Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade.
Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade.
复制标题
DOI：
10.1016/j.ccell.2020.11.005
复制
发表时间：
2021-02-08
期刊：
影响因子：
50.3
通讯作者：
Riddell SR
中科院分区：
文献类型：
--
作者：
Srivastava S;Furlan SN;Jaeger-Ruckstuhl CA;Sarvothama M;Berger C;Smythe KS;Garrison SM;Specht JM;Lee SM;Amezquita RA;Voillet V;Muhunthan V;Yechan-Gunja S;Pillai SPS;Rader C;Houghton AM;Pierce RH;Gottardo R;Maloney DG;Riddell SR
使用嵌合抗原受体修饰 T 细胞（CAR-T 细胞）的过继疗法对血液系统肿瘤有效，但对上皮恶性肿瘤无效，而上皮恶性肿瘤的死亡率最高。在乳腺癌和肺癌患者中，靶向肿瘤相关抗原受体酪氨酸激酶样孤儿受体 1 (ROR1) 的 CAR-T 细胞无法很好地浸润肿瘤并变得功能障碍。为了测试增强疗效的策略，我们采用了 KrasLSL-G12D/+;p53f/f 肺腺癌本地模型来表达 CAR 靶点 ROR1。用环磷酰胺 (Cy) 进行淋巴清除后转移的鼠 ROR1 CAR-T 细胞可暂时控制肿瘤生长，但与患者类似，其浸润肿瘤效果较差且丧失功能。在淋巴清除方案中添加奥沙利铂 (Ox) 可激活肿瘤巨噬细胞表达 T 细胞募集趋化因子，从而改善 CAR-T 细胞浸润，重塑肿瘤微环境，并增加肿瘤对抗 PD-L1 的敏感性。 Ox/Cy 和抗 PD-L1 联合治疗可协同改善 CAR-T 介导的肿瘤控制和生存，为提高 CAR-T 细胞临床疗效提供策略。斯里瓦斯塔瓦等人。证明在 CAR-T 细胞输注前给予的淋巴细胞清除方案中添加奥沙利铂可激活肺肿瘤巨噬细胞，产生 T 细胞募集趋化因子。这导致 CAR-T 细胞浸润、肿瘤重塑和检查点封锁反应得到改善，从而提供了提高 CAR-T 细胞临床疗效的策略。
Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic. Srivastava et al. demonstrate that adding oxaliplatin to the lymphodepletion regimen given before CAR-T cell infusion activates lung tumor macrophages to produce T cell-recruiting chemokines. This results in improved CAR-T cell infiltration, tumor remodeling, and response to checkpoint blockade, providing a strategy to improve CAR-T cell efficacy in the clinic.
登录
查看更多内容
影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
20.3
作者：
Hudecek, Michael;Schmitt, Thomas M.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
沉默轮状病毒 NSP4 蛋白可降低小鼠模型中胆道闭锁的发生率
影响因子：
3.7
作者：
Feng J;Yang J;Zheng S;Qiu Y;Chai C
通讯作者：
Chai C