Understanding heterogeneous responses to T cell engagers: Binding characteristics and dosing thresholds determine cytotoxic efficacy
Simmons, T.; Kulkarni, A.; Rodriguez, F.; Dahlberg, D.; Rozumalski, L.; Kaveh, K.; Wagner, C. R.; Leder, K.; Foo, J.
Show abstract
Therapeutic efficacy of T cell engagers (TE) varies widely across individuals, but the basis for this heterogeneity remains poorly understood. Here, we integrate in vitro experiments of tumor-immune response to TEs with a mechanistic modeling framework, to investigate sources of response variability across T cell donors and TE constructs. We focus on novel multivalent bispecific T cell engager design that is currently in development. We identify parameter regimes that accurately recapitulate dose-response behaviors across T cell donors and doses, and perform cross-validation studies that demonstrate the models predictive accuracy. We find that variability in therapy efficacy is governed by the relationship between binding affinity and dose. When dose exceeds the binding affinity, responses are relatively robust across donors; when dose is below the binding affinity, responses are more donor dependent. At smaller doses, the TE-specific shape characteristics of the tumor-binding dose response, its steepness in particular, is a key marker of therapy efficacy. More generally, our integrated modeling and experimental framework offers insights and tools that are applicable to other bispecific T-cell engagers, and provides a quantitative foundation for the systematic, in silico optimization of TE design and dosing strategies.
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