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T cell-engaging therapies — BiTEs and beyond

Abstract

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.

Key points

  • The first-in-class bispecific T cell engager (BiTE), blinatumomab, has been approved for the treatment of patients with relapsed and/or refractory B cell-precursor acute lymphoblastic leukaemia (B-ALL).

  • Blinatumomab is also the first targeted immunotherapy approved specifically for the treatment of minimal residual disease in patients with B-ALL who are in haematological complete remission.

  • BiTE therapy might be effective not only in a small group of B cell malignancies, but also in a broader range of malignancies, including common types of solid cancer.

  • An understanding of the mechanisms of resistance and immune escape might pave the way for innovative drug development with the intention to mitigate toxicity and to enhance efficacy.

  • New constructs, 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), have been developed to integrate various immune functions into one therapeutic approach or cellular vector, thereby enhancing anticancer activity without substantially increasing the risk of immune-related adverse effects.

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Fig. 1: BiTE antibodies — mechanisms of action and resistance, and strategies to restore T cell function.
Fig. 2: Schematic overview of novel killer cell-engaging constructs for antibody-based or TCR-based tumour cell targeting.

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Acknowledgements

The authors particularly thank A. Wenzl for graphic design support and M. Goebeler for his thorough reading and editing of the manuscript.

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Nature Reviews Clinical Oncology thanks D. Vallera, E. Jabbour and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Correspondence to Ralf C. Bargou.

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M.-E.G. has consulted for and received honoraria from Gemoab. R.C.B. has consulted for and received honoraria from Amgen, Cellex and Gemoab. R.C.B. is patent holder for blinatumomab, from which he receives royalty payments. M.-E.G and R.C.B. have both received honoraria for serving on the advisory boards of Amgen, Bristol-Myers Squibb, Gemoab, Novartis and Roche.

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Goebeler, ME., Bargou, R.C. T cell-engaging therapies — BiTEs and beyond. Nat Rev Clin Oncol 17, 418–434 (2020). https://doi.org/10.1038/s41571-020-0347-5

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