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T-cell-engager cytokine-release network

A cytokine-network QSP model coupling drug exposure to resting, activated, cytotoxic, and exhausted T cells and to IL-6, IL-10, IL-1beta, IFN-gamma, and TNF-alpha dynamics.

A PK-Driven Quantitative Systems Pharmacology Model Predicts Cytokine Release Syndrome Severity Across T Cell-Activating Therapies via a Locked Cytokine Amplification Network ↗
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MODEL IN MOTION 18 sec

What changes after the modeled cytokine-rescue intervention?

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blinatumomab 28 ug/day continuous infusion through day 28

How do drug exposure and immune feedback shape T-cell activation and the timing and magnitude of cytokine release? Explore this biological starting configuration through T-cell agonist concentration, Activated T cells, IL-6, IFN-gamma, TNF-alpha.

0–672 hour

Scenario details

blinatumomab 28 ug/day continuous infusion through day 28

How do drug exposure and immune feedback shape T-cell activation and the timing and magnitude of cytokine release? Explore this biological starting configuration through T-cell agonist concentration, Activated T cells, IL-6, IFN-gamma, TNF-alpha.

Readouts

Drug concentration · nM
Drug concentration over the selected simulation window.
Activated t · cell/uL
Activated t over the selected simulation window.
Il 6 · pg/mL
Il 6 over the selected simulation window.
Ifn gamma · pg/mL
Ifn gamma over the selected simulation window.
Tnf alpha · pg/mL
Tnf alpha over the selected simulation window.

Study purpose

  • How do drug exposure and immune feedback shape T-cell activation and the timing and magnitude of cytokine release?

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Model parameter

Systemic clearance governing removal of modeled material from the relevant compartment.

L/h

Suggested: 1.05–3.15. You can explore beyond this range.

2.1 → —

T-cell activation EC50 at which the corresponding modeled effect reaches half of its maximum.

nM

Suggested: 0.5–1.5. You can explore beyond this range.

1 → —

Maximum activated T-cell concentration coefficient used by the released system of model equations.

cell/µL

Suggested: 2,500–7,500. You can explore beyond this range.

5000 → —

Macrophage activation EC50 at which the corresponding modeled effect reaches half of its maximum.

pg/mL

Suggested: 24.3–72.9. You can explore beyond this range.

48.6 → —

IC50 IL-10 at which the corresponding modeled process is inhibited by half.

pg/mL

Suggested: 25–75. You can explore beyond this range.

50 → —
Simulation time
h
h
672 → 168

Time between reported samples.

h
2 → 1

2 changes · Variation 1

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Biology

A continuous or initialized T-cell agonist exposure activates a resting-to-activated-to-cytotoxic and exhausted T-cell program. Cytotoxic T cells and an algebraic macrophage signal produce cytokines, while IL-10 suppresses pro-inflammatory production and an optional rescue switch changes IL-6 feedback behavior.

How do T-cell agonist exposure and immune feedback shape cytokine release?A continuous or initialized T-cell agonist exposure activates a resting-to-activated-to-cytotoxic and exhausted T-cell program. Cytotoxic T cells and an algebraic macrophage signal produce cytokines, while IL-10 suppresses pro-inflammatory production and an optional rescue switch changes IL-6 feedback behavior.BIOLOGY OVERVIEWHow do T-cell agonist exposure and immune feedback shape cytokine release?T-cell agonist input: Infusion or initialized comparatorT-cell agonistinputInfusion or initializedcomparatorAgonist exposure: Modeled concentration CdrugAgonist exposureModeled concentration CdrugT-cell program: Resting, activated, cytotoxic, exhaustedT-cell programResting, activated, cytotoxic,exhaustedMacrophage signal: Algebraic cytokine-production driveMacrophage signalAlgebraic cytokine-productiondrivePro-inflammatory cytokines: IL-6, IL-1β, IFN-γ and TNF-αPro-inflammatorycytokinesIL-6, IL-1β, IFN-γ and TNF-αIL-10 feedback: Suppresses modeled productionIL-10 feedbackSuppresses modeled productionOptional IL-6 feedback: Scenario switch includes rescue behaviorOptional IL-6feedbackScenario switch includesrescue behaviorPRIMARY READOUTSAgonist concentrationAgonist concentrationActivated T cellsActivated T cellsIL-6IL-6IFN-γIFN-γTNF-αTNF-α

Solid arrows show modeled movement or change; two-headed arrows show reversible exchange; dashed arrows show modulation without material transfer.

Model scope: CD19/CD3/CD28 and IL-6R binding, tissue compartments, dynamic macrophage-cell states, and tocilizumab PK or occupancy are not represented.

Modeled relationships (9)
  • T-cell agonist input → Agonist exposure: input (flow)
  • Agonist exposure → T-cell program: activation (modulation)
  • T-cell program → Pro-inflammatory cytokines: IFN-γ / TNF-α (production)
  • Pro-inflammatory cytokines → Macrophage signal: macrophage drive (modulation)
  • Macrophage signal → Pro-inflammatory cytokines: IL-6 / IL-1β (production)
  • Macrophage signal → IL-10 feedback: IL-10 (production)
  • IL-10 feedback → Pro-inflammatory cytokines: suppression (modulation)
  • Pro-inflammatory cytokines → Optional IL-6 feedback: IL-6 feedback (modulation)
  • Optional IL-6 feedback → Pro-inflammatory cytokines: switchable (modulation)

Modeled relationships: T-cell agonist input to Agonist exposure: input (flow); Agonist exposure to T-cell program: activation (modulation); T-cell program to Pro-inflammatory cytokines: IFN-γ / TNF-α (production); Pro-inflammatory cytokines to Macrophage signal: macrophage drive (modulation); Macrophage signal to Pro-inflammatory cytokines: IL-6 / IL-1β (production); Macrophage signal to IL-10 feedback: IL-10 (production); IL-10 feedback to Pro-inflammatory cytokines: suppression (modulation); Pro-inflammatory cytokines to Optional IL-6 feedback: IL-6 feedback (modulation); Optional IL-6 feedback to Pro-inflammatory cytokines: switchable (modulation).

