Abstract 6713: TICTE, A trispecific T-cell engager with immune checkpoint modulation for solid tumors

Abstract

Abstract Background: Bispecific T-cell engager (BiTE) is a targeted cancer immunotherapy which bridges T-cells to cancer cells, leading to activation of T-cells and killing cancer cells. While BiTEs have shown promising therapeutic efficacy in the treatment of hematological malignancies, therapeutic benefit of T-cell engagers are still in exploration for the treatment of solid tumors. Upregulation of immune checkpoints presents one of the major resistant mechanisms of the BiTE therapy. Here, we report a Trispecific Immune Check-point T-Cell Engager (TICTE) platform that targets both CD3 and PD-L1 simultaneously, which activates the T-cells as well as modulates the immune checkpoint blockade through the PD/PD-L1 axis, respectively. Our in vitro and in vivo studies demonstrate that the TICTEs induce dramatic and superior antitumor activity compared to its counterpart BiTE alone and the BiTE with anti-PD-L1 combination. These studies suggest that the TICTE (CD3xTAAxPD-L1), a single-agent with dual function of T-cell activation and immune checkpoint modulation, may provide an efficacious therapy to patients with solid tumors. Methods: Various TICTEs and BiTEs formats using the human IgG like architecture in three different TAA examples were generated. Their biophysical and biological activities were characterized. The cell binding activity and antigen density of cell lines were determined using flow cytometry. TDCC activity was measured using xCELLigence RTCA eSight system. In vitro efficacy was evaluated with multiple cancer cell lines and toxicity was evaluated with normal cell lines. The humanized xenograft models were utilized to investigate the TICTEs efficacy in vivo. Results: All TICTEs adopted their intended forms and showed robust biophysical properties. The TICTEs demonstrated the blockade activity of PD1/PD-L1 axis, as well preferentially targeted tumor cells expressed both TAAs and PD-L1. Large therapeutic windows were observed in three TAA (cMET, Her2 and Trop2) TICTEs. TICTEs showed a superior efficacy compared to counterpart BiTEs and combination of BiTE with a PD-L1 inhibitor in vitro and in vivo. Low cytokine release was observed compared to combination of BiTEs with a PD-L1 inhibitor, signifying the reduced risk of cytokine release syndrome (CRS) often associated with BiTE therapy. Conclusion: A single agent of the TICTE platform with unique biological property, superior efficacy and low cytokine release could represent an alternative combination immunotherapy for solid tumors. Citation Format: Xiufeng Wu, Xiaoshan Min, Yinan Wu, Lin Liu, Jing Zhou, Silvia Hudson, Shih-ping Chen, Jennifer Li, Will Draper, Subhadra Dash, Shidong Ma, Hang Chen, Zhulun Wang. TICTE, A trispecific T-cell engager with immune checkpoint modulation for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6713.