covered in nanometric protrusions resembling tiny arms.

The researchers asked: Could T cells sense the mechanical and structural properties of the surfaces they encounter, and could this sensing affect the strength and longevity of their activation?

To explore this, they engineered artificial surfaces covered with nanostructures mimicking those on natural activating cells. They found that human T cells, taken from blood samples and activated on these artificial surfaces, exhibited significantly stronger and longer-lasting activation—as if they were in their natural environment. Moreover, they found that the activation strength could be fine-tuned by adjusting the geometry and stiffness of the nanostructures, findings they published in several papers in recent years.

Encouraged by these findings, Prof. Schvartzman and Prof. Porgador set the next ambitious goal: to design artificial nanostructured surfaces specifically optimized for generating potent CAR T cells with long-lasting immunotherapeutic activity.

To that end, they created a library of surfaces with systematically varied nanogeometries and elasticities and evaluated their impact on a number of success criteria in T-cell response, including activation, exhaustion, proliferation, and CAR reprogramming.

“Suddenly,” says Prof. Porgador, “we found ourselves overwhelmed by data from various surface designs, success criteria, in addition to the fact that T cells of multiple donors were used, each with person-specific responses. It felt like a multi-round competition, where we had to identify the best performer overall.”

To find the winning design, they collaborated with their colleague Dr. Ofir Cohen, a bioinformatician who used advanced computational analysis to identify the most promising surface based on aggregate performance metrics.

The selected “champion” nanostructured surface delivered more surprises. CAR T cells generated with it expressed high levels of genes associated with long-lasting anti-cancer activity, particularly those tied to a subpopulation known as “central memory T cells,” which are key to effective immunotherapy.

Indeed, CAR T cells made using this surface contained significantly more of these central memory cells than those made using conventional plastic beads. The researchers then confirmed their findings experimentally in the lab and in mouse models.

Their findings were recently published in the journal Advanced Materials.

In parallel with ongoing optimization of CAR T-cell generation methods, the researchers are now focusing on scaling up their technology and transitioning from the research lab to clinical application.

“To produce these activating nanostructures,” explains Prof. Schvartzman, “we initially used nanofabrication techniques adapted from microchip production technology. The ongoing demand for ever-smaller electronic components in microchips has driven this technology to the point where structures of virtually any size—even down to the molecular level—can be fabricated.

“Furthermore, the wide range of compatible materials enables the production not only of miniaturized structures from silicon, as used in microchips, but also of bioactive materials suitable for integration with living systems. However, such methods are expensive and impractical for mass production of biomedical products.”

Therefore, the team developed cost-effective nanotechnological methods suitable for scalable, clinical-grade fabrication, and have already produced the first prototypes of activating surfaces able to generate CAR T cells in the amount sufficient for cancer treatment of a human adult.

To validate its technology, the research team is now collaborating with ADVA Bio, an Israeli company that manufactures bioreactors for automated CAR T-cell production. In pilot studies, the team has already fabricated large nanostructured activating surfaces sufficient for producing clinical-scale quantities of CAR T cells, now undergoing testing in ADVA’s bioreactors.

The research was led by Ph.D. student Abed Al Kader Yassin and postdoctoral researcher Dr. Carlos Urena Martinas well as members of several research groups from BGU and the University of Pennsylvania.