Integrating Innate Priming, Personalized Neoantigens, and Blood-Brain Barrier Penetrating Delivery
This repository contains educational materials developed for medical school application portfolio purposes and is not intended for clinical application or vaccine development.
This is not:
- A clinical trial protocol or investigational new drug (IND) application
- An approved therapeutic intervention
- Medical advice or treatment recommendation for glioblastoma patients
- A functional vaccine design ready for preclinical testing
- Affiliated with any pharmaceutical company or vaccine development program
This is:
- Independent pre-medical conceptual framework
- Literature synthesis and translational thinking demonstration
- Medical school application portfolio material
- Educational exploration of immunotherapy concepts
Institutional Affiliation:
This is an independent educational project. It is not an official University of Washington or UW Medicine document and is not affiliated with, endorsed by, or approved by UW Medicine, its faculty, or staff.
Regulatory Status:
This conceptual framework has NOT undergone preclinical validation, regulatory review, or safety testing. Any actual vaccine development would require:
- Extensive preclinical studies (in vitro and animal models)
- IND application to FDA
- Phase I/II/III clinical trials with IRB oversight
- Regulatory approval before any human use
Clinical Application:
This framework is theoretical only. Glioblastoma treatment requires oncologist oversight, established clinical protocols, and participation in approved clinical trials when appropriate.
Intellectual Property:
No patents or proprietary technologies are claimed. This work is freely available under CC BY 4.0 license for educational and research purposes.
Financial Disclosure:
No external funding received. No conflicts of interest.
Liability:
This work is provided "as is" without warranty of any kind. Users assume full responsibility for any use of these materials.
Author Status:
Pre-medical student. Not a licensed healthcare professional. Not engaged in vaccine development, clinical trials, or patient care.
Title: A Translational Framework for a Hybrid mRNA Vaccine Targeting Glioblastoma: Integrating Innate Priming, Personalized Neoantigens, and Blood-Brain Barrier Penetrating Delivery
Author: Collin B. George, BS
Project Type: Independent pre-medical translational research framework
Status: Manuscript in preparation
Initial Publication Date: November 25, 2025
Repository Version: 1.0.0
Glioblastoma (GBM) remains lethal despite multimodal therapy, with median survival under 15 months. Immunotherapy has failed in over 100 clinical trials due to three fundamental barriers:
- Inadequate immune priming in "cold" tumors
- Blood-brain barrier (BBB) exclusion of therapeutics
- Profound local immunosuppression
This conceptual framework proposes a hybrid mRNA vaccine strategy integrating:
- Innate immune activation (TLR agonists, STING pathway)
- Personalized neoantigen targeting (tumor-specific mutations)
- BBB-penetrating delivery (focused ultrasound + microbubbles)
Educational Purpose:
This work demonstrates translational thinking, integration of immunology and neuroscience principles, and understanding of clinical trial design for medical school application portfolio purposes.
Background:
Glioblastoma is the most aggressive primary brain tumor, with dismal prognosis despite standard therapy (surgery, radiation, temozolomide). The blood-brain barrier, immunosuppressive tumor microenvironment, and low mutational burden have rendered immunotherapy largely ineffective.
Objective:
To develop a conceptual framework for a hybrid mRNA vaccine that addresses GBM's unique immunological challenges through multi-pronged approach: innate immune priming, personalized neoantigen presentation, and BBB-penetrating delivery.
Methods:
This narrative framework synthesizes:
- Preclinical mRNA vaccine studies
- GBM immunotherapy clinical trial data
- Blood-brain barrier penetration strategies
- Tumor immunology and neoantigen prediction literature
Literature searches of PubMed, EMBASE, and ClinicalTrials.gov were conducted through November 2025.
Proposed Framework:
Component 1: Innate Priming Module
- TLR 7/8 agonists (resiquimod) + STING agonists (cGAMP)
- Converts "cold" GBM tumors to "hot" inflammatory phenotype
- Recruits dendritic cells and cytotoxic T cells
Component 2: Personalized Neoantigen Payload
- Patient-specific tumor sequencing (whole exome + RNA-seq)
- Neoantigen prediction algorithms (MHC-I/II binding)
- mRNA encoding top 20-30 patient-specific neoantigens
Component 3: BBB-Penetrating Delivery
- Focused ultrasound (FUS) + microbubble technology
- Transient, localized BBB disruption
- Lipid nanoparticle (LNP) encapsulated mRNA
Component 4: Combination with Checkpoint Inhibition
- Anti-PD-1/PD-L1 therapy
- Synergistic with vaccine-induced T cell responses
Expected Outcomes (Hypothetical):
- Enhanced tumor-infiltrating lymphocytes
- Tumor-specific T cell responses
- Prolonged progression-free survival
- Potential for durable responses in subset of patients
Conclusions:
This framework provides a conceptual roadmap for addressing GBM's immunotherapy resistance. Translation to clinical reality requires extensive preclinical validation, toxicology studies, and phased clinical trials. This work demonstrates translational thinking for educational purposes.
