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Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung
Thanyavi Chinsuwan1,2, Koichi Hirabayashi1, Shuji Mishima3
1Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
Abstract:
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.
Insights
New chimeric antigen receptor (CAR)-T cells targeting epidermal growth factor receptor (EGFR) show potent anti-non-small cell lung cancer (NSCLC) activity. This novel CAR-T therapy is effective and safe in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in cancer therapy due to its overexpression in non-small cell lung cancer (NSCLC).
- Chimeric antigen receptor (CAR)-T cell therapy offers a promising approach for cancer treatment.
Purpose of the Study:
- To engineer and evaluate novel CAR-T cells targeting EGFR for NSCLC treatment.
- To assess the efficacy and safety of EGFR-targeted CAR-T cells in preclinical settings.
Main Methods:
- Engineered CAR-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural EGFR ligands.
- Tested CAR-T cell efficacy in vitro and in vivo against NSCLC models.
- Evaluated CAR-T cell toxicity in tumor-bearing mice and non-tumor-bearing cynomolgus macaques.
Main Results:
- The engineered CAR-T cells demonstrated favorable phenotypes and high CAR positivity.
- Potent antitumor activity against NSCLC was observed both in vitro and in vivo.
- No toxicity was elicited in mice or macaques, even with cross-reactivity to murine and simian EGFRs.
Conclusions:
- Ligand-based, piggyBac-engineered CAR-T cells are a feasible and safe strategy for targeting EGFR-expressing NSCLCs.
- The affinity of CAR molecules plays a crucial role in potency and safety, with higher affinity showing greater efficacy without adverse events.
