Abstract 3598: A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager

Abstract TCR-engineered T (TCR-T) cells and TCR-anti-CD3 bispecific T-cell engagers (TCEs) are potent TCR-based therapeutic agents with distinct advantages and limitations in tumor treatment. TCR-T cells offer durable persistence within patients but necessitate personalized manufacturing and lack the capacity to harness bystander T cells. Conversely, TCEs are readily available as "off-the-shelf" products and can recruit bystander T cells, yet they exhibit a shorter lifespan. In our study, we sought to merge the merits of both approaches by engineering T cells to secrete a TCR-anti-CD3 TCE specific for alpha fetoprotein (AFP), a tumor-associated antigen abundantly expressed in hepatocellular carcinoma (HCC). We initially identified a TCR with specificity for the AFP158-166 peptide bound to HLA-A*02: 01 and enhanced its affinity to picomolar via phage display. To facilitate efficient secretion by T cells, we adapted the high-affinity TCR to a single-chain format (scTCR) and fused it with a CD3-specific single-chain antibody fragment (scAFP-TCE). Our findings demonstrated that scAFP-TCE effectively redirected bystander T cells to engage in the lysis of HCC cells. Moreover, scAFP-TCE could be secreted by T cells transduced with lentiviral particles encoding the TCE gene. These transduced T cells exhibited potent antitumor activity both independently and by enlisting bystander T cells. This innovative T cell strategy, combining the bystander-recruiting ability of fusion proteins with the durable persistence seen in T cell therapy after a single infusion, presents a promising alternative to conventional TCR-based therapeutic agents. We anticipate that this novel approach may hold substantial potential for enhancing HCC treatment and expanding the scope of TCR-based immunotherapies. Citation Format: Hanli Sun, Jiao Huang, Kai Zhan, Wanli Wu, Xianqing Tang, Min Liu, Shanshan Guo, Hongjun Zheng, Yingjie Huang, Shi Zhong. A new strategy for T cell therapy: T cells secreting TCR anti-CD3 bispecific T-cell engager 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 (6Suppl): Abstract nr 3598.