DV-07 — Neuroimmune Safety & CNS Compatibility Report

PROJECT HELIX-HTT | Huntington’s-Adjacent Neuro-Oncology Vaccine Program

HELIX-VAX-01 / HELIX-VAX-02 Neuroimmune Risk Assessment Package

DOCUMENT CONTROL HEADER

Program: PROJECT HELIX-HTT

Phase: II — Preclinical Vaccine Development

Module: 7 — Neuroimmune Safety & CNS Compatibility Program

Document Code: SCF-DV07-NSCR-NO-0001

Purpose: Establish neuroimmune safety, CNS compatibility, blood-brain barrier interaction profiles, autoimmune risk boundaries, and maximum tolerated immune activation thresholds prior to PK/PD and GLP toxicology advancement.

1. EXECUTIVE SUMMARY

Unlike conventional oncology vaccines, HELIX-VAX operates in a disease setting closely associated with the central nervous system.

The greatest developmental risk is not lack of efficacy.

The greatest risk is:

Generating sufficient anti-tumor immunity without triggering neuroimmune toxicity.

DV-07 establishes the biological operating window where:

✓ Anti-tumor immunity remains effective

✓ Neuroimmune homeostasis remains preserved

✓ Microglial overactivation is avoided

✓ Autoimmune neurotoxicity is prevented

✓ BBB integrity remains intact

2. SCF NEUROIMMUNE SAFETY ARCHITECTURE

HELIX-VAX
      ↓
APC Activation
      ↓
T Cell Expansion
      ↓
Tumor Recognition
      ↓
Immune Amplification
      ↓
CNS Exposure Risk
      ↓
Neuroimmune Compatibility Assessment
      ↓
Safety Envelope Determination

3. MASTER SAFETY EVALUATION PROGRAM

4. NS-A1 BLOOD-BRAIN BARRIER COMPATIBILITY

Objective

Determine whether vaccine-induced immune activation compromises BBB integrity.

Core Biomarkers

BBB Integrity Score (BBIS)

BBIS =
Claudin-5
+
Occludin
+
ZO-1

-
Albumin Leakage
-
MMP9

Classification

5. NS-A2 CNS AUTOIMMUNITY RISK ASSESSMENT

Objective

Identify potential immune attack against healthy neural tissue.

Evaluation Domains

Antigen Homology

Compare vaccine antigens against:

• neuronal proteins
• synaptic proteins
• myelin-associated proteins

T-cell Cross-Reactivity

Evaluate:

• off-target recognition
• neuronal antigen mimicry

Autoimmune Risk Score (ARS)

6. NS-A3 MICROGLIAL ACTIVATION PROGRAM

Objective

Determine whether HELIX-VAX drives harmful CNS innate immune activation.

Biomarkers

Microglial Activation Score (MAS)

Desired Outcome

Moderate adaptive activation without inflammatory escalation.

Classification

7. NS-A4 NEUROINFLAMMATION ASSESSMENT

Objective

Quantify inflammatory burden.

Cytokines

Neuroinflammatory Burden Score (NBS)

NBS =
IL1β
+
IL6
+
TNFα
+
IFNγ

8. NS-A5 CYTOKINE STORM RISK MODEL

Objective

Prevent systemic hyperinflammation.

Evaluate

Cytokine Risk Score (CRS)

9. NS-A6 NEURONAL CROSS-REACTIVITY ANALYSIS

Objective

Prevent T-cell recognition of healthy neural tissue.

Assessment Layers

Protein Homology

Peptide Homology

HLA-Presentation Similarity

Functional Mimicry

Cross-Reactivity Score (XRS)

XRS =
Sequence Similarity
+
Presentation Similarity
+
Functional Similarity

Threshold

Any high-risk antigen is removed from vaccine design.

10. NS-A7 NEUROIMMUNE TOLERANCE PRESERVATION

Objective

Maintain normal CNS self-tolerance.

Biomarkers

Tolerance Preservation Score (TPS)

Measures:

• tolerance maintenance
• immune balance
• CNS protection

11. RHENOVA NEUROIMMUNE OVERLAY

Evaluate Influence of:

Hypoxia

Can amplify inflammation.

Oxidative Stress

Can promote microglial activation.

Immune Suppression

Can mask toxicity signals.

RHENOVA Neuroimmune Stability Index (RNSI)

RNSI =
Tolerance
+
BBB Stability
+
Microglial Balance

-
Hypoxia
-
Oxidative Stress

12. MAXIMUM TOLERATED IMMUNE ACTIVATION ENVELOPE

SCF MTAE

Defines:

Maximum immune activation before safety deterioration occurs.

Parameters

Purpose

Optimize efficacy without crossing neurotoxicity thresholds.

13. SCF NEUROIMMUNE COMPATIBILITY INDEX

SNCI

Master safety endpoint.

SNCI =
BBB Integrity
+
Tolerance Preservation
+
Microglial Stability
+
Low Cross-Reactivity

-
Neuroinflammation
-
Cytokine Risk

Classification

14. SAFETY DECISION MATRIX

GO

✓ SNCI ≥ 85

✓ BBIS ≥ 75

✓ Low ARS

✓ Balanced MAS

✓ Low CRS

CONDITIONAL GO

✓ SNCI 70–84

✓ Correctable findings

NO-GO

✗ SNCI < 70

✗ Severe autoimmunity risk

✗ Hyperactivated microglia

✗ BBB disruption

✗ High neuronal cross-reactivity

15. INTEGRATED SAFETY DASHBOARD

16. OUTPUT FILES

DV07-01

BBB Compatibility Report

DV07-02

Autoimmunity Risk Assessment

DV07-03

Microglial Activation Report

DV07-04

Neuroinflammation Assessment

DV07-05

Cytokine Storm Risk Report

DV07-06

Neuronal Cross-Reactivity Report

DV07-07

Tolerance Preservation Report

DV07-08

Integrated Neuroimmune Safety Dashboard

17. STRATEGIC VALUE TO PROJECT HELIX-HTT

DV-07 establishes the critical safety framework separating:

Effective Immune Activation
                from
Dangerous Neuroimmune Activation

This module defines the operational immune window that permits therapeutic benefit while minimizing CNS toxicity risk.

For Huntington’s-adjacent neuro-oncology applications, DV-07 becomes one of the most important IND-enabling packages because it directly addresses:

• neurotoxicity risk
• autoimmune encephalitis risk
• BBB disruption risk
• chronic neuroinflammation risk
• long-term CNS tolerability

STATUS

DV-07 — Neuroimmune Safety & CNS Compatibility Report: COMPLETE

NEXT DELIVERABLE

DV-08 — PK/PD, Biodistribution & Systems Pharmacology Report

This module will establish:

• vaccine biodistribution
• lymphatic trafficking
• antigen persistence
• pharmacodynamic response kinetics
• CNS exposure profile
• systems-level immune response modeling
• SCF Whole-Body Immunologic Communication Map
• IND-enabling pharmacology package for HELIX-VAX advancement into GLP toxicology.