Study Finds Modified CAR T Cells Can Selectively Target Solid Tumor Cells While Sparing Healthy Cells
Chimeric antigen receptor (CAR) T cells that are currently being tested to treat B-cell malignancies target a specific protein present on leukemia and lymphoma cells, but these immune cells cannot distinguish the cancer cells from healthy cells. However, the side effects from these CAR T cells attacking both cancer and normal cells are manageable in these blood cancers, which may not be the case in solid tumor cancers.
In a preclinical study investigating CAR T-cell therapy that is applicable to solid tumors, researchers modified CAR T cells to lower their affinity for wild-type epithelial growth factor receptor (EGFR), a protein found in high levels in more than 60% of adult glioblastomas but also found at low levels on some normal cells. The researchers found that the modification made the cells preferentially recognize and eliminate tumor cells with high levels of EGFR while sparing normal cells that have lower amounts of the protein. The study results may enable the technology to be fine-tuned to target other overexpressed cancer proteins in solid tumor cancers. The study by Caruso et al is published in Cancer Research.
Study Methodology and Findings
To develop CAR molecules with reduced affinity for wild-type EGFR, the researchers derived two CAR species using two monoclonal antibodies, cetuximab (Erbitux), which has a higher affinity for EGFR, and nimotuzumab, which has a lower affinity for EGFR. From these second-generation EGFR-specific CARs, the researchers engineered high-affinity cetuximab-CAR T cells and low-affinity nimotuzumab-CAR T cells.
The researchers tested the CAR T cells on cancer cell lines with high levels of EGFR and normal cells with low levels of EGFR and found that while the cetuximab-CAR T cells killed both cancer and normal cells, the nimotuzumab-CAR T cells were selectively activated only in response to cancer cells.
The researchers then tested the CAR T cells in mice with glioma cancer cells expressing high levels of EGFR and found that both the cetuximab- and nimotuzumab-CAR T cells were equally effective in halting tumor growth. However, the cetuximab-CAR T cells caused significant toxicity, leading to death in some mice, whereas the infused nimotuzumab-CAR T cells were safe.
The researchers next tested the CAR T cells in mice with cells that had low levels of EGFR, to mimic normal human cells, and found that unlike the cetuximab-CAR T cells, the nimotuzumab-CAR T cells did not impact the growth of these cells.
Advancing CAR T-Cell Therapy
“The goal of the study was to make CAR-expressing T cells differentiate friend from foe,” said Laurence J.N. Cooper, MD, PhD, CEO of ZIOPHARM Oncology, and a coauthor of this study, in a statement. “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.”
“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. 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. 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,” Dr. Cooper said.
Dr. Cooper is the corresponding author of Cancer Research article.
For full disclosures of the study authors, visit cancerres.aacrjournals.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
