Table 1.

Mitigation strategies to overcome the challenges associated with CD3+ bispecific T-cell redirection in cancer.

Challenges associated with CD3+ T-cell redirection in cancer	Resulting consequences	Mitigation strategies
Recruitment of pan T-cell populations	Activation/redirection of counterproductive CD3+ T-cell subsets (e.g., Tregs, naive/exhausted T cells, CD4+ T cells that secrete excessive amounts of cytokines)	Selective redirection of CD8+ cytotoxic T lymphocytes or CD8+ tissue-resident memory T cells
Cytokine release syndrome	Cytokine storm (life-threatening immune-related adverse event); dose-limiting; efficacy-limiting; narrow therapeutic window	Pharmacological intervention with IL-6R antagonists, TNF-α blockers, or corticosteroids; quantitative cytokine modelling to improve clinical dosing strategy; sequence-based antibody discovery to decouple cytokine release from anti-tumour activity
Expression of immune checkpoint molecules	T-cell dysfunction and exhaustion lead to suppressed anti-tumour immunity	Combination therapy with co-inhibitory receptor antagonists (e.g., anti-PD-1, anti-CTLA-4) or co-stimulatory receptor agonists (e.g., anti-4-1BB, anti-CD28)
Immunosuppressive tumour microenvironment	Hostile TME components (e.g., stromal cells, immune cells, cytokines, soluble factors) contribute to suppression of anti-tumour immune response	Combination therapy with IL-10 inhibitors, adenosine receptor antagonists, or VLA4 inhibitors; oncolytic adenoviruses armed with CD3 redirectors that target immunosuppressive stromal cells
Tumour antigen escape	Resistance to CD3+ T-cell redirection	Development of CD3+ T-cell redirectors with dual tumour antigen targeting
Lack of tumour antigen selectivity	On-target off-tumour toxicity	Protease-activated T-cell engagers; hemibodies; development of a multivalent avidity-based antigen-binding strategy to generate bispecific antibodies that selectively redirect T cells towards tumour cells while avoiding healthy tissue
Suboptimal potency	Diminished anti-tumour immune response	Consideration of target antigen copy number and size; modulation of binding domain positioning (e.g., epitope distance) and valency