小柯机器人

美国斯坦福大学医学院Crystal L. Mackall团队发现，低抗原密度的GPC2-CAR T细胞介导对神经母细胞瘤的有效活性而无毒性。这一研究成果于2021年12月30日在线发表在国际学术期刊《癌细胞》上。

研究人员开发了表达嵌合抗原受体（CAR）的T细胞，靶向glypican-2（GPC2），一种在神经母细胞瘤（NB）和其他几种实体瘤上表达的胎儿抗原。使用标准设计产生的CAR可以控制转基因GPC2过表达的NB，但不能控制表达临床相关的GPC2位点密度（5000分子/细胞，范围1-6×10³）的NB。跨膜（TM）和共刺激结构域的迭代工程加上c-Jun的过表达降低了GPC2-CAR抗原密度的阈值，使表达临床相关GPC2抗原密度的NB得到有效和持久的根除，而且没有毒性。

这些研究强调了CAR设计和抗原密度阈值之间的关键相互作用，证明了适合临床测试的主要GPC2-CAR候选者的有效疗效和安全性，并证明胎儿抗原是CAR T细胞治疗实体瘤的一类有望靶点。

据悉，儿科癌症通常模仿胎儿组织，并表达通常在产后沉默的蛋白质，可作为免疫靶标。

附：英文原文

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

Author: 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

Issue&Volume: 2021-12-30

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.

DOI: 10.1016/j.ccell.2021.12.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00658-9

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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