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<p>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.</p><p>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.</p><p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

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  • Yuka Sato,
  • Kumiko Goto,
  • Shigehiro Yagishita,
  • Kotoko Miyata,
  • Noriko Uesugi,
  • Yu-suke Torisawa,
  • Yoichi Naritomi,
  • Ryuta Takahashi,
  • Rumiko Sho,
  • Yuriko Takeno,
  • Kenji Kurachi,
  • Masashi Yamada,
  • Yasuyuki Higashi,
  • Hironobu Kimura,
  • Akinobu Hamada,
  • Fusako Nishigaki,
  • Kouichi Tamura

摘要

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.