gbm-hybrid-mrna-framework/
├── README.md # This file
├── manuscript/
│ ├── GBM_mRNA_Framework.pdf # Complete framework document
│ ├── GBM_mRNA_Framework.tex # LaTeX source
│ └── bibliography.bib # References
├── figures/
│ ├── Figure_1_GBM_Barriers.pdf # Immunotherapy resistance mechanisms
│ ├── Figure_2_Vaccine_Design.pdf # Hybrid vaccine schematic
│ ├── Figure_3_BBB_Delivery.pdf # FUS + microbubble delivery
│ └── Figure_4_Clinical_Pathway.pdf # Proposed clinical trial design
└── supplementary/
├── Neoantigen_Prediction.pdf # Computational pipeline
├── FUS_Safety_Profile.pdf # Focused ultrasound safety data
└── GBM_Trial_Landscape.pdf # Analysis of failed trials
Rationale:
GBM tumors are immunologically "cold" with minimal T cell infiltration. Innate activation converts tumors to inflammatory phenotype.
Proposed Approach:
- TLR 7/8 agonists (resiquimod) in mRNA formulation
- STING pathway agonists (cGAMP analogs)
- Type I interferon induction
Preclinical Evidence:
- TLR agonists enhance mRNA vaccine efficacy (multiple cancer models)
- STING activation overcomes GBM immunosuppression (mouse studies)
Challenges:
- Systemic toxicity of innate agonists
- Optimal dosing and delivery route
- Potential for cytokine release syndrome
Rationale:
GBM has low mutational burden but patient-specific neoantigens exist. Personalized approach maximizes immunogenicity.
Proposed Pipeline:
- Tumor and germline whole exome sequencing
- RNA-seq for expression validation
- MHC-I/II binding prediction (NetMHCpan, MHCflurry)
- Immunogenicity scoring (TCR recognition likelihood)
- Selection of top 20-30 neoantigens per patient
Preclinical Evidence:
- Personalized cancer vaccines show promise in melanoma, NSCLC
- Neoantigen-specific T cells correlate with clinical response
Challenges:
- Manufacturing timeline (4-6 weeks per patient)
- Cost of personalized production
- Neoantigen prediction accuracy (~30-40% validated immunogenicity)
Rationale:
Blood-brain barrier excludes >98% of large molecules. Focused ultrasound enables transient, localized BBB disruption.
Proposed Technology:
- MRI-guided focused ultrasound (FUS)
- Co-administered lipid-shelled microbubbles
- Transient BBB opening (4-24 hours)
- LNP-encapsulated mRNA delivered IV during BBB window
Preclinical Evidence:
- FUS + microbubbles safely opens BBB in humans (Phase I trials)
- Enhanced antibody delivery to brain tumors demonstrated
- mRNA-LNP delivery to CNS shown in animal models
Challenges:
- FUS equipment availability and cost
- Optimal timing of mRNA administration relative to FUS
- Potential for vasogenic edema or microhemorrhage
Rationale:
Vaccine-induced T cells require checkpoint blockade to function in immunosuppressive GBM microenvironment.
Proposed Combination:
- Anti-PD-1 therapy (nivolumab, pembrolizumab)
- Potential anti-CTLA-4 in select patients
- Sequencing: Vaccine primes, checkpoint inhibitor amplifies
Clinical Evidence:
- Checkpoint inhibitors alone largely ineffective in GBM (5-8% response rate)
- Combination with vaccines shows synergy in other cancers
- GBM trials of vaccine + checkpoint inhibitor ongoing
Objectives:
- Establish safety of hybrid mRNA vaccine
- Assess FUS + microbubble BBB disruption safety in GBM patients
- Determine maximum tolerated dose
- Measure immune responses (T cell, antibody)
Design:
- Dose escalation (3-6 dose levels)
- Recurrent GBM patients (post-standard therapy)
- n=18-24 patients
Primary Endpoints:
- Dose-limiting toxicities
- Adverse events (CTCAE grading)
Secondary Endpoints:
- Immune response rates (ELISpot, flow cytometry)
- Preliminary efficacy (PFS, OS)
Objectives:
- Assess clinical efficacy
- Identify predictive biomarkers
- Refine neoantigen selection algorithms
Design:
- Single-arm or randomized vs. standard of care
- Newly diagnosed or recurrent GBM
- n=40-60 patients
Primary Endpoint:
- Progression-free survival at 6 months (PFS-6)
Secondary Endpoints:
- Overall survival
- Objective response rate (RANO criteria)
- Quality of life measures
Note: Phase III only if Phase II shows promising signal
Low Mutational Burden:
- GBM has fewer neoantigens than other cancers (~30-50 mutations vs. >200 in melanoma)
- Limits personalized neoantigen pool
Tumor Heterogeneity:
- Intratumoral heterogeneity means neoantigens vary by region
- Potential for antigen-negative escape
Immunosuppressive Microenvironment:
- Tregs, MDSCs, TAMs suppress effector T cells
- TGF-β, IL-10, IDO create hostile environment
Manufacturing:
- 4-6 week turnaround for personalized vaccines
- GMP-compliant mRNA production capacity
- Cost ($100,000-$300,000 per patient estimate)
BBB Delivery:
- FUS equipment not widely available
