美国福瑞德·哈金森癌症研究中心Shivani Srivastava等研究人员发现，免疫原性化疗结合检查点阻断可增强对肺癌的CAR-T细胞招募并提高抗肿瘤功效。2020年12月24日，《癌细胞》杂志在线发表了这项成果。

研究人员表示，使用嵌合抗原受体修饰的T细胞（CAR-T细胞）的过继疗法在血液病中有效，但对上皮性恶性肿瘤无效，这种肿瘤会导致最大的死亡率。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细胞很难渗透到肿瘤中，并且功能失调。

为了测试增强功效的策略，研究人员采用了肺腺癌的Kras^LSL-G12D/+; p53^f/f自发模型来表达CAR靶点ROR1。用环磷酰胺（Cy）进行淋巴清除后转移的鼠ROR1 CAR-T细胞可瞬时控制肿瘤的生长，但浸润性差、功能丧失，与患者相似。将奥沙利铂（Ox）添加到淋巴切除方案中可激活肿瘤巨噬细胞来表达T细胞招募趋化因子，从而改善CAR-T细胞浸润、肿瘤微环境重塑，并增加肿瘤对PD-L1的敏感性。Ox/Cy和抗PD-L1的联合治疗可协同改善CAR-T细胞介导的肿瘤控制和生存，为临床提供了改善CAR-T细胞功效的策略。

附：英文原文

Title: Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade

Author: Shivani Srivastava, Scott N. Furlan, Carla A. Jaeger-Ruckstuhl, Megha Sarvothama, Carolina Berger, Kimberly S. Smythe, Sarah M. Garrison, Jennifer M. Specht, Sylvia M. Lee, Robert A. Amezquita, Valentin Voillet, Vishaka Muhunthan, Sushma Yechan-Gunja, Smitha P.S. Pillai, Christoph Rader, A. McGarry Houghton, Robert H. Pierce, Raphael Gottardo, David G. Maloney, Stanley R. Riddell

Issue&Volume: 2020-12-24

Abstract: Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) iseffective in hematologic but not epithelial malignancies, which cause the greatestmortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associatedantigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorlyand become dysfunctional. To test strategies for enhancing efficacy, we adapted theKrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. MurineROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transientlycontrol tumor growth but infiltrate tumors poorly and lose function, similar to whatis seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activatestumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-Tcell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivityto anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improvesCAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-Tcell efficacy in the clinic.

DOI: 10.1016/j.ccell.2020.11.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30597-3