Scientists Find New Way to Eliminate Tumor Cells

Engineered chimeric antigen receptor T-cells differentiate between cancerous and normal cells.

Researchers may be on the verge of a new method for killing cancer cells.

In a recent study, investigators engineered chimeric antigen receptor (CAR) T-cells to lower its affinity for the protein epithelial growth factor receptor (EGFR), which made the cells preferentially recognize and eliminate tumor cells that have high amounts of EGFR while sparing normal cells that have lower amounts of the protein.

While the CAR T-cells are currently being tested to treat B-cell malignancies and target specific proteins present in leukemia and lymphoma, the immune cells cannot distinguish cancer cells from normal cells, according to the study. CAR T-cells attack cancer cells and normal B-cells alike, but the side effects are manageable.

This may not be the case in solid tumors.

“Many proteins that are present on solid tumors may also be present on normal cells that are vital to the body,” said Laurence J. N. Cooper, MD, PhD. “So, while recipients of CAR T-cells can tolerate the loss of normal B-cells, they cannot endure damage to vital structures if the engineered T-cells inappropriately damage essential tissues. Because of this, CAR T-cell-based immunotherapy may not yet be entirely safe for patients with solid tumors.”

Cooper and colleagues worked to make this effect applicable on solid tumors by developing CAR molecules with reduced affinity for a target on solid tumors. They chose EGFR as their main target that is present in high levels in brain cancer but also appears in lower levels on normal cells.

The scientists generated high-affinity cetux-CAR T-cells using the monoclonal antibody cetuximab, and low-affinity nimo-CAR T-cells using the monoclonal antibody nimotuzumab.

The researchers tested both types of CAR T-cells on cancer cells to observe how they eliminated EGFR. They found that the cetux-CAR T-cells killed both cancerous and normal cells while the nimo-CAR T-cells only killed cancerous cells.

The researchers tested the cells again in mice bearing human brain cancer cells expressing high levels of EGFR and found that both cetux- and nimo-CAR T-cells were equally effective in inhibiting tumor growth. However, the cetux-CAR T-cells lead to serious side effects and in some cases death in the mice.

The nimo-CAR T-cells did not have this effect. The researchers further tested the new CAR T-cells in mice bearing cells that had low levels of EGFR. It was found that unlike cetux-CAR T-cells, nimo-CAR T-cells did not impact the growth of these cells.

“The goal of the study was to make CAR-expressing T-cells differentiate friend from foe. We wanted to provide CAR T-cells an improved opportunity of targeting a protein that is overexpressed on a cancer cell and spare normal cells that may also have the same protein, but at lower levels.

“We think this provides an advance in the field of CAR T-cell therapy, because until now the focus in terms of T-cell activation was on the intracellular portion of the CAR design, which led to the development of second- and third-generation CARs with different abilities to signal T cells,” Cooper said. “Our study has shown that another possibility is to tweak the extracellular portion of the CAR that docks with the tumor by adjusting its affinity for the target protein.”

The technology provides scientists with the opportunity to fine-tune CAR T cells to attack other over-expressed cancer proteins besides EGFR.

“An important derivative of this study is that scientists can now tweak, or modulate, the affinity of a CAR T cell to meet the needs of a given tumor,” Cooper said.