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Turning cancer's defense against itself using novel CAR-T therapy

Scientists found a way to help immune cells attack cancer more effectively using CAR-T cell therapy. Cancer cells are notorious for their ability to evade the human immune system, a trait that makes them particularly challenging targets for treatment.

These cells deploy a molecule known as programmed death-ligand 1 (PD-L1), effectively creating a “shield” that suppresses immune cells and complicates the development of effective cancer immunotherapies.

CAR T-cell therapy and cancer

At the Wang Lab in the Alfred E. Mann Department of Biomedical Engineering at the University of Southern California, led by Peter Yingxiao Wang, researchers are pioneering a groundbreaking method that cleverly uses a tumor’s own defensive mechanism against it.

The experts have developed a novel form of Chimeric Antigen Receptor (CAR) T-cell therapy, where T-cells – crucial white blood cells in our immune response – are altered to detect and destroy cancer cells.

The innovative approach includes the creation of a unique molecule named “PDbody,” specifically designed to target the PD-L1 protein that tumors use as a shield. This enables the CAR T-cells to recognize and attack the cancer cells, effectively breaching their defenses.

Targeted cancer destruction

The study at the Wang Lab, led by postdoctoral researcher Linshan Zhu and supported by Professor Longwei Liu, has made significant strides in cancer research.

Their latest publication showcases an engineered monobody that specifically binds to the PD-L1 molecule, a protective mechanism used by tumor cells. This strategic binding targets the cancer cells and disables their defenses, making them susceptible to an immune attack.

“Imagine the CAR is a real car. You have the engine and the gas. But you also have a brake. Essentially, the engine and gas push the CAR T to move forward and kill the tumor. But the PD-L1 works like the brake that stops it,” explained Peter Yingxiao Wang, the Chair of the department and leader of the research team.

By transforming PD-L1 from a brake into a target, the engineered CAR T-cells can aggressively attack and eliminate tumor cells.

“This chimeric PDbody-CAR molecule can lead the CAR T we designed to start to attack, recognize, and clear the tumor. At the same time, it will block and prevent the tumor cell from stopping the CAR-T’s attack. In that way, our CAR T will be more potent,” noted Wang, highlighting the enhanced effectiveness of this innovative approach.

Precision and safety of CAR-T in cancer treatment

The researchers focused on a highly invasive form of breast cancer that expresses PD-L1, but the molecule is also found in other cells, posing a potential risk of damage to healthy tissue. To tackle this, the team explored the unique microenvironment of tumors – specifically, their typically lower pH levels.

“We know that the pH is relatively low in the tumor microenvironment – it is a little acidic,” noted one team member. “So, we wanted our PDbody to have a better binding ability in an acidic environment, which will help our PDbody distinguish the tumor cells from other surrounding cells.”

To enhance the precision of the therapy further, the researchers employed an engineered genetic “gate” system called SynNotch, ensuring the PDbody CAR T-cells only target cancer cells expressing another protein, CD19.

This reduces the risk of harming healthy cells. “In simple terms, the T-cells will only be activated at the tumor site because of this SynNotch gating system,” the researcher elaborated. “Not only is the pH more acidic, but also the tumor cell’s surface will determine whether the T-cell will be activated, giving us two layers of control.”

Evolutionary inspiration for advanced solutions

To perfect their engineered molecule, the team used a process inspired by natural selection, known as directed evolution. This involved creating a vast library of monobody variants and selecting the most effective one for targeting PD-L1.

“Using directed evolution, we screened a large number of different monobody mutations to select which one will bind to the PD-L1. The one selected has these features that can not only recognize the tumor PD-L1 but can block the brake mechanism that PD-L1 has and then guide the CAR T-cell to the tumor’s surface to attack and kill the tumor cells,” explained Wang.

Promising progress toward clinical application

With promising initial results in a mouse model, where the SynNotch gate system effectively guided the PDbody CAR T-cells to activate precisely at tumor sites, the research team is optimistic about the potential of this therapy.

The experts will continue to refine the technique, aiming to enhance its precision and effectiveness before progressing to clinical trials. As they look to integrate these findings with other innovative treatments like focused ultrasound, the potential for a new generation of cancer therapies appears bright.

“We now have all these genetic tools to manipulate, control, and program those immune cells to have so much power and function,” said Wang. “We hope to create new ways to guide their function for particularly complicated solid tumor treatments.”

The study is published in the journal ACS Nano.


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