Lung Cancer Vaccine

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Principal Investigator: NASSER Khaled ALTORKI
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2022
Award: $362,579
Funding agency: National Cancer Institute

PROJECT SUMMARY
Computerized chest tomography (CT) lung cancer screening programs have increased the detection of 
premalignant non-solid (NS) nodules that harbor preinