Glypican-3-Specific CAR T Cells Coexpressing IL15 and IL21 Have Superior Expansion and Antitumor Activity against Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world, and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy i...

Full description

Saved in:
Bibliographic Details
Published in:Cancer immunology research 2020-03, Vol.8 (3), p.309-320
Main Authors: Batra, Sai Arun, Rathi, Purva, Guo, Linjie, Courtney, Amy N, Fleurence, Julien, Balzeau, Julien, Shaik, Rahamthulla S, Nguyen, Thao P, Wu, Meng-Fen, Bulsara, Shaun, Mamonkin, Maksim, Metelitsa, Leonid S, Heczey, Andras
Format: Article
Language:English
Subjects:
Animals
Apoptosis - immunology
Carcinoma, Hepatocellular - immunology
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Carcinoma, Hepatocellular - therapy
Cell Proliferation - physiology
Female
Glypicans - genetics
Glypicans - immunology
Humans
Immunotherapy, Adoptive - methods
Interleukin-15 - biosynthesis
Interleukin-15 - genetics
Interleukin-15 - immunology
Interleukins - biosynthesis
Interleukins - genetics
Interleukins - immunology
Liver Neoplasms - immunology
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Liver Neoplasms - therapy
Mice
Mice, Inbred NOD
Mice, SCID
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world, and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy in patients with solid tumors, including HCC. IL15 and IL21 promote T-cell expansion, survival, and function and can improve the antitumor properties of T cells. We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC. We previously optimized the costimulation in GPC3-CARs and selected a second-generation GPC3-CAR incorporating a 4-1BB costimulatory endodomain (GBBz) for development. Here, we generated constructs encoding IL15, IL21, or both with GBBz (15.GBBz, 21.GBBz, and 21.15.GBBz, respectively) and examined the ability of transduced T cells to kill, produce effector cytokines, and expand in an antigen-dependent manner. We performed gene-expression and phenotypic analyses of GPC3-CAR T cells and CRISPR-Cas9 knockout of the gene. Finally, we measured GPC3-CAR T-cell antitumor activity in murine xenograft models of GPC3 tumors. The increased proliferation of 21.15.GBBz T cells was at least in part dependent on the upregulation and maintenance of TCF-1 (encoded by ) and associated with a higher percentage of stem cell memory and central memory populations after manufacturing. T cells expressing 21.15.GBBz had superior and expansion and persistence, and the most robust antitumor activity These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-19-0293