T cell engagers: expanding horizons in oncology and beyond

Abstract

Background/introduction: T cell engagers (TCEs) are engineered immunotherapeutic molecules designed to direct the body's immune system against tumour or infected cells by bridging T cells and their targets, triggering potent cytotoxic responses. Over the past decade, TCE-based therapies have gained momentum in oncology, resulting in several FDA approvals for haematologic malignancies and showing growing promise in solid tumours.

Objective: This review elaborates on TCE mechanisms of action, emphasising their ability to activate T cells, target tumour antigens, and modulate the tumour microenvironment.

Methods/results: We also delve into the clinical outcomes demonstrating TCE efficacy, alongside challenges such as cytokine release syndrome, antigen heterogeneity, and short half-lives. Recent advances in TCE design have incorporated multispecific constructs and conditional activation strategies and expansion in target molecules has enabled broadening applications to non-oncology indications like autoimmune and infectious diseases. Moreover, the use of artificial intelligence (AI) has also accelerated TCE discovery by identifying favourable epitope interactions, reducing immunogenicity risks, and enhancing overall design efficiency.

Conclusions: Looking further, these advances open up a new era to redefine success for TCEs in both cancer and beyond, offering hope for more effective, safer immunotherapies.

Fig. 1. Major conventional and conditionally active T cell engager formats.

a 1+1 format comprising two single-chain variable fragments (scFvs) connected by a flexible linker. b Half-life extended 1+1 format incorporating an Fc region to prolong systemic circulation. c 2+1 format containing two tumour-binding domains and one T cell-binding domain. Alternatively, this structure could be trispecific, with each domain recognising a distinct antigen. d TCE targeting intracellular antigens, consisting of an anti-CD3 arm fused to a T cell receptor (TCR)-based domain. e Protease-activated TCE in which a masking peptide containing protease cleavage sites conceals the antigen-binding domain, enabling conditional activation. f pH-sensitive TCE with the antigen-binding domain capped by pH-responsive physiological chemicals, allowing selective activation in the acidic tumour microenvironment. g Split TCE design where the variable light (VL) and variable heavy (VH) chains of the anti-CD3 domain are separated and fused to two distinct tumour-targeting antibodies, requiring co-localisation for full activity.

Fig. 2. T cell engager target profiles in clinical development for cancer therapy.

More than 200 TCE antibodies are currently in clinical trials. Approximately half of the bispecific antibodies are targeted to CD20, CD19 and BCMA. Nonetheless, newer targets have also entered early-phase clinical trials.