L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.

Hao Hong,Stephen J Forman,Wen-Chung Chang,Paul Lin,Christine E Brown,Julie R Ostberg,Mark T Wakabayashi,Michael C Jensen,Saul J Priceman,Lihong Weng,Nupur Gangopadhyay

doi:10.1371/journal.pone.0146885

Hao Hong, Stephen J Forman + Show 9 more

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https://doi.org/10.1371/journal.pone.0146885

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Journal: PloS one	Publication Date: Jan 13, 2016
Citations: 37	License type: CC BY 4.0

Affiliation: City Of Hope National Medical Center

Abstract

New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.

Highlights

Ovarian cancer is the most lethal among all gynecological malignancies, and is responsible for the majority of gynecologic cancer deaths, with an estimated 14,030 deaths in 2013 [1]
The CE7 epitope of L1-cell adhesion molecule (L1-CAM) has been suggested to have tumor-restricted expression, as it has been detected on various tumor tissues and malignant cell lines, while many normal tissues do not express this antigen, and some non-malignant cells, like monocytes, express L1-CAM, but not its CE7 epitope [12]
We report here that the CE7-epitope of L1-CAM is a clinically relevant ovarian cancer-associated antigen as it is absent on normal ovaries, but highly expressed on established ovarian cancer cell lines, primary ovarian cancer tissues regardless of histological subtypes, and ovarian cancer cells derived from patient ascites

Summary

Introduction

Ovarian cancer is the most lethal among all gynecological malignancies, and is responsible for the majority of gynecologic cancer deaths, with an estimated 14,030 deaths in 2013 [1]. CARs are unique in endowing T cells with cytotoxic effector functions in an HLA-unrestrictive manner, and are not subject to tumor escape as a consequence of HLA downregulation (reviewed in [6]). This is important in ovarian cancer, where advanced disease is correlated with HLA downregulation [7]. Folate receptor-specific CAR-modified T cells have been tested in a phase I trial for recurrent ovarian cancer, but lack of T cell persistence and localization to the tumor, as well as lack of tumor regression suggests that the strategy requires further optimization [10]

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