Below is the complete, end-to-end Tier I–V sequencing and escalation logic for PRISM, written in regulatory-grade, FDA-appropriate language, and structured so it can be used as:

• an IND Module 2/2.7 appendix
• a DSMB operating manual
• a clinical decision algorithm

No claims, no ethnomedical assertions, no operational extraction steps.

PRISM TIER I–V SEQUENCING & ESCALATION LOGIC

Synergistic Compatibility Framework (SCF)

Mechanistic · Biomarker-Gated · Safety-First

EXECUTIVE PRINCIPLE

Immune restoration is hierarchical.

Higher tiers cannot succeed unless lower tiers are stabilized.

Escalation is earned biologically, not scheduled temporally.

PRISM enforces five mandatory tiers, each with:

• Defined scope
• Entry criteria
• Exit criteria
• Escalation rules
• Rollback conditions

TIER I — METABOLIC & REDOX STABILITY

(Foundational permissivity tier)

Biological Scope

• Cellular energy availability
• Redox balance
• Mitochondrial competence

Why This Tier Exists

Immune regeneration is energy-intensive.

If Tier I is unstable, all downstream signals misfire.

Entry Condition

• Evidence of chronic illness, immune collapse, or failed recovery

Tier I GO Criteria

All required:

• No uncontrolled metabolic derangement
• No acute oxidative stress state
• Clinical stability (no cachexia, shock, organ failure)

Tier I NO-GO / HOLD Triggers

• Progressive metabolic decline
• Acute catabolic state
• ICU-level instability

Escalation Rule

Tier II may not begin until Tier I is stable.

No immune-directed intervention proceeds otherwise.

TIER II — INFLAMMATORY & CYTOKINE CONTROL

(Signal clarity tier)

Biological Scope

• Baseline cytokine noise
• Innate immune overactivation
• Systemic inflammatory tone

Why This Tier Exists

Inflammation corrupts biological signals.

Restorative signals delivered here are misinterpreted.

Tier II GO Criteria

All required:

• No uncontrolled inflammatory markers
• No active cytokine storm or flare
• Stable innate immune profile

Tier II NO-GO / ROLLBACK Triggers

• Rising IL-6 / TNF-α
• New inflammatory syndrome
• Autoimmune flare

Escalation Rule

No Tier III, IV, or V intervention is interpretable if Tier II is active.

Inflammation must be controlled before structure or lineage is addressed.

TIER III — STRUCTURAL / STROMAL NICHE READINESS

(Architectural tier)

Primary domain of SGSNS-01

Biological Scope

• Bone marrow stromal integrity
• Lymphoid ECM elasticity
• Progenitor niche viability

Why This Tier Exists

Immune cells regenerate in physical niches.

If the niche is damaged, identity cannot be restored.

Tier III GO Criteria

All required:

• Evidence of niche stabilization or improvement
• No progressive fibrosis signal
• Stromal viability maintained
• No immune proliferation induced

Tier III NO-GO / HOLD Triggers

• Fibrotic progression
• Structural collapse markers
• Any immune activation during conditioning

Escalation Rule

Tier V (IL-7) is absolutely prohibited unless Tier III exit criteria are met.

This is the most common historical failure point.

TIER IV — EPIGENOMIC & LINEAGE READINESS

(Signal interpretation tier)

Biological Scope

• Lineage gene accessibility
• Exhaustion program dominance
• Receptor fidelity (e.g., CD127 preservation)

Why This Tier Exists

Signals can be delivered correctly but decoded incorrectly if epigenomic readiness is absent.

Tier IV GO Criteria

All required:

• No dominant exhaustion phenotype
• Receptor expression preserved
• No lineage mis-programming signals

Tier IV NO-GO / HOLD Triggers

• Rapid exhaustion marker emergence
• Lineage skewing
• Loss of signal receptor fidelity

Escalation Rule

Tier V may proceed only if Tier IV is permissive or neutral.

Tier IV does not require intervention, but it can block escalation.

TIER V — LINEAGE RESTORATION

(Identity restoration tier)

Domain of IL-7 (CYT107)

Biological Scope

• Thymic-dependent naïve T-cell generation
• TCR repertoire diversification
• Durable immune identity restoration

Why This Tier Is Last

This tier carries the highest biological leverage and risk.

All prior tiers exist to protect this step.

Tier V GO Criteria

All required:

• Tier I–III stable or resolved
• Tier IV permissive
• No inflammatory noise
• Disease-specific control maintained (e.g., viral suppression)

Tier V STOP Rules (Immediate)

• Hyper-expansion (Ki-67↑ without TRECs↑)
• Receptor down-regulation (CD127↓)
• Inflammatory rebound
• CXCR4 shift (where applicable)

Non-Negotiable Rule

Tier V failure is never corrected by dose escalation.

Failure mandates rollback to the lowest unstable tier.

ESCALATION & ROLLBACK LOGIC (GLOBAL)

Escalation

• Only one tier at a time
• Only after biomarker confirmation
• Never by calendar alone

Rollback

Triggered by:

• Any Tier II inflammatory reactivation
• Any Tier III structural regression
• Any Tier V safety signal

Rollback target = lowest tier showing instability

WHY THIS LOGIC IS UNIQUE (REGULATORY SYNTHESIS)

ONE-PARAGRAPH FDA-READY SUMMARY

The PRISM framework enforces a hierarchical, biomarker-gated sequencing of metabolic stability, inflammatory control, stromal niche readiness, epigenomic permissivity, and lineage restoration. Escalation is permitted only when upstream tiers are stabilized, and failure at any tier mandates rollback rather than dose intensification. This design reflects current biological understanding that immune identity restoration is constrained by structural and contextual prerequisites.

MASTER DOCUMENT REGISTRY INDEX

• SCF-PRISM-TIER-LOGIC-0068
• SCF-REG-SEQUENCING-ALGORITHM-0069
• SCF-DSMB-ESCALATION-RULESET-0070

If you want next

I can convert this into:

1. a DSMB decision tree (flowchart)
2. a single-page clinical algorithm
3. IND-ready Module 2 language

Just tell me which one.