Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma

Zhiwu Jiang,Duanqing Pei,Qiubin Liang,Yao Yao,Qifa Liu,Suna Wang,Yunxin Lai,Xiaofeng Jiang,Xin Du,Pentao Liu,Fenglei Yu,Muyun Peng,Baiheng Li,Suimin Chen,Jianyu Weng,Ping Xue,Xinru Wei,Shudong Lin ,Qianni Wu ,Li P

doi:10.3389/fimmu.2016.00690

Abstract

The lack of a general clinic-relevant model for human cancer is a major impediment to the acceleration of novel therapeutic approaches for clinical use. We propose to establish and characterize primary human hepatocellular carcinoma (HCC) xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR) T cells and accelerate the clinical translation of CAR T cells used in HCC. Primary HCCs were used to establish the xenografts. The morphology, immunological markers, and gene expression characteristics of xenografts were detected and compared to those of the corresponding primary tumors. CAR T cells were adoptively transplanted into patient-derived xenograft (PDX) models of HCC. The cytotoxicity of CAR T cells in vivo was evaluated. PDX1, PDX2, and PDX3 were established using primary tumors from three individual HCC patients. All three PDXs maintained original tumor characteristics in their morphology, immunological markers, and gene expression. Tumors in PDX1 grew relatively slower than that in PDX2 and PDX3. Glypican 3 (GPC3)-CAR T cells efficiently suppressed tumor growth in PDX3 and impressively eradicated tumor cells from PDX1 and PDX2, in which GPC3 proteins were highly expressed. GPC3-CAR T cells were capable of effectively eliminating tumors in PDX model of HCC. Therefore, GPC3-CAR T cell therapy is a promising candidate for HCC treatment.

Highlights

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and is one of the deadliest cancers in Asia [1,2,3]
Our results show that Glypican 3 (GPC3) protein was highly expressed in xenografts of HCCs, so we tested the effect of GPC3-chimeric antigen receptor (CAR) T cells in these Patient-derived xenografts (PDXs) models
We report the establishment of three PDX models from primary HCC in NSI mice

Summary

Introduction

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and is one of the deadliest cancers in Asia [1,2,3]. Patient-derived xenografts (PDXs) refer to a procedure in which cancerous tissue from a patient’s primary tumor is implanted directly into an immunodeficient mouse [8]. This technique offers several advantages over standard cell line xenograft models. PDX models are more biologically stable when passaged in mice in terms of mutational status, gene expression patterns, drug responsiveness, and tumor heterogeneity [9] Despite these benefits, only two studies report the use of PDX models of HCCs in drug testing [10, 11]. We propose to establish and characterize primary human hepatocellular carcinoma (HCC) xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR) T cells and accelerate the clinical translation of CAR T cells used in HCC

Methods

Results

Conclusion