DEVELOPMENT OF CLAUDIN 18.2 TAC T CELLS FOR THE TREATMENT OF GASTRIC CANCER

Background The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit a safe and durable anti-tumor response. In preclinical models of cancer, TAC-engineered T cells effectively eradicate tumor cells in vitro and in vivo without TAC-related toxicities. TAC01-HER2, a first-in-class TAC T product targeting HER2 (ERBB2), has recently entered a phase I/II clinical trial in patients with HER2-positive solid tumors. Here, we present the development of a new TAC T product targeting Claudin 18.2 (CLDN18.2) to treat gastric cancer. CLDN18.2 belongs to a family of Claudin tight junction proteins whose expression is naturally exclusive to normal stomach. In gastric cancer cells, however, cell polarity is perturbed, leading to tumor-selective surface expression of CLDN18.2. Thus, CLDN18.2 is a preferred antigen for the specific targeting of tumor cells via TAC T cells. Methods The functionality of the CLDN18.2-TAC receptor was characterized using a variety of in vitro and in vivo assays. In vitro assays were based on flow cytometric analysis of TAC surface staining and cytokine release. Cytotoxicity was assessed via luminescence-based co-culture assays and real-time microscopy. In vivo studies examined the anti-tumor effect of TAC-engineered T-cells against established CLDN18.2 expressing tumor xenografts. Results T cells virally transduced with the CLDN18.2-TAC transgene demonstrated satisfactory surface expression of the TAC receptor and showed increased cytokine production when activated by CLDN18.2 expressing target cells in vitro. Secretion of IL2, IFNg and TNFa were comparable with cytokine levels produced by activated HER2-TAC T cells used as a positive control. In vitro cytotoxicity assays demonstrated a strong anti-CLDN18.2 response and killing of CLDN18.2 expressing target cell lines. No increases in cytokine levels and no cytotoxicity were observed in non-transduced T cells and CLDN18.2-TAC T cells co-cultured with CLDN18.2-negative target cells, indicating that the T cell response is specific to the CLDN18.2 antigen. Intravenous administration of CLDN18.2-TAC T cells in mice carrying CLDN18.2-positive tumor xenografts led to a sustained anti-tumor response. Conclusions The in vitro and in vivo data confirm strong and specific activity of CLDN18.2-targeted TAC T cells against CLDN18.2-expressing cancer cells and highlight the versatility of the TAC platform for therapeutic applications in solid tumors.