An innovative treatment for lung cancer using gene-engineered human-induced pluripotent stem cell- derived natural killer cells

Various therapeutic approaches have been developed for lung cancer, including chemotherapy, radiation therapy, and immune checkpoint inhibitors. However, none of these approaches, including chimeric antigen receptor (CAR)-T cell therapy, have been effective against solid tumors.To enhance the therapeutic effect, we focused on the multiple effects of a new modality of cell therapy and created engineered natural killer (eNK) cells, which are gene-engineered induced pluripotential stem cell (iPSC)-derived NK cells armed with CC motif ligand 19 (CCL19), CC chemokine receptor type 2B (CCR2B), high-affinity cluster of differentiation 16 (CD16), interleukin (IL)-15, and natural killer group 2, member D (NKG2D)-DNAX-activating protein 10 (DAP10) complex. In vitro studies showed that eNK cells showed significant long-lasting cytotoxicity and antibody dependent cell-mediated cytotoxicity (ADCC) against human lung cancer cell lines. Intravenous and intra-tumoral treatment with eNK cells almost completely inhibited tumor growth in both orthotopically and subcutaneously transplanted cell line-derived xenograft (CDX) models, respectively. Moreover, intra-tumoral eNK cells administered as a single dose or in combination with cetuximab in the patient-derived xenograft (PDX) model of lung cancer showed clear tumor growth inhibition. This study demonstrates that eNK cells exhibit significant antitumor effects in both CDX and PDX models, and that these effects are further enhanced via ADCC.We successfully demonstrated that eNK cells having the ability to migrate to tumor cells and become activated in the tumor microenvironment and having the ability to induce tumor-specific killing activity without targeting CAR, are an innovative mode of treating lung cancer in pre-clinical studies.