GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity.

Abstract

Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 103). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.

• Authors: Sabine Heitzeneder, Kristopher R Bosse, Zhongyu Zhu, Doncho Zhelev, Robbie G Majzner, Molly T Radosevich, Shaurya Dhingra, Elena Sotillo, Samantha Buongervino, Guillem Pascual-Pasto, Emily Garrigan, Peng Xu, Jing Huang, Benjamin Salzer, Alberto Delaidelli, Swetha Raman, Hong Cui, Benjamin Martinez, Scott J Bornheimer, Bita Sahaf, Anya Alag, Irfete S Fetahu, Martin Hasselblatt, Kevin R Parker, Hima Anbunathan, Jennifer Hwang, Min Huang, Kathleen Sakamoto, Norman J Lacayo, Dorota D Klysz, Johanna Theruvath, José G Vilches-Moure, Ansuman T Satpathy, Howard Y Chang, Manfred Lehner, Sabine Taschner-Mandl, Jean-Phillipe Julien, Poul H Sorensen, Dimiter S Dimitrov, John M Maris, Crystal L Mackall
• Journal: Cancer cell (Cancer Cell) Vol. 40 Issue 1 Pg. 53-69.e9 (01 10 2022) ISSN: 1878-3686 [Electronic] United States
• PMID: 34971569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Glypicans
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen

Topics

• Animals
• Cell Line, Tumor
• Glypicans (immunology, metabolism)
• Humans
• Immunotherapy (methods)
• Immunotherapy, Adoptive
• Neuroblastoma (drug therapy, pathology)
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Receptors, Chimeric Antigen (immunology)
• T-Lymphocytes (drug effects, immunology)
• Xenograft Model Antitumor Assays (methods)