T-cell engager toxicity in clinical phase trials; A systematic review and meta-analysis

Engineered to activate a patient's own immune response, T Cell Engagers (TCEs) are positioned to mediate T cell directed cytotoxicity through targeted engagement of a tumour antigen. Despite their attractive properties TCE therapies have yet to be widely used in the treatment of solid tumours with several obstacles that include adverse toxicity profiles. This systematic review and meta-analysis assessed the toxicity associated with T-cell engagers (TCEs) in the treatment of solid tumours. Papers were sourced from MEDLINE, Cochrane Library, CINHL, EMBASE, Web of Knowledge, Scopus. Prevalence data from the identified primary studies was pooled using an inverse variance method with a restricted maximum likelihood estimator. Freeman-Tukey double arcsine transformation to determine toxicity prevalence and confidence intervals. A total of 1147 publications were identified of which 30 were included for systematic review. Toxicity profiles from 17 TCEs, comprising 9 different ligands that utilised the CD3, CD40, CD28 or CD64 signalling pathways were characterised in this study. Of these studies, 21 publications were included for meta-analysis, focussing on four TCEs: catumaxomab, ertumaxomab, tebentafusb, and MDX-H210. Meta-analysis found that the most prevalent toxicities were gastrointestinal and inflammatory. Subgroup analysis revealed that Gastrointestinal toxicity (GI) toxicity was independent of tumour type or ligand. Cytokine Release Syndrome (CRS) is potentially being under-reported due to challenges of differentiation of CRS from other inflammatory mediated constituent symptoms, although Fc-independent TCEs were linked to lower inflammatory toxicity. The review highlights TCE-dependent toxicity profiles and highlights key features that may ameliorate TCE tolerance.