title: L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.
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.
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ostberg
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Priceman
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Lihong
authors.initials: L
authors.lastname: Weng
authors.affiliation: Department of Gynecologic Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Gynecologic Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Wakabayashi
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology and Hematology & Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D017404:In Situ Hybridization, Fluorescence; D016086:Lentivirus / Q000235:genetics; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D039842:Neural Cell Adhesion Molecule L1; D011948:Receptors, Antigen, T-Cell; D017493:Leukocyte Common Antigens