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, these approaches, including chimeric antigen receptor (CAR)-T cell therapy, have shown limited efficacy against solid tumors, especially in advanced disease.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 pluripotent 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 exhibit significant long-lasting cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) against human lung cancer cell lines. In vivo, eNK cells achieved near-complete tumor regression in orthotopic and subcutaneous cell line-derived xenograft (CDX) models. In contrast, in patient-derived xenograft (PDX) models, eNK cells demonstrated modest tumor growth inhibition (28% reduction) as monotherapy and significantly enhanced efficacy (53% inhibition) in combination with cetuximab via antibody-dependent cellular cytotoxicity. In treated PDX tumors, human CD45-positive cells were detected within the tumor parenchyma, supporting intratumoral presence of administered human cells.These findings support the potential contribution of the five-gene modifications in enhancing tumor homing, persistence, and cytotoxicity in solid tumor treatment. This study underscores the potential of eNK cells as a novel, "off-the-shelf" allogeneic therapy for refractory solid tumors, including lung cancer.