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.

Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis

“…Another CAR-T platform-derived T cell with chimeric antigen receptor CE7R (CE7 + R T CM ) against the CE7 epitope of L1 cell adhesion molecule (L1-CAM) was investigated in a human ovarian cancer (SKOV3) xenograft PM model by Hong et al . [ 61 ]. This mouse model used IP injections of SKOV3 cells into NOD/scid-IL2Rγnull (NSG) mice, resulting in large volume malignant ascites.…”

“…However, T cells against L1-CAM could not prevent tumor recurrence due to the subsequent loss of L1-CAM expression in residual disease. Importantly, combination of CE7 + R T CM cells with CAR-T cells targeting other antigens may improve the efficiency of this treatment [ 61 , 62 ].…”

PET of Adoptively Transferred Chimeric Antigen Receptor T Cells with 89Zr-Oxine

“…One of the primary goals of this study was to provide proof-ofprinciple data for a clinical imaging platform using 89 Zr-oxine to track CAR T cells after adoptive transfer in patients. Our team has a longstanding interest in the locoregional delivery of CAR T cells for the treatment of brain tumors and other solid tumors (1,24,27,28,31). In our ongoing clinical trial (NCT02208362), we are evaluating the safety and antitumor effects of up to 200 · 10 6 IL13Ra2-CAR T cells for the treatment of recurrent glioblastoma via intratumoral and intraventricular routes of administration.…”

“…This second-generation IL13Ra2-CAR consists of a membrane-bound interleukin 13 (IL13) mutein with a mutation at the E13 site, an extracellular IgG4-Fc spacer containing L235E and N297Q point mutations (26), a CD4 transmembrane domain, and intracellular signaling domains of 4-1BB and CD3z. The lentiviral cassette also includes a truncated CD19 separated from the CAR via a T2A ribosomal skip sequence (27). The PSCA-CAR is identical to the IL13Ra2-CAR except that the extracellular tumor-targeting domain comprises a single-chain variable fragment derived from the humanized anti-PSCA antibody clone A11 (kindly provided by Drs.…”

CAR T‐cell therapy of solid tumors

“…Examples of novel targets include the type 1 insulin‐like growth factor receptor (IGF1R) and receptor tyrosine kinase‐like orphan receptor 1 (ROR1) for sarcoma 57 as well as the L1‐cell adhesion molecule (L1‐CAM) for ovarian cancer 58 . However, in all cases low‐level expression is still present on non‐malignant tissue, and thus caution must be used before moving these CARs into clinical trials.…”