T-Cell Engager Therapy in Prostate Cancer: Molecular Insights into a New Frontier in Immunotherapy

Abstract

Advanced prostate cancer (PCa) remains lethal despite standard therapies, and immune checkpoint inhibitors offer limited benefit in its "immune-cold" microenvironment. T-cell engagers (TCEs)-bispecific antibodies linking CD3 on T-cells to tumor-associated antigens (TAAs)-provide potent, MHC-independent cytotoxicity, overcoming a key resistance mechanism. While early PSMA-targeted TCEs established proof-of-concept, recent data, notably for six transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeting agents like Xaluritamig, demonstrate more substantial objective responses, highlighting progress through improved target selection and molecular design. This review synthesizes the evolving landscape of TCEs targeting PSMA, STEAP1, and DLL3 in PCa. We critically evaluate emerging clinical evidence, arguing that realizing the significant therapeutic potential of TCEs requires overcoming key challenges, including cytokine release syndrome (CRS), limited response durability, and antigen escape. We contend that future success hinges on sophisticated engineering strategies (e.g., affinity tuning, masking, multispecific constructs) and rationally designed combination therapies tailored to disease-specific hurdles. Strategies for toxicity mitigation, the crucial role of biomarker-driven patient selection, and potential integration with existing treatments are also discussed. Accumulating evidence supports TCEs becoming a new therapeutic pillar for advanced PCa, but achieving this demands sustained innovation focused on optimizing efficacy and safety. This review critically connects molecular engineering advancements with clinical realities and future imperatives.

Keywords: DLL3; PSMA; STEAP1; T-cell engager (TCE); bispecific antibody; combination therapy; cytokine release syndrome (CRS); immunotherapy; molecular engineering; prostate cancer.

Figure 1

Mechanisms of action for T-cell-engaging cancer immunotherapies. (a) Mechanism of action of Bispecific T-cell Engager (TCE). TCEs are engineered proteins, commonly bispecific antibodies, that physically link a T-cell to a cancer cell. One arm of the TCE (e.g., an anti-CD3 scFv) binds to the CD3 complex on T-cells, while the other arm (e.g., an anti-TAA scFv) binds to a tumor-associated antigen (TAA) expressed on the cancer cell surface. This forced interaction creates an immunological synapse, leading to potent T-cell activation and targeted, MHC-independent lysis of the cancer cell. BiTE^® (Bispecific T-cell Engager) molecules are a specific format of scFv-based TCEs, as illustrated. In prostate cancer, relevant TAAs include prostate-specific membrane antigen (PSMA), six transmembrane epithelial antigen of the prostate 1 (STEAP1), and delta-like ligand 3 (DLL3). The figure illustrates this concept with examples of TCEs developed for prostate cancer: Xaluritamig (AMG 509) targeting STEAP1; Pasotuxizumab (AMG 212), Acapatamab (AMG 160), and HPN424 targeting PSMA; and Tarlatamab (AMG 757) targeting DLL3, all inducing cancer cell death. (b) Mechanism of action of chimeric antigen receptor T-cell (CAR-T). CAR-T cells are T-cells that have been genetically modified to express a synthetic Chimeric Antigen Receptor (CAR) on their surface. The CAR typically consists of an extracellular antigen-binding domain (commonly a single-chain variable fragment—scFv) specific for a TAA on cancer cells, a transmembrane domain, and one or more intracellular signaling domains. This engineered receptor allows the CAR-T cell to directly recognize and bind to the TAA on cancer cells, independently of MHC presentation. Upon antigen engagement, the intracellular signaling domains activate the CAR-T cell, leading to targeted cytotoxic killing of the cancer cell. Created with BioRender.com. Abbreviations: APC, antigen-presenting Cell; BiTE, bispecific T-cell Engager; CAR, chimeric antigen receptor; CAR-T cell, chimeric antigen receptor T-cell; CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; scFv, single-chain variable fragment; TAA, tumor-associated antigen; TCE, T-cell engager.

Figure 2

Evolution of TCE formats.

Figure 3

Future directions and research priorities for advancing TCE therapy in PCa. The continued development and optimization of TCE therapy for PCa encompass several key research priorities. These include broadening the range of targetable antigens and expanding TCE therapeutic platforms; optimizing biomarker-driven patient selection to identify individuals most likely to benefit; enhancing the safety profile and mitigating treatment-related toxicities; developing rational combination strategies with other therapeutic modalities; advancing clinical development pathways and streamlining regulatory approval processes; exploring the utility of TCEs in earlier stages of the disease course; and understanding and overcoming mechanisms of resistance to TCE therapy. Each area represents a critical avenue for research to maximize the therapeutic potential of TCEs in PCa. Created with BioRender.com. Abbreviations: PCa, prostate cancer; TCE, T-cell engager.