Abstract
Effective control of non-small-cell lung cancer (NSCLC) remains clinically challenging, especially during advanced stages of the disease. This study developed an adoptive T-cell treatment through expression of a chimeric antigen receptor (CAR) to target human epidermal growth factor receptor (EGFR) in NSCLC. We optimized the non-viral piggyBac transposon system to engineer human T cells for the expression of EGFR-CAR, consisting of EGFR scFv, transmembrane domain, and intracellular 4-1BB-CD3ζ signaling domains. The modified CAR T cells exhibited expansion capability and anticancer efficacy in a time- and antigen-dependent manner in vitro as well as regression of EGFR-positive human lung cancer xenografts in vivo. EGFR-CAR T therapy is a promising strategy to improve the efficacy and potency of the adoptive immunotherapy in NSCLC. Moreover, EGFR-CAR T therapy could become a clinical application for NSCLC patients in the future.
Highlights
Lung cancer is a frequently diagnosed malignancy.in 2012 it was one of the leading causes of cancerrelated death in both men and women worldwide[1,2]
We transduced these plasmids into primary human peripheral blood cells, and after efficient enrichment and expansion following approximately 10–14 days of co-culture with anti-CD3/CD28 monoclonal antibodies and interleukin (IL)-2, we obtained the chimeric antigen receptor (CAR) T cells, i.e., the level of the exogenous CD3ζ expression was much higher in epidermal growth factor receptor (EGFR) CAR-expressed T cells than in un-transduced (UTD) T cells (Fig. 1b), while relative exogenous CD28-CD3ζ mRNA levels were significant (Fig. 1d)
Our data showed that there was a higher proportion of CD3+CD8+ EGFR-CAR T cells (54.91%) compared with UTD cells (34.88%), indicating that the cytotoxic T lymphocyte (CTL) population increased significantly after co-culture of these EGFR-CAR T cells with tumor cells (Fig. 2a and Figure S1)
Summary
Lung cancer is a frequently diagnosed malignancy.in 2012 it was one of the leading causes of cancerrelated death in both men and women worldwide[1,2]. Lung cancer is a frequently diagnosed malignancy. Despite several advances in early detection, prevention, and treatment of lung cancer during the past three decades, the 5-year overall survival of patients remains low, especially for those in advanced stages of disease[3] when patients are often only first diagnosed making. Recent novel strategies targeting therapy and immunotherapy are promising, patients still experience tumor metastasis or emergence of treatment resistance[4]. There has been some compelling evidence from studies ranging from targeted kinase inhibitor regimen to immunotherapy when randomized trials were compared with classical chemotherapy[5]. Immunotherapy could form the basis of lung cancer control in the future
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