Lee, Young Eun Ju, Anna Choi, Hwi Wan Kim, Jin-Chul Kim, Eunice EunKyeong Kim, Tae Sung Kang, Hyo Jeong Kim, Sang-Yeob Jang, Jin-Young Ku, Ja-Lok Kim, Song Cheol Jun, Eunsung Jang, Mihue 2024-01-19T16:31:25Z 2024-01-19T16:31:25Z 2021-09-02 2020-10-10 0168-3659 https://pubs.kist.re.kr/handle/201004/117998 The emergence of T-cell engineering with chimeric antigen receptors (CARs) has led to attractive therapeutics; however, autologous CAR-T cells are associated with poor clinical outcomes in solid tumors because of low safety and efficacy. Therefore, the aim of our study was to develop a CAR therapy with enhanced cytotoxicity against solid cancer using allogeneic NK cells. In this study, we engineered "off-the-shelf" NK cells to redirect them towards pancreatic ductal adenocarcinoma (PDAC) by improving their target-specific cytotoxic potential. By integrated bioinformatic and clinicopathological analyses, folate receptor alpha (FR alpha) and death receptor 4 (DR4) were significantly highly expressed in patient-derived tumor cells. The combined expression of FR alpha and DR4/5 was associated with inferior clinical outcomes, therefore indicating their use as potential targets for biomolecular treatment. Thus, FR alpha and DR4 expression pattern can be a strong prognostic factor as promising therapeutic targets for the treatment of PDAC. For effective PDAC treatment, allogeneic CAR-NK cells were reprogrammed to carry an apoptosis-inducing ligand and to redirect them towards FR alpha and initiate DR4/5-mediated cancer-selective cell death in FR alpha- and DR4/5-positive tumors. As a result, the redirected cytotoxic ligand-loaded NK cells led to a significantly enhanced tumor-selective apoptosis. Accordingly, use of allogeneic CAR-NK cells that respond to FR alpha and DR4/5 double-positive cancers might improve clinical outcomes based on personal genome profiles. Thus, therapeutic modalities based on allogeneic NK cells can potentially be used to treat large numbers of patients with optimally selective cytotoxicity. English ELSEVIER CHIMERIC ANTIGEN RECEPTOR APOPTOSIS-INDUCING LIGAND CLASS-I EXPRESSION T-CELLS NK CELLS ANTITUMOR-ACTIVITY DEATH RECEPTORS IMMUNOTHERAPY GEMCITABINE EXPANSION Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment Article 10.1016/j.jconrel.2020.07.016 1 JOURNAL OF CONTROLLED RELEASE, v.326, pp.310 - 323 JOURNAL OF CONTROLLED RELEASE 326 310 323 scie scopus 000572080200003 2-s2.0-85088301681 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article CHIMERIC ANTIGEN RECEPTOR APOPTOSIS-INDUCING LIGAND CLASS-I EXPRESSION T-CELLS NK CELLS ANTITUMOR-ACTIVITY DEATH RECEPTORS IMMUNOTHERAPY GEMCITABINE EXPANSION CAR-NK Caner immunotherapy Pancreatic cancer Allogeneic therapy TRAIL