iCasp9 Safety-Switch Simulator (2D)

Engineered T-Cell Population

iCasp9 switch-positive fraction 80%

Baseline proliferation rate 40%/day

Dimerizer (rimiducid) dose 10 nM

No dimerizer in circulation

Live Readouts

Live engineered cells

Switch⁺ cleared

Time since dosing

— h

Legend

iCasp9 switch⁺ (drug-sensitive) Switch⁻ (drug-immune) Undergoing apoptosis

How it works

Cells engineered with the inducible caspase-9 (iCasp9) safety switch carry a fusion protein: a drug-binding FKBP domain welded to a truncated caspase-9. Alone it is inert. The small-molecule dimerizer rimiducid (AP1903) binds two FKBP domains at once, forcing two iCasp9 molecules together. That forced dimerization is enough to trigger caspase-9's protease activity without any upstream death receptor — it cleaves and activates caspase-3, and the cell commits to apoptosis within hours, letting clinicians pharmacologically clear a misbehaving cell product.

This 2D view tracks the same two-population model as the 3D simulator: switch-positive (transduced) count N_s and switch-negative (untransduced) count N_o, both growing logistically toward a shared carrying capacity K, with only N_s exposed to drug-driven killing:

dN_s/dt = r·N_s·(1 − N/K) − k(t)·N_s
dN_o/dt = r·N_o·(1 − N/K)          (drug-immune)

drug level:  D(t) = D0 · e^(−λ(t−t0))         λ = ln2 / t½
kill rate:   k(t) = k_max · D(t)ⁿ / (EC50ⁿ + D(t)ⁿ)   (Hill, n = 2)

iCasp9 fraction — the transduction efficiency of the cell product; only this share of cells ever carries the switch, so it caps how much of the population the drug can ever clear.
Proliferation rate — logistic growth toward the shared carrying capacity, competing against the drug's killing.
Dimerizer dose — the administered rimiducid level; kill rate follows Hill saturation kinetics, and circulating drug decays exponentially (t½ ≈ 2 h) after each dose.
Administer — injects the current dose at the current simulated time; switch⁺ cells flash red as instantaneous kill rate rises, then are cleared from the field as they die.
Field view — drag to pan, scroll/pinch to zoom the 2D cell field; the same instanced population is rendered as flat circles instead of a 3D cloud.

Real-world relevance: this exact mechanism underlies the FDA-approved iCasp9 safety switch used in haploidentical stem-cell transplant T-cells and is being engineered into next-generation CAR-T products as a pharmacologic emergency brake against severe cytokine release syndrome or graft-versus-host disease.

Population 60 / 220 Kill rate 0.00 /h

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