CAR-NK Cells Show Potential in Solid Tumor Immunotherapy

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The engineered natural killer cells lack the off-target effects of typical CAR T-cell therapy and similarly lack any concerning safety signals.

CAR-engineered natural killer (NK) cells may be an efficacious and safe source of immunotherapy for solid tumors, according to data from a recent study.1

Researchers found that human epidermal growth factor receptor 2 (HER2) CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances antitumor function against HER2-expressing cancer cells, regardless of major histocompatibility complex class I (MHC1) expression. These cells also exerted higher cytotoxicity than donor-matched HER2 CAR-T cells against their targets, which was maintained in the presence of immunosuppressive factors in solid tumors. In terms of safety, HER2 CAR-NK cells did not elicit enhanced cytotoxicity or inflammatory cytokine production against nonmalignant human lung epithelial cells with basal HER2 expression, unlike 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, PhD candidate, department of medicine, McMaster University, in a statement.2 “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.”

Portillo and colleagues assessed HER2 CAR-NK cell anti-tumor functions against cancer cell lines with varying levels of HER2 and MHC I expression. They then tested HER2 CAR-NK cell killing against nonmalignant human bronchial epithelial cells expressing low levels of target antigen to investigate off-tumor effects. Additionally, they tested whether HER2 CAR-NK cells can overcome the immunosuppressive effects of factors present in the tumor microenvironment (TME).

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The HER2 CAR-NK cells exhibited significantly higher cytotoxicity and interferon-gamma (IFN-g) release against the HER2-overexpressing SKBR3 breast cancer cell line compared to HER2 CAR-NK-92 cells and exhibited a trend toward higher killing and IFN-g release in response to triple-negative MDA-MD-231 breast cancer cell line.

The investigative cells had a 1.7-fold mean increase in cytotoxicity relative to the nontransduced-NK cells and released significantly greater amounts of IFN-g after 5-hour incubation with HER2-positive breast cancer cells, with a 1.6-fold mean increase in IFN-g production relative to the nontransduced controls. No significant differences were seen in cytotoxicity and IFN-g release between the control vector transduced and nontransduced NK cells.

Expanded breast cancer patient-NK cells had similar transduction efficiencies compared to healthy donors, with a mean 50% (range, 27.3-68.4) HER2 CAR and mean 33.5% (range, 23.4-43.3) nerve growth factor receptor (NGFR) transgene expression. HER2 CAR expression increased expanded BCP-NK cell-mediated cytotoxicity with a significant 1.5-fold mean increase in killing relative to nontransduced controls. The cells also produced significantly greater amounts of IFN-g than nontransduced NK cells.

The investigators also found that HER2 CAR-NK cells exhibited a significant 1.9-fold mean increase in killing relative to nontransduced expanded NK cells against the highly NK cell-resistant and HER2-expressing BT-474 breast cancer cell line. Similarly, against the SKOV-3 ovarian cancer cell line which overexpresses HER2 and expresses MHC class I significantly higher than SKBR3 breast cancer cells, HER2 CAR-NK cells demonstrated a significant 1.5-fold mean increase in killing compared to nontransduced controls

In terms of off target effects and potential safety in solid tumors, Portillo and colleagues evaluated bronchial HBEC-6KT cells and found they expressed significantly lower levels of all stress-induced ligands tested except for CD155 in response to the CAR-NK cells compared to other tumor cell lines used in the study. Furthermore, HER2 CAR expression in expanded NK cells did not lead to enhanced killing of nonmalignant HBEC-6KT cells relative to the control vector transduced-NK cells.

Unlike the CAR-NK cells, donor-matched HER2 CAR-T cells became highly activated and exhibited a significant 7.8-fold mean increase in killing against the low HER2-expressing HBEC-6KT cells. These cells also killed SKBR3 breast cancer targets less efficiently than the HBEC-6KT cells unlike HER2 CAR-NK cells which exhibited significantly higher cytotoxicity toward tumor cells compared to bronchial cells.

“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,” added senior author Ali Ashkar, PhD, DVM, professor,
pathology and molecular medicine, McMaster Immunology Research Centre, McMaster University, to the statement. “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.”

The researchers compared HER2 CAR-NK cells to nontransduced NK cells which were significantly inhibited in the presence of TGF-b and PGE2 and found that the investigational cells did not have a significant reduction in cytotoxic function. The HER2 CAR-NK cells exhibited significantly higher cytotoxicity than nontransduced NK cells within the same inhibitory conditions.

“These are very exciting results, as to date the benefits of immunotherapy in breast cancer have lagged behind that of other malignancies,” Portillo added. “These engineered CAR-NK cells are an important step towards having a viable immunotherapy option in this large group of patients.”

REFERENCES
1. Portillo AL, Hogg R, Poznanski SM, et al. Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors. IScience. 2021: 24, 102619 doi: 10.1016/ j.isci.2021.102619
2. Researchers engineer cells to destroy malignant tumor cells but leave the rest alone. News release. McMaster University. June 29, 2021. https://www.firstwordpharma.com/node/1842062?al=393810-60599dc1813c197123c2a753c96df36d%5E%7C%5EMTExMDM5Ng%3D%3D%5E%7C%5ENQ%3D%3D&cp1=bmV3c2xldHRlcl9yZWdpb25faWQ9dHJlbmRz
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