- Requires MRI-compatible OR or specialized suite
- Operator expertise needed
Clinical Trial Design:
- Small patient population (rare disease)
- Heterogeneous disease course (difficult powering)
- Ethical considerations (experimental therapy in terminal illness)
FDA Pathway:
- mRNA vaccines: Biologics License Application (BLA)
- FUS device: 510(k) or PMA
- Combination product regulatory complexity
GMP Manufacturing:
- Personalized vaccines challenge traditional batch production
- Potency testing for patient-specific products
This framework demonstrates:
Translational Thinking:
- Integration of basic science (immunology, neuroscience) with clinical need
- Problem identification → mechanism-based solution design
Clinical Trial Design:
- Understanding of phased development (Phase I → II → III)
- Endpoint selection and biomarker strategy
Regulatory Awareness:
- FDA pathways for biologics and devices
- GMP manufacturing considerations
Limitations Acknowledgment:
- Intellectual honesty about challenges and unknowns
- Recognition of gap between concept and clinical reality
This framework synthesizes:
mRNA Vaccine Literature:
- COVID-19 vaccine development and clinical data
- Cancer vaccine trials (melanoma, NSCLC)
- Neoantigen prediction methodologies
GBM Immunotherapy:
- Failed checkpoint inhibitor trials
- Vaccine monotherapy attempts (DCVax, etc.)
- Combination immunotherapy strategies
BBB Delivery:
- Focused ultrasound clinical trials
- Lipid nanoparticle CNS delivery studies
- Microbubble-mediated drug delivery
Complete bibliography: See manuscript/bibliography.bib
Requirements:
- TeX Live, MiKTeX, or MacTeX
- BibTeX or Biber
- TikZ package (for figures)
Compile:
pdflatex GBM_mRNA_Framework.tex
bibtex GBM_mRNA_Framework
pdflatex GBM_mRNA_Framework.tex
pdflatex GBM_mRNA_Framework.texOverleaf:
- Upload entire repository to Overleaf
- Compile with PDF LaTeX
Completed:
- Manuscript drafted
- Figures generated (TikZ/inline)
- Literature review completed
- Framework validated against published data
In Progress:
- Peer review submission (educational review, not clinical journal)
- Pre-print publication (bioRxiv or medRxiv if appropriate)
Not Planned:
- Preclinical validation (beyond scope of educational project)
- IND application (requires institutional/commercial partnership)
- Clinical trial initiation (not author's role as pre-med student)
George CB. A translational framework for a hybrid mRNA vaccine targeting
glioblastoma: integrating innate priming, personalized neoantigens, and
blood-brain barrier penetrating delivery [Internet]. Published November 2025.
Available from: https://github.com/collingeorge/gbm-hybrid-mrna-framework
[Accessed: date]
George, C. B. (2025). A translational framework for a hybrid mRNA vaccine
targeting glioblastoma: Integrating innate priming, personalized neoantigens,
and blood-brain barrier penetrating delivery [Manuscript in preparation].
https://github.com/collingeorge/gbm-hybrid-mrna-framework
If published: Update with journal citation.
Author: Collin B. George, BS
Project Type: Independent pre-medical translational research framework
Educational Context: Conceptual vaccine design integrating immunology, neuroscience, and clinical trial methodology
Status: Preparing for medical school matriculation 2026
GitHub: github.com/collingeorge
ORCID: 0009-0007-8162-6839
Email: cbg24@uw.edu
License: CC BY 4.0
The author is grateful to University of Washington faculty for educational discussions on translational immunotherapy, focused ultrasound applications in neuro-oncology, and mRNA vaccine development.
Special appreciation to the GBM research community for openly sharing clinical trial data and preclinical insights that informed this conceptual framework.
This work represents independent educational exploration and does not constitute collaboration with any clinical institution, pharmaceutical company, or vaccine development program.
This work is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0).
You are free to:
- Share and redistribute the material in any medium or format
- Adapt, remix, transform, and build upon the material for any purpose
Under the following terms:
- Attribution: Give appropriate credit to Collin B. George, provide a link to the license, and indicate if changes were made
Full license: https://creativecommons.org/licenses/by/4.0/
© 2025 Collin B. George — Licensed under CC BY 4.0
Glioblastoma, mRNA Vaccine, Immunotherapy, Neoantigens, Blood-Brain Barrier, Focused Ultrasound, Personalized Medicine, Cancer Vaccine, Translational Oncology, Clinical Trial Design, Checkpoint Inhibitors, Tumor Immunology
Last Updated: November 25, 2025
Repository Version: 1.0.0