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

January 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 0 1 Christine E. Brown 0 1 Julie R. Ostberg 0 1 Saul J. Priceman 0 1 Wen- Chung Chang 0 1 Lihong Weng 0 1 Paul Lin 1 Mark T. Wakabayashi 1 Michael C. Jensen 1 Stephen J. Forman 0 1 0 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, 2 Department of Gynecologic Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America, 3 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute , Seattle, Washington , United States of America 1 Editor: Nupur Gangopadhyay, University of Pittsburgh , UNITED STATES 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. - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the Hoeven Family Kidney Cancer Research Fund, and the NCI Cancer Center Support Grant (P30 CA33572). Competing Interests: MCJ reports receiving commercial research support from, has ownership interest (including patents) in, and is a consultant/ advisory board member for Juno Therapeutics, Inc. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. All other authors have no conflicts of interest to disclose. 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 ]. Despite improvements in surgical approaches and the refinements of frontline cytotoxic combinations over the past two decades, the majority of patients in advanced stages of disease at the time of diagnosis eventually succumb to tumor recurrence [ 2 ]. Thus, novel therapeutic approaches are desperately needed. With the growing recognition that ovarian tumors are immunogenic, and can be recognized and attacked by the immune system, various immune-based modalities have been actively explored to augment the efficacy of conventional therapies with the potential to prevent recurrence. Indeed, a number of peptide vaccines, dendritic cell vaccines and adoptive cell therapy strategies have been examined in clinical trials (reviewed in [ 3 ]). The recent clinical efficacy of chimeric antigen receptor (CAR)-based adoptive T cell immunotherapy in the treatment of subsets of patients with acute lymphoblastic leukemia, and chronic lymphocytic leukemia (reviewed in [ 4, 5 ]) has provided important support for extending this form of immunotherapy to the treatment a wider scope of malignancies. CARs are unique in endowing T cells with cytotoxic effector functions in an HLA-unrestrictive manner, and thus are not subject to tumor escape as a consequence of HLA downregulation (reviewed in [6]). This is particularly important in ovarian cancer, where advanced disease is correlated with HLA downregulation [ 7 ]. Indeed, efforts to design CAR T cells for the treatment of ovarian cancer has been the focus of several preclinical and clinical studies. Preclinical anti-tumor activity against ovarian tumors has been reported using T cells expressing CARs specific for mesothelin [ 8 ] and MUC16 (...truncated)