Modified CAR T Cells Can Preferentially Target Cancer Cells, Sparing Normal Cells
Engineering chimeric antigen receptor (CAR) T cells to lower their affinity for the protein epithelial growth factor receptor (EGFR) made the cells preferentially recognize and eliminate tumor cells, which have high amounts of EGFR, sparing normal cells, which have lower amounts of the protein, according to a preclinical study. These findings were published in Cancer Research (2015; doi:10.1158/0008-5472.CAN-15-0139).
CAR T cells currently being tested to treat B-cell malignancies target a specific protein present on leukemia and lymphoma cells. However, the immune cells cannot distinguish cancer cells from normal cells, explained corresponding author Laurence Cooper, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston. Therefore, even though CAR T cells attack cancer cells and normal B cells alike, with manageable side effects, this may not be the case with solid tumors.
"Many proteins that are present on solid tumors may also be present on normal cells that are vital to the body. 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. [Therefore], CAR T-cell-based immunotherapy may not yet be entirely safe for patients with solid tumors," added Cooper.
To make CAR T-cell therapy applicable to solid tumors, Cooper and his colleagues developed CAR molecules with reduced affinity for a target on solid tumors. The target they chose in this study was wild-type EGFR, a protein present at high levels in certain brain cancers, but also found at low levels on some normal cells.
The researchers used two monoclonal antibodies, cetuximab, which has higher affinity for EGFR, and nimotuzumab, which has lower affinity for EGFR. From these, they engineered high-affinity cetux-CAR T cells and low-affinity nimo-CAR T cells.
The researchers tested the different CAR T cells on cancer cells with high levels of EGFR and normal cells with low levels of EGFR and found that while the cetux-CAR T cells killed both cancer and normal cells, the nimo-CAR T cells were selectively activated only in response to the cancer cells.
The researchers then tested the CAR T cells in mice bearing human brain cancer cells expressing high levels of EGFR. They found that both cetux- and nimo-CAR T cells were equally effective in inhibiting tumor growth. However, the cetux-CAR T cells caused significant toxicity to the mice, leading to death in some, whereas the infused nimo-CAR T cells did not cause this effect. The researchers further tested the new CAR T cells in mice bearing cells that had low levels of EGFR (to mimic normal human cells), and found that unlike cetux-CAR T cells, the 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,” said Cooper in an interview. "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."