Immuno-oncology approaches have entered clinical practice, with tremendous progress
particularly in the field of T cell-engaging therapies over the past decade. Herein,
we provide an overview of the current status of bispecific T cell engager (BiTE) therapy,
considering the unprecedented new indication for such therapy in combating minimal
(or measurable) residual disease in patients with acute lymphoblastic leukaemia, and
the development of novel approaches based on this concept. Key aspects that we discuss
include the current clinical data, challenges relating to treatment administration
and patient monitoring, toxicities and resistance to treatment, and novel strategies
to overcome these hurdles as well as to broaden the indications for BiTE therapy,
particularly to common solid cancers. Elucidation of mechanisms of resistance and
immune escape and new technologies used in drug development pave the way for new and
more-effective therapies and rational combinatorial approaches. In particular, we
highlight novel therapeutic agents, such as bifunctional checkpoint-inhibitory T cell
engagers (CiTEs), simultaneous multiple interaction T cell engagers (SMITEs), trispecific
killer engagers (TriKEs) and BiTE-expressing chimeric antigen receptor (CAR) T cells
(CART.BiTE cells), designed to integrate various immune functions into one molecule
or a single cellular vector and thereby enhance efficacy without compromising safety.
We also discuss the targeting of intracellular tumour-associated epitopes using bispecific
constructs with T cell receptor (TCR)-derived, rather than an antibody-based, antigen-recognition
domains, termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs), which
might broaden the armamentarium of T cell-engaging therapies.