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Overcoming the challenges associated with CD3+ T-cell redirection in cancer

Abstract

The development of bispecific antibodies that redirect the cytotoxic activity of CD3+ T cells to tumours is a promising immunotherapeutic strategy for the treatment of haematological malignancies and solid cancers. Since the landmark FDA approval at the end of 2014 of the anti-CD3 × anti-CD19 bispecific antibody blinatumomab (Blincyto®) for the treatment of relapsed/refractory B-cell acute lymphoblastic leukaemia, ~100 clinical trials investigating the safety and efficacy of CD3+ bispecific T-cell redirectors for cancer have been initiated. However, despite early success, numerous challenges pertaining to CD3+ T-cell redirection in the context of cancer exist, including the recruitment of counterproductive CD3+ T-cell subsets, the release of systemic cytokines, the expansion of immune checkpoint molecules, the presence of an immunosuppressive tumour microenvironment, tumour antigen loss/escape, on-target off-tumour toxicity and suboptimal potency. The aim of the present review is to discuss novel approaches to overcome the key challenges associated with CD3+ bispecific T-cell redirection in order to achieve an optimal balance of anti-tumour activity and safety.

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Fig. 1: Mechanism of action of CD3+ bispecific T-cell redirection in cancer.
Fig. 2: Bispecific antibody constructs for CD3+ T-cell redirection.
Fig. 3: Next-generation anti-CD3 × anti-CD28 × anti-CD38 tri-specific T-cell-engaging antibody.

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Acknowledgements

The authors thank Bidisha Dasgupta and Anna Sberna for providing information regarding CD3+ T-cell redirection molecules in development.

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All authors (A.S., S.D. and I.S.G.) made a substantial contribution to all aspects of the preparation of this paper, including conceiving the work that led to the submission, drafting and revising the paper and approving the final version. First authorship is shared by A.S. and S.D.

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Correspondence to Iqbal S. Grewal.

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S.D. and I.S.G. are paid employees of the Janssen Pharmaceutical Companies of Johnson & Johnson and receive salary and other compensation.

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Singh, A., Dees, S. & Grewal, I.S. Overcoming the challenges associated with CD3+ T-cell redirection in cancer. Br J Cancer (2021). https://doi.org/10.1038/s41416-020-01225-5

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