Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer

doi:10.1016/j.canlet.2022.215697

	Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer
	Taromi, Sanaz 1,2; Firat, Elke 3; Simonis, Alexander 4,5; Braun, Lukas M.1; Apostolova, Petya 1; Elze, Mirjam 6; Passlick, Bernward 6; Schumacher, Alicia 1; Lagies, Simon 7,8,16; Frey, Anna 9; Schmitt-Graeff, Annette 9; Burger, Meike 1,2; Schmittlutz, Katrin 1; Follo, Marie 1; von Elverfeldt, Dominik 10; Zhu, Xuekai11 ; Kammerer, Bernd 7,8,12,16; Diederichs, Sven 6,13; Duyster, Justus 1,13; Manz, Markus G.4,5; Niedermann, Gabriele 3,13; Zeiser, Robert 1,13,14,15
	2022-07-10
发表期刊	CANCER LETTERS (IF:9.1[JCR-2023],8.3[5-Year])
ISSN	0304-3835
EISSN	1872-7980
卷号	538 页码:385-399
DOI	10.1016/j.canlet.2022.215697
摘要	Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells postchemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This tripleimmunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133+ cancer stem cells and PD-L1+CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.
关键词	SCLC CAR T cells CD73 PD-1 CD133
收录类别	SCIE
语种	英语
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:000799098200002
出版者	ELSEVIER IRELAND LTD
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/243342
专题	免疫化学研究所_PI研究组_朱学锴组 T细胞工程实验室
通讯作者	Taromi, Sanaz; Zeiser, Robert
作者单位	1.Univ Freiburg, Fac Med, Dept Med 1, Med Ctr, Freiburg, Germany; 2.Univ Furtwangen, Fac Med & Life Sci, Campus VS Schwenningen, Furtwangen, Germany; 3.Univ Freiburg, Fac Med, Dept Radiat Oncol, Freiburg, Germany; 4.Zurich Univ, Dept Med Oncol & Hematol & Oncol, Zurich, Switzerland; 5.Univ Hosp Med Ctr Zurich, Zurich, Switzerland; 6.Univ Freiburg, Fac Med, Dept Thorac Surg, Med Ctr, Freiburg, Germany; 7.Univ Freiburg, Ctr Biol Syst Anal ZBSA, Freiburg, Germany; 8.Albert Ludwigs Univ Freiburg, Inst Biol 2, Freiburg, Germany; 9.Albert Ludwigs Univ ALU Freiburg, Freiburg Univ, Dept Pathol, Med Ctr, Freiburg, Germany; 10.Albert Ludwigs Univ ALU Freiburg, Freiburg Univ, Fac Med, Med Phys,Med Ctr, Freiburg, Germany; 11.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies SIAIS, Shanghai, Peoples R China; 12.Univ Freiburg, BIOSS Ctr Biol Signalling Studies, Freiburg, Germany; 13.German Canc Consortium DKTK, Freiburg, Germany; 14.Univ Freiburg, Signalling Res Ctr BIOSS, Freiburg, Germany; 15.Univ Freiburg, CIBSS Ctr Integrat Biol Signalling Studies, Freiburg, Germany; 16.Albert Ludwigs Univ Freiburg, Spemann Grad Sch Biol & Med, Freiburg, Germany
推荐引用方式 GB/T 7714	Taromi, Sanaz,Firat, Elke,Simonis, Alexander,et al. Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer[J]. CANCER LETTERS,2022,538:385-399.
APA	Taromi, Sanaz.,Firat, Elke.,Simonis, Alexander.,Braun, Lukas M..,Apostolova, Petya.,...&Zeiser, Robert.(2022).Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer.CANCER LETTERS,538,385-399.
MLA	Taromi, Sanaz,et al."Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer".CANCER LETTERS 538(2022):385-399.