Primary readouts: Agonist concentration; Activated T cells; IL-6; IFN-γ; TNF-α.

Model details

33 parameters · 11 states · 11 equations · 46 derived outputs

Classification & API access
Therapeutic
Blinatumomab and comparator T-cell agonists
Modality
Bispecific antibody / T-cell engager
Target
CD19, CD3, CD28, IL-6R / CD126
Disease / scope
Cytokine-release syndrome
ParameterDefaultUnitDescription
Systemic clearanceCL_L_h2.1L/hSystemic clearance governing removal of modeled material from the relevant compartment.
T-cell activation EC50EC50_act_nM1nMT-cell activation EC50 at which the corresponding modeled effect reaches half of its maximum.
Macrophage activation EC50EC50_mac_pg_ml48.6pg/mLMacrophage activation EC50 at which the corresponding modeled effect reaches half of its maximum.
IC50 IL-10IC50_IL10_pg_ml50pg/mLIC50 IL-10 at which the corresponding modeled process is inhibited by half.
IL-6 baselineIL6_baseline_pg_ml5pg/mLIL-6 baseline coefficient used by the released system of model equations.
Km fbKm_fb_pg_ml50pg/mLKm fb coefficient used by the released system of model equations.
Km recruitKm_recruit_pg_ml1000pg/mLKm recruit coefficient used by the released system of model equations.
Maximum activated T-cell concentrationTact_max_cells_ul5000cell/µLMaximum activated T-cell concentration coefficient used by the released system of model equations.
VcentralVcentral_L3.5LVcentral coefficient used by the released system of model equations.
Drugdrug_nmol_per_mg18.484288354898336nmol/mgDrug coefficient used by the released system of model equations.
Infusioninfusion_mg_h0.0011666666666666668mg/hInfusion coefficient used by the released system of model equations.
Kactkact_h0.081/hKact coefficient used by the released system of model equations.
Degradation rate IFNγkdeg_IFNg_h0.31/hDegradation rate IFNγ governing loss, degradation, or removal in the modeled biological process.
Degradation rate IL-10kdeg_IL10_h0.351/hDegradation rate IL-10 governing loss, degradation, or removal in the modeled biological process.
Degradation rate il1bkdeg_IL1b_h0.41/hDegradation rate il1b governing loss, degradation, or removal in the modeled biological process.
Degradation rate IL-6kdeg_IL6_h0.5191/hDegradation rate IL-6 governing loss, degradation, or removal in the modeled biological process.
Degradation rate TNFαkdeg_TNFa_h0.71/hDegradation rate TNFα governing loss, degradation, or removal in the modeled biological process.
Kdiffkdiff_h0.031/hKdiff coefficient used by the released system of model equations.
Kexhaustkexhaust_h0.0051/hKexhaust coefficient used by the released system of model equations.
Kfbkfb_h0.5281/hKfb coefficient used by the released system of model equations.
Kmac recruitkmac_recruit5—Kmac recruit coefficient used by the released system of model equations.
Kprod IFNγkprod_IFNg_pg_ml_h_per_cell_ul0.3(pg/mL/h)/(cell/µL)Kprod IFNγ governing production or formation in the modeled biological process.
Kprod IL-10 mackprod_IL10_mac_pg_ml_h_per_cell_ul0.01(pg/mL/h)/(cell/µL)Kprod IL-10 mac governing production or formation in the modeled biological process.
Kprod il1b mackprod_IL1b_mac_pg_ml_h_per_cell_ul0.002(pg/mL/h)/(cell/µL)Kprod il1b mac governing production or formation in the modeled biological process.
Kprod IL-6 mackprod_IL6_mac_pg_ml_h_per_cell_ul0.108(pg/mL/h)/(cell/µL)Kprod IL-6 mac governing production or formation in the modeled biological process.
Kprod TNFαkprod_TNFa_pg_ml_h_per_cell_ul0.15(pg/mL/h)/(cell/µL)Kprod TNFα governing production or formation in the modeled biological process.
Kprolifkprolif_h0.031/hKprolif coefficient used by the released system of model equations.
Macpoolmacpool_cells_ul_equiv465cell/µLMacpool coefficient used by the released system of model equations.
NnH1.5—N coefficient used by the released system of model equations.
Tocilizumab enabledtocilizumab_enabled0—Tocilizumab enabled coefficient used by the released system of model equations.
Tocilizumab starttocilizumab_start_h1000000000hTocilizumab start coefficient used by the released system of model equations.
Zero cytokinezero_cytokine_pg_ml0pg/mLZero cytokine coefficient used by the released system of model equations.
Zero drugzero_drug_nm0nMZero drug coefficient used by the released system of model equations.

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