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

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.

Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development

“…CRS is a systemic inflammatory response associated with a transient but massive release of pro-inflammatory cytokines resulting from T-cell activation. 88 BTCEs-related transient CRS mostly occurs during the first cycle of treatment (e.g., 1-3 weeks), 89,90 and gradual dose increase (i.e., step-up dosing) has been shown to mitigate its risk and severity. 84,87,88 It has been hypothesized that a gradual increase in concentration-conceptually, better achieved with s.c. administration, given its typical lower peak-to-trough ratio compared with i.v.-allows for a gradual "priming" of the immune system 88 and slow "debulking" of the tumor 91 before reaching an active dose.…”

“…An important on‐target adverse effect of BTCEs is CRS, which may be associated with life‐threatening symptoms. CRS is a systemic inflammatory response associated with a transient but massive release of pro‐inflammatory cytokines resulting from T‐cell activation 88 . BTCEs‐related transient CRS mostly occurs during the first cycle of treatment (e.g., 1–3 weeks), 89,90 and gradual dose increase (i.e., step‐up dosing) has been shown to mitigate its risk and severity 84,87,88 .…”

Teclistamab: Mechanism of action, clinical, and translational science

“…With evolving clinical experience, different effector-to-tumor cell ratio, more relevant T-cell assay using whole blood, and higher percentage of maximal effect (such as EC 50 ) could be used for an improved starting dose selection that is both safe and closer to the efficacious dose range. 23 Although the MajesTEC-1 study began at a conservative starting dose that was thousands-fold lower than the active doses, several approaches were used to shorten the time to escalate to active doses and maximize patients' clinical benefit. Two-fold dose escalation increment and single patient dose escalation in early cohorts minimized the number of patients exposed to subtherapeutic levels of teclistamab.…”

“…As a novel modality, a conservative approach based on the lowest EC 20 was used for starting dose determination. With evolving clinical experience, different effector‐to‐tumor cell ratio, more relevant T‐cell assay using whole blood, and higher percentage of maximal effect (such as EC 50 ) could be used for an improved starting dose selection that is both safe and closer to the efficacious dose range 23 . Although the MajesTEC‐1 study began at a conservative starting dose that was thousands‐fold lower than the active doses, several approaches were used to shorten the time to escalate to active doses and maximize patients' clinical benefit.…”

Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta‐Analysis

“…14 This strategy enables gradual priming of the immune system, mitigating the development of early and uncontrollable immune responses and ultimately CRS, in response to these drugs. 15 CRS is typically manifested with varying severity of fever, hypotension, hypoxia, and respiratory complications, that may be accompanied with multi-organ dysfunctions. 13 The CRS severity grading systems based on diagnostic criteria (such as American Society for Transplantation and Cellular Therapy (ASTCT)) 16 provide recommendations for grading.…”