Summary
This project aims to develop an RNA-based vaccine targeting non-solid (NS) lung nodules to prevent their progression to invasive adenocarcinoma, by identifying immunogenic antigens and testing vaccine efficacy in preclinical models.
Lung Cancer Vaccine
US · IL
National Institutes of Health (NIH)
grant
awarded
#nih-5U54CA272688-04
What they want
The project will test the hypothesis that RNA-based vaccination against NS nodule-associated antigens and/or neoantigens can activate T helper and cytotoxic CD8+ T cells while reducing tumor-infiltrating Tregs to impair NS nodule progression. Aim 1 involves manufacturing and optimizing a lipo-nanoparticle RNA (LNP RNA) XAGE-1b vaccine and testing its efficacy in intercepting NS nodule progression in preclinical syngeneic models of NSCLC, elucidating mechanisms with comprehensive immune profiling. Aim 2 will delineate the most immunogenic and cytotoxic patient lung NS nodule antigens and neoantigens from a multi-ethnic cohort for vaccine payloads, using human class I MHC (HLA) transgenic mice, patient-specific tumoroid/autologous T-cell cocultures, and immunopeptidomics to confirm immunogenicity and rank neoantigens.
Deliverables
- Manufactured and optimized LNP-XAGE-1b RNA vaccine
- Efficacy data of XAGE-1b vaccine in intercepting NSN progression in a novel mouse model
- Elucidation of mechanisms associated with LNP RNA vaccine immune interception
- Delineation of most immunogenic and cytotoxic patient lung NS nodule antigens and neoantigens
- Identification of most immunogenic lung NSN vaccine cargo in vivo using HLA transgenic mice
- Confirmation of immunogenicity and antigenic presentation on autologous patient HLA
- Ranking of neoantigens based on cytotoxic potential against autologous tumoroids
- Informative correlative studies for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials
- Critical mechanistic insights into effective patient LNP RNA immune interception vaccines
Technical requirements
- Computerized chest tomography (CT) lung cancer screening programs
- RNA-based vaccination
- Lipo-nanoparticle RNA (LNP RNA) technology
- Preclinical syngeneic models of NSCLC
- Novel physiologically relevant mouse model recapitulating NS nodule progression
- Comprehensive immune profiling approaches
- Human class I MHC (HLA) transgenic mice
- Patient-specific tumoroid/autologous T-cell cocultures
- Immunopeptidomics
