Molecular Therapy: Oncolytics (Dec 2023)

Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers

  • Thanyavi Chinsuwan,
  • Koichi Hirabayashi,
  • Shuji Mishima,
  • Aiko Hasegawa,
  • Miyuki Tanaka,
  • Hidemi Mochizuki,
  • Akihito Shimoi,
  • Takashi Murakami,
  • Shigeki Yagyu,
  • Kimihiro Shimizu,
  • Yozo Nakazawa

Journal volume & issue
Vol. 31
p. 100728

Abstract

Read online

Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.

Keywords