AI-powered design of armored CAR-T cells with cytokine/chemokine expression for enhanced solid tumor efficacy, including IL-12, IL-15, IL-18, and IL-7 armoring strategies.
The Armored CAR-T Design Agent provides AI-assisted design of next-generation armored CAR-T cells engineered to express cytokines, chemokines, or other enhancing factors. These armored T cells overcome solid tumor challenges including immunosuppressive TME, poor trafficking, and T cell exhaustion, with recent clinical success in lymphoma (IL-18) and ongoing trials with IL-12, IL-15, and IL-7.
Armoring Payload Selection: Choose optimal cytokines for tumor type.
Expression Level Optimization: Balance efficacy vs toxicity.
Inducible System Design: Engineer regulated expression systems.
Safety Switch Integration: Design kill switches and controls.
Construct Optimization: Optimize transgene configuration.
Efficacy Prediction: Predict enhanced tumor killing.
| Cytokine | Mechanism | Clinical Status | Tumor Types |
|---|---|---|---|
| IL-12 | Th1 polarization, IFN-gamma | Phase I/II | Solid tumors |
| IL-15 | T/NK persistence | Phase I/II | Hematologic, solid |
| IL-18 | Inflammasome, IFN-gamma | Phase I (promising) | Lymphoma |
| IL-7 | T cell survival | Phase I | Multiple |
| IL-21 | T cell proliferation | Preclinical | Multiple |
| CCL19/21 | T cell trafficking | Preclinical | Solid tumors |
| Component | Options | Consideration |
|---|---|---|
| Promoter | EF1a, PGK, CAG, NFAT-inducible | Expression level/timing |
| Signal Peptide | Native, IL-2ss, IgK | Secretion efficiency |
| Cytokine | Membrane-bound vs secreted | Local vs systemic |
| Linker | T2A, P2A, IRES | Co-expression efficiency |
| Kill Switch | iCasp9, HSV-TK, CD20 | Safety control |
| Position | Before/after CAR | Expression balance |
Input: Target tumor type, TME characteristics, CAR design.
Payload Selection: Rank armoring strategies for tumor context.
Expression Design: Optimize promoter, levels, regulation.
Safety Engineering: Add appropriate control switches.
Construct Assembly: Generate optimized DNA sequence.
Efficacy Prediction: Model enhanced killing and persistence.
Output: Optimized armored CAR construct with annotations.
User: "Design an armored CAR-T for pancreatic cancer targeting mesothelin with IL-12 armoring for TME remodeling."
Agent Action:
python3 Skills/Immunology_Vaccines/Armored_CART_Design_Agent/design_armored_cart.py \
--car_target mesothelin \
--tumor_type pancreatic \
--armoring_payload IL-12 \
--expression_system NFAT_inducible \
--safety_switch iCasp9 \
--backbone lentiviral \
--optimize_codon human \
--output armored_cart_design/
| Output | Description | Format |
|---|---|---|
| Construct Sequence | Full transgene DNA | .fasta, .gb |
| Construct Map | Annotated visualization | .png, .pdf |
| Expression Model | Predicted levels | .json |
| Safety Analysis | Risk assessment | .json |
| Manufacturing Guide | Production recommendations | .md |
| Predicted Efficacy | Tumor killing model | .json |
| Aspect | Design Choice | Rationale |
|---|---|---|
| Configuration | Tethered IL-12 (p70) | Localized, reduced toxicity |
| Expression | NFAT-inducible | Activation-dependent |
| Dose | Low-level expression | Safety optimization |
| Combination | With PD-1 knockout | Enhanced activity |
| Aspect | Design Choice | Rationale |
|---|---|---|
| Configuration | Secreted mature IL-18 | Enhanced IFN-gamma |
| Expression | Constitutive or inducible | Context-dependent |
| Clinical Results | Lymphoma responses | Validated approach |
| Combination | With IL-21 | Synergistic |
| Aspect | Design Choice | Rationale |
|---|---|---|
| Configuration | Membrane-tethered IL-15/IL-15Ra | Cis-presentation |
| Expression | Constitutive moderate | Persistence without toxicity |
| Benefit | Reduced IL-2 dependence | Manufacturing advantage |
| Safety | Lower CRS risk | Clinical benefit |
Payload Selection:
Expression Optimization:
Safety Prediction:
| Risk | Mitigation | Implementation |
|---|---|---|
| Cytokine storm | Inducible expression | NFAT promoter |
| Systemic toxicity | Membrane tethering | Localized effect |
| Uncontrolled proliferation | Kill switch | iCasp9 |
| On-target off-tumor | Regulatable CAR | Logic gates |
| Trial | Armoring | Target | Cancer | Status |
|---|---|---|---|---|
| NCT03721068 | IL-18 | CD19 | Lymphoma | Phase I (positive) |
| NCT04119024 | IL-12 | GD2 | Neuroblastoma | Phase I |
| NCT03932565 | IL-15/21 | CD19 | B-ALL | Phase I |
| Multiple | IL-7/CCL19 | Various | Solid | Preclinical |
| Aspect | Armored CAR Challenge | Solution |
|---|---|---|
| Vector Size | Larger transgene | Optimize construct |
| Transduction | Lower efficiency | Increase MOI |
| Expansion | Cytokine effects | Tune expression |
| Characterization | Complex phenotype | Enhanced QC |
| Mechanism | Cytokine | Effect |
|---|---|---|
| Persistence | IL-15, IL-7 | Longer survival |
| TME Remodeling | IL-12 | M2→M1, DC activation |
| Bystander Killing | IL-18 | Enhanced IFN-gamma |
| Trafficking | CCL19/21 | T cell recruitment |
| Anti-exhaustion | IL-21 | Stem-like maintenance |
AI Group - Biomedical AI Platform