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Review
. 2023 Jan-Dec;15(1):2181016.
doi: 10.1080/19420862.2023.2181016.

Strategies for clinical dose optimization of T cell-engaging therapies in oncology

Kathryn Ball  1 , Simon J Dovedi  2 , Pavan Vajjah  1 , Alex Phipps  1
Affiliations
Review

Strategies for clinical dose optimization of T cell-engaging therapies in oncology

Kathryn Ball et al. MAbs. 2023 Jan-Dec.

Abstract

Innovative approaches in the design of T cell-engaging (TCE) molecules are ushering in a new wave of promising immunotherapies for the treatment of cancer. Their mechanism of action, which generates an in trans interaction to create a synthetic immune synapse, leads to complex and interconnected relationships between the exposure, efficacy, and toxicity of these drugs. Challenges thus arise when designing optimal clinical dose regimens for TCEs with narrow therapeutic windows, with a variety of dosing strategies being evaluated to mitigate key side effects such as cytokine release syndrome, neurotoxicity, and on-target off-tumor toxicities. This review evaluates the current approaches to dose optimization throughout the preclinical and clinical development of TCEs, along with perspectives for improvement of these strategies. Quantitative approaches used to aid the understanding of dose-exposure-response relationships are highlighted, along with opportunities to guide the rational design of next-generation TCE molecules, and optimize their dose regimens in patients.

Keywords: T-cell engager; bispecific antibody; dose optimization; immune oncology; quantitative clinical pharmacology; quantitative systems pharmacology; translational PK/PD modeling.

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Conflict of interest statement

The authors report there are no competing interests to declare.

Figures

Figure 1.
Figure 1.
Schematic representation of the relationship between dose, exposure and pharmacodynamic response for the TCE, and for the trimeric complex (“trimer”) formed upon dual target engagement of TCE with CD3 and TAA.
Figure 2.
Figure 2.
Schematic representation of the impact of fixed and step-up dose regimens on drug concentration versus time profiles (solid black lines). Dose level and frequency is indicated by arrows, and the maximum desired peak concentration is indicated by the dashed red lines.
Figure 3.
Figure 3.
Comparison of different clinical dosing strategies for TCEs.
See this image and copyright information in PMC

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