Preclinical Evaluation of Novel Folate Receptor 1-Directed CAR T Cells for Ovarian Cancer

被引:6
作者
Daigre, Julie [1 ]
Martinez-Osuna, Manuel [1 ]
Bethke, Maria [1 ]
Steiner, Larissa [1 ]
Dittmer, Vera [1 ]
Krischer, Katrin [1 ]
Bleilevens, Cathrin [1 ]
Brauner, Janina [1 ]
Kopatz, Jens [1 ]
Grundmann, Matthias David [1 ]
Praveen, Paurush [1 ]
Eckardt, Dominik [1 ]
Bosio, Andreas [1 ]
Herbel, Christoph [1 ]
机构
[1] Miltenyi Botec BV & Co KG, Friedrich Ebert Str 68, D-51429 Bergisch Gladbach, Germany
关键词
ovarian cancer; immunotherapy; cancer cell therapy; CAR T cells; FOLR1; cell surface targets; solid tumor; EXTENSIVE METHYLATION; TUMOR TARGET; ALPHA; EXPRESSION; CD28;
D O I
10.3390/cancers16020333
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary Ovarian cancer is a devastating disease due to the late diagnosis of advanced stage disease and high recurrence rates. Thus, new long-lasting, efficient drugs are needed. Since chimeric antigen receptor (CAR)-expressing T cell treatments have led to efficient and persisting anti-tumor responses, our study aimed to design and characterize CAR T cells targeting ovarian cancer. We confirmed folate receptor 1 (FOLR1) as a promising tumor-associated antigen in ovarian cancer patient samples. After designing a library of FOLR1-directed CAR T cells, their functionality and specificity were assessed in vitro against cell lines as well as in vivo in a mouse model of ovarian cancer. Finally, we selected a lead candidate for further characterization. The anti-FOLR1 CAR was successfully tested, including assays, reflecting the solid tumor microenvironment. These characteristics will support the clinical translation of our new FOLR1-specific CAR T cell asset.Abstract Treatment options for ovarian cancer patients are limited, and a high unmet clinical need remains for targeted and long-lasting, efficient drugs. Genetically modified T cells expressing chimeric antigen receptors (CAR), are promising new drugs that can be directed towards a defined target and have shown efficient, as well as persisting, anti-tumor responses in many patients. We sought to develop novel CAR T cells targeting ovarian cancer and to assess these candidates preclinically. First, we identified potential CAR targets on ovarian cancer samples. We confirmed high and consistent expressions of the tumor-associated antigen FOLR1 on primary ovarian cancer samples. Subsequently, we designed a series of CAR T cell candidates against the identified target and demonstrated their functionality against ovarian cancer cell lines in vitro and in an in vivo xenograft model. Finally, we performed additional in vitro assays recapitulating immune suppressive mechanisms present in solid tumors and developed a process for the automated manufacturing of our CAR T cell candidate. These findings demonstrate the feasibility of anti-FOLR1 CAR T cells for ovarian cancer and potentially other FOLR1-expressing tumors.
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页数:21
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