NK cells can differentiate between cancer cells and healthy cells and have the ability to recognize and kill only cancer cells. In the past, NK cells have shown high clinical efficacy against hematologic tumors, but their use has been limited in solid tumors due to the harsh immunosuppressive tumor microenvironment.
The tumor microenvironment consists of a variety of cells including tumor cells, stromal cells, and tumor-induced immunosuppressive immune cells that can release immunosuppressive cytokines and factors such as transforming growth factor beta (TGFb) and prostaglandin E2 (PGE2).
CARs can be used to redirect and activate immune cells against tumor cells that express CAR antigens. CAR T cells have also shown great promise against hematological tumors. Significantly, the U.S. Food and Drug Administration (FDA) approved a CAR T-cell product for the treatment of B-cell lymphomas in 2017. However, CAR T cells recognize and attack antigens on both cancer cells and normal cells, and therefore, off-tumor effects have constrained the use of CAR T cells against solid tumors.
As an alternative to CAR T cells, CAR-NK cells may be more effective in the treatment of solid tumors due to the presence of inhibitory receptors that restrict their killing to normal cells. Therefore, researchers from McMaster University hypothesized that expanded NK cells engineered to express the HER2 CAR will be specific and effective against HER2-expressing cancer cells, with minimal toxicity against normal cells.
The team engineered HER2 CAR-expression in NK cells generated from ex vivo expanded NK cells derived from healthy donors and patients with breast cancer. They chose HER2 as the target because in breast cancer, HER2 overexpression accounts for 15%-30% of cases and is a predictor of poor clinical outcomes and reduced survival rates.
In vitro, the HER2 CAR-NK cells displayed enhanced cytotoxicity and interferon gamma production against HER2-expressing breast and ovarian cancer cells, compared to HER2 CAR T cells. While engineered CAR-NK cells displayed higher potency, in cell culture experiments inflammatory cytokine (interferon gamma and tumor necrosis factor alpha) production remained markedly lower than CAR T cells.
"We want to be able to attack these malignancies that have been so resistant to other treatments," said lead author Ana Portillo, a doctoral student in the department of medicine at McMaster University, in a statement. "The efficacy we see with CAR-NK cells in the laboratory is very promising and seeing that this technology is feasible is very important. Now, we have much better and safer options for solid tumors."
To determine the potential off-tumor effects of HER2 CAR-NK cells, the researchers tested the engineered cells in a translational cell model containing nonmalignant human bronchial epithelial cell lines (HBEC-6KT). The cells exhibited a significant 7.8-fold mean decrease in killing against low HER2-expressing HBEC-6KT cells (normal cells) over CAR T cells. Overall, CAR T cells were less effective at killing tumor cells and produced significantly higher levels of inflammatory cytokines.
"These CAR-NK cells are a little bit smarter, in a way, in that they only kill the enemy cells and not good cells that happen to have the same marker," explained Ali Ashkar, PhD, senior author and professor of Medicine at McMaster University. "These cells have a sober second thought that says, 'I recognize this target, but is this target part of a healthy cell or a cancer cell?' They are able to leave the healthy cells alone and kill the cancer cells."
Furthermore, the team investigated the antitumor effects of HER2 CAR-NK cells in the harsh tumor microenvironment. They found that the cells maintained their cytotoxic functions in the presence of highly immunosuppressive factors in the tumor microenvironment (TGFb and PEG2).
"These are very exciting results, as to date the benefits of immunotherapy in breast cancer have lagged behind that of other malignancies," said Bindi Dhesy-Thind, PhD, an associate professor at McMaster. "These engineered CAR-NK cells are an important step toward having a viable immunotherapy option in this large group of patients."
The researchers plan on investigating the technology for the treatment of other solid tumors such as lung and ovarian cancers. They are currently planning to investigate the clinical efficacy of these treatments in clinical trials.
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