Strategies for clinical dose optimization of T cell-engaging therapies in oncology. Issue 1 (31st December 2023)

• Record Type: Journal Article
• Authors: Ball, Kathryn; Dovedi, Simon J; Vajjah, Pavan; Phipps, Alex
• Is Part Of: MAbs. Volume 15:Issue 1(2023)
• Publication Date: 2023-12-31
• Subjects: T-cell engager -- immune oncology -- bispecific antibody -- dose optimization -- quantitative clinical pharmacology -- translational PK/PD modeling -- quantitative systems pharmacology; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2023.2181016
• Languages: English
• ISSNs: 1942-0862

Abstract

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.