Bispecific T-cell engagers (
BiTEs) redirect endogenous T-cell populations to cells expressing tumour-associated
antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many
cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of
BiTE therapy. Furthermore, there is evidence that
BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the
BiTE therapy blinatumomab. To overcome these inadequate T-cell responses,
BiTEs may be combined with checkpoint inhibitors,
chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of
BiTEs in solid
malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination
therapies and a few other less-studied combinations.