T-cell-engaging antibodies for the treatment of solid tumors: challenges and opportunities

Abstract

Purpose of review: T-cell-engaging antibodies or T-cell engagers (TCEs) can connect a patient's cytotoxic T cells with cancer cells, leading to potent redirected lysis. Until very recently, only one TCE was approved, the CD19/CD3-bispecific blinatumomab. Many new TCEs in late-stage clinical development target various hematopoietic lineage markers like CD20, BCMA, or CD123. Although very compelling single-agent activity of TCEs was observed with various blood-borne cancers, therapy of solid tumor indications has thus far been less successful.

Recent findings: The approval in 2022 of the gp100 peptide-major histocompatibility complex (MHC)/CD3 bispecific TCE tebentafusp in uveal melanoma confirms that TCEs can also efficiently work against solid tumors. TCEs targeting peptide-MHC complexes will expand the target space for solid tumor therapy to intracellular targets. Likewise, early clinical trial data from TCEs targeting DLL3 in small cell lunger cancer showed promising antitumor activity. Various technologies for conditional activation of TCEs in the tumor microenvironment (TME) may expand the scope of conventional surface targets that suffer from a narrow therapeutic window. Finally, pharmacological enhancements for TCE therapies by engagement of certain costimulatory receptors and cytokines, or blockade of checkpoints, are showing promise.

Summary: Targeting peptide-MHC complexes, conditional TCE technologies, and concepts enhancing TCE-activated T cells are paving the way towards overcoming challenges associated with solid tumor therapy.

Box 1

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FIGURE 1

T-cell engager mechanism of action. T-cell engagers (TCEs) are therapeutic proteins that can connect a T cell with a tumor cell. Most TCEs have three domains: one domain binds to a component of the T-cell receptor, one domain binds to a tumor-associated antigen, and a third domain provides additional functionality like half-life-extension.

FIGURE 2

Conditionally active T-cell engager. Various approaches to conditionally active T-cell engagers are under investigation. Five of the six platforms depicted here are either in clinical development or expected to enter the clinic in 2022.