Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment

Young Eun Lee, Anna Ju, Hwi Wan Choi, Jin Chul Kim, Eunice Eun Kyeong Kim, Tae Sung Kim, Hyo Jeong Kang, Sang Yeob Kim, Jin Young Jang, Ja Lok Ku, Song Cheol Kim, Eunsung Jun, Mihue Jang

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

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 (FRα) and death receptor 4 (DR4) were significantly highly expressed in patient-derived tumor cells. The combined expression of FRα and DR4/5 was associated with inferior clinical outcomes, therefore indicating their use as potential targets for biomolecular treatment. Thus, FRα 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 FRα and initiate DR4/5-mediated cancer-selective cell death in FRα- 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 FRα 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.

Original languageEnglish
Pages (from-to)310-323
Number of pages14
JournalJournal of Controlled Release
Volume326
DOIs
Publication statusPublished - 2020 Oct 10

Bibliographical note

Funding Information:
We would like to thank Dr. Daechan Park for scientific and strategic discussions. M.J. designed the experiments. S.C·K conducted a cohort study of patients. This research was supported by the intramural research program [ 2E30350 to M.J.] of KIST, by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) [No. 2020R1C1C1006421 and 2020M3A9I4038662 to M.J.], by the R&D Convergence Program of NST [ National Research Council of Science & Technology) of Republic of Korea ( CAP-16-03-KRIBB to E.K.), and by a grant [ 2018-0806 to E.J.] from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea, respectively.

Publisher Copyright:
© 2020 Elsevier B.V.

Keywords

  • Allogeneic therapy
  • CAR-NK
  • Caner immunotherapy
  • Pancreatic cancer
  • TRAIL

ASJC Scopus subject areas

  • Pharmaceutical Science

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