Researchers at McMaster University have developed a form of cancer immunotherapy that uses cancer-killing natural killer (NK) cells genetically engineered outside the body to target and destroy cancer cells, including solid tumor types. Their in vitro studies showed that these chimeric antigen receptor (CAR)-engineered NK cells can differentiate between cancer cells and healthy cells that are found in and around tumors, and destroy only the targeted cells. The team says that this ability of NK cells to distinguish the target cells from healthy cells that express similar markers suggest that CAR-NK therapeutic approaches may offer new promise for cancer immunotherapy.

“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,” said Ali A. Ashkar, PhD, a professor of medicine at McMaster. “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.”

Ashkar is senior author of the team’s published paper in iScience (“Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors”), in which they concluded, “These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors.”

Natural killer cells play a critical role in cancer immunosurveillance through their innate ability to recognize and kill malignant cells without prior antigen sensitization, the authors explained. “Hence, NK cell-based cancer immunotherapy has been of recent interest due to their selective and potent anti-tumor activity.” This experimental form of cancer therapy treatment is being developed as an alternative to CAR T-cell therapy, which first received FDA approval in 2017. The engineered T cells used in CAR-T therapy are highly effective against some blood-borne cancers but cannot distinguish between cancerous and non-cancerous cells, so while they offer important benefits, they are not uniformly applicable to all forms of cancer. In patients with solid tumors, the T cells can cause devastating, even lethal side effects. “Indeed high-grade toxicities, namely cytokine release syndrome (CRS) and neurotoxicity are severe and at times, lethal complications from CAR-T cell therapy,” the investigators continued. “Given the inherent ability of NK cells to discriminate between healthy and malignant cells, NK cells are being considered as a safe alternative for CAR-based therapies.”

The researchers aimed to develop a treatment that had the same power as CAR-T cell immunotherapy, but which could be used safely against solid tumors. To do this they propagated natural killer cells derived from both breast cancer patients and from healthy donors, and then genetically modified the cells to target the HER2 receptors on cancer cells. “We chose HER2 as the target antigen in this study as a proof of concept …” they noted. “In breast cancer, HER2 overexpression accounts for 15–30% of cases and is a predictor of poor clinical outcome and reduced survival rates. We hypothesized that expanded NK cells engineered to express the HER2 CAR will be specific against HER2-expressing cancer cells, exert high cytotoxicity in the presence of immunosuppressive factors, and have minimal to no toxicity against non-malignant cells.”

The researchers successfully tested the engineered CAR-NK cells in the laboratory, against tumor cells derived from breast cancer patients. Their in vitro experiments showed that the CAR-NK cells effectively killed different breast cancer cell lines and an HER2-over-expressing ovarian cancer line. And unlike CAR-T cells, the HER2 CAR-NK cells could discriminate between HER2-expressing cancer cells and healthy HER2-expressing cells. “Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression,” the team commented. Encouragingly, the CAR-NK cells retained their effectiveness against cancer cells, even in the presence of immunosuppressive factors found in the tumor microenvironment (TME).

The authors concluded, “Using HER2 CAR-NK cells as a model, we have demonstrated that CAR-engineered NK cells have the capacity to overcome major obstacles that adoptive cell therapies have faced in achieving therapeutic efficacy against solid tumors, including suppression by the TME, tumor heterogeneity, and off-tumor toxicity. This strategy could be used as a personalized treatment option for patients with current unmet therapeutic need.”

Lead author Ana Portillo, a PhD candidate in the department of medicine, stated, “We want to be able to attack these malignancies that have been so resistant to other treatments. 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. These are very exciting results, as to date the benefits of immunotherapy in breast cancer have lagged behind that of other malignancies. These engineered CAR-NK cells are an important step towards having a viable immunotherapy option in this large group of patients.”

Ashkar suggests that there is good reason to believe the technology would have a similar effect on solid tumors associated with lung, ovarian, and other cancers. The researchers are now working towards human trials, as the next step in development of the treatment for clinical use.