Objectives: Bispecific T cell engagers (bsTCEs) are a promising class of cancer immunotherapy. One pivotal challenge in early clinical trials bsTCEs is the selection First-In-Human (FIH) dose, due to their narrow therapeutic windows. Given limited translatability most preclinical animal models, vitro culture systems more commonly used assess bsTCE potency for FIH dose. However, protocol variabilities between assays make it difficult comprehensively evaluate potency. Variations experimental...

Effector T cells need to form immunological synapses (IS) with recognized target elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most cell-based cancer immunotherapies. However, dynamics at cell population level, primary driver pharmacodynamics many immunotherapies, remains poorly defined. Using classic immunotherapy CD3/CD19 bispecific engager (BiTE) as our model system, we integrate experimental and theoretical approaches investigate their...

Lipid droplets (LD) are affected in multiple human disorders. These highly dynamic organelles involved many cellular roles. While their intracellular dispersion is crucial to ensure function and other organelles-contact, underlying mechanisms still unclear. Here we show that Spastin, one of the major proteins Hereditary Spastic Paraplegia (HSP), controls LD dispersion. Spastin depletion zebrafish affects metabolic properties organelle dynamics. functions ensured by a conserved complex set...

Biosensors that report endogenous protein activity in vivo can be based on environment-sensing fluorescent dyes. The dyes attached to reagents bind selectively a specific conformation of the targeted protein, such binding leads fluorescence change. Dyes are sufficiently bright for use at low, nonperturbing intracellular concentrations typically undergo changes intensity rather than shifts excitation or emission maxima would enable precise quantitation through ratiometric imaging. We here...

Abstract Enrolling patients in immunotherapy clinical trials is becoming increasingly competitive. Virtual can help investigators answer key questions despite this. For example, pembrolizumab the recommended first‐line treatment for non‐small cell lung cancer (NSCLC) with no driver alterations and a programmed death ligand 1 (PD‐L1) Tumor Proportion Score ≥50%. Salvage therapies relapsed/refractory are limited. Retrospective studies suggest that subset of may benefit from beyond progression;...

Bispecific T-cell engagers (bsTCEs) have emerged as a promising class of cancer immunotherapy. BsTCEs enable physical connections between T cells and tumor to enhance activity against cancer. Despite several marketing approvals, the development bsTCEs remains challenging, especially at early clinical translational stages. The intricate design makes their pharmacologic effects safety profiles highly dependent on patient's immunological conditions. Such context-dependent pharmacology...

Despite the success in B-cell malignancies, chimeric antigen receptor (CAR)-T cell therapies have not yet demonstrated consistent efficacy across all patients and tumor types, particularly against solid tumors. Higher rates of T exhaustion are associated with inferior clinical outcomes following CAR-T therapy, which is prevalent may originate from persistent chronic stimulation by cells that resist and/or evade cell-mediated killing. We exploited a classic negative feedback model (incoherent...

Despite their use to treat cancers with specific genetic aberrations, targeted therapies elicit heterogeneous responses. Sources of variability are critical therapy drug development, yet there exists no method discern relative contribution response heterogeneity.We HER2-amplified breast cancer and two agents, neratinib lapatinib, develop a platform for dissecting sources in patient response. The comprises four components: pharmacokinetics, tumor burden growth kinetics, clonal composition,...

Abstract Effector T cells form immunological synapses (IS) with recognized target to elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most cell-based cancer immunotherapies. However, dynamics at cell population level, primary driver pharmacodynamics many immunotherapies, remains poorly defined. With classic immunotherapy CD3/CD19 bispecific engager (BiTE) as a model system, we integrate experimental and theoretical approaches investigate their...

Predator-prey theory is commonly used to describe tumor growth in the presence of selective pressure from adaptive immune system. These interactions are mediated by immunopeptidome (what "shows" body) and T-cell receptor (TCR) repertoire (how well body "sees" cancer cells). The comprises neoantigens which can be gained lost throughout tumorigenesis treatment. Heterogeneity predictive poor response immunotherapy some types, suggesting that TCR unable support a fully polyclonal against every...

ABSTRACT Predator-prey theory is commonly used to approximately describe tumor growth in the presence of selective pressure from adaptive immune system. These interactions are mediated by immunopeptidome (what “shows” body) and T-cell receptor (TCR) repertoire (how well body “sees” cancer cells). Importantly, both T cell populations dynamic competition with each other their fraternal lineages. In particular, comprises neoantigens which can be gained lost throughout tumorigenesis treatment....

ABSTRACT Background Pembrolizumab is the recommended first-line treatment for non-small cell lung cancer (NSCLC) with no driver alterations and PD-L1 Tumor Proportion Score (TPS) ≥ 50%. Salvage therapies patients who develop resistance in this setting are limited. Several retrospective studies have highlighted a subset of benefit from pembrolizumab beyond progression (TBP), but these results yet to be validated rigorous prospective study. Methods Due heterogeneity within-patient responses...