Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma.

Kesang Li,Shengli Yang,Bizhi Shi,Wen Xu,Liyan Jiang,Cheng Chen,Zonghai Li,Yanyu Bi,Xiaorong Pan,Hua Jiang,Huiping Gao

doi:10.18632/oncotarget.6595

Kesang Li, Shengli Yang + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.6595

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Abstract

There are unmet medical needs for patients with lung squamous cell carcinoma (LSCC). Therefore, in this study, we explored the antitumor potential of third-generation glypican 3 (GPC3)-redirected chimeric antigen receptor (CAR)-engineered T lymphocytes (CARgpc3 T cells) in tumor models of LSCC. First, we demonstrated by immunohistochemistry (IHC) that GPC3 was expressed in 66.3% of LSCC samples and in 3.3% of lung adenocarcinoma (LAD) samples but not in normal lung tissues. In the presence of GPC3-positive LSCC cells, CARgpc3 T cells were highly activated and increased in number. CARgpc3 T cells could specifically lyse GPC3-positive LSCC cells in vitro. In two established LSCC xenograft models, CARgpc3 T cells could almost completely eliminate the growth of GPC3-positive cells. Additionally, the CARgpc3 T cells were able to persist in vivo and efficiently infiltrate the cancerous tissues. Taken together, these findings indicate that CARgpc3 T cells might be a novel potential therapeutic agent for the treatment of patients with LSCC.

Highlights

Lung adenocarcinoma (LAD, 50–60%), squamous cell carcinoma (LSCC, 30–35%) and large cell carcinoma (5–10%) are the most common histologic subtypes of non-small cell lung cancer (NSCLC) [1, 2]
Given that glypican 3 (GPC3) is expressed in lung squamous cell carcinoma (LSCC), in this study we explored the potential application of CARgpc3 T cells as a novel intervention for this deadly disease
The results indicated that the numbers of chimeric antigen receptor (CAR) T cells were significantly higher in mice treated with CARgpc3 T cells compared with mice treated with other T cells (p < 0.01) (Figure 6A–6B)

Summary

Introduction

Lung adenocarcinoma (LAD, 50–60%), squamous cell carcinoma (LSCC, 30–35%) and large cell carcinoma (5–10%) are the most common histologic subtypes of non-small cell lung cancer (NSCLC) [1, 2]. In the past several years, more and more target therapies have been approved in the treatment of LAD cases [3,4,5,6]. No targeted agents had been developed for LSCC before 2015, and chemotherapy continues to be the standard treatment [7, 8]. Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, was approved this year by the US Food and Drug Administration (FDA) as a second-line treatment for LSCC [9]. The overall response rate of patients with LSCC to nivolumab is only approximately 15%. Novel treatments are still urgently needed for patients with LSCC

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