Preclinical Models Suggest Promise of CAR-NK Cell Treatment in Several Solid Tumors

As researchers continue to improve on the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies and work to bring the promise of the treatment to solid tumors, CAR natural killer (CAR-NK) cell treatment has shown early promise.

Previous research has suggested the efficacy of CAR-NK cells in hematological malignancies, and more recently, preclinical findings have raised the question of whether the type of treatment could be a viable, potentially more attractive option for solid tumors.

“Despite its confirmed anti-tumor activity, CAR-T cell therapy has several drawbacks: production is time-consuming and requires advanced technical support, and the therapy is very expensive and has a significant toxicity profile,” commented the researchers. “In the light of these shortcomings, the substitution of T cells with NK cells, i.e., CAR-NK therapy, may be a better alternative, one that maintains the effectivity of CAR-T but is free of its drawbacks.”

To date, most of the published research on the success of CAR-NK cells has been in hematologic malignancies, with a recent phase 1/2 trial showing that CD19-directed CAR-NK cells demonstrated responses in 8 of 11 healthy pretreated patients with lymphoma, 7 of which maintained complete responses 30 days following infusion.

Preclinical data has started to emerge on CAR-NK cells in several solid tumors, including glioblastoma (GBM), breast cancer, pancreatic cancer, and ovarian cancer.

“Of all solid tumors, GBMs have acquired the most extensive body of preclinical data regarding CAR-NK cell treatment,” explained the researchers. “Although NK cells found in GBM tissue have been found to be suppressed by the TME [tumor microenvironment], the fact that approximately 89% of GBM are naturally infiltrated by NK cells indicates that trafficking CAR-NK cells into the tumor tissue is plausible.”

A study of 9 patients with GBM showed that unmodified, activated autologous NK cells achieved partial or mixed responses in 4 patients, with another 3 achieving stable disease. While the responses were transient because of the strong immunosuppressive effect of the tumor microenvironment, the findings indicate that NK cells have potential in the treatment of GBM, say the researchers.

While no clinical trials have been initiated yet for patients with breast cancer, in vitro and in vivo models have suggested efficacy of CAR-NK cells against the disease. Compared with unmodified NK-92MI cells in one tumor-derived xenograft model, CAR-NK cells demonstrated superior anti-tumor activity against tissue factor-expressing breast cancer cells, as well as an active ADCC. The model chose tissue factor as the antigen target because it’s present in 50% to 85% of patients with triple-negative breast cancer.

In ovarian cancer, several studies have assessed the impact of CAR-NK cells. In mice models, mesothelin-directed CAR-NK92 cells effectively eliminated MSLN-expressing cell line and subcutaneous and intraperitoneal ovarian cancer, and prolonged survival in the tested mice.

Other research has shown CAR-NK cells to be effective against CD24-expressing ovarian cancer cell lines and patient-derived cells.

Reference

Wrona E, Borowiec M, Potemski P. CAR-NK cells in the treatment of solid tumors. Int J Mol Sci. 2021;22(11):5899. doi:10.3390/ijms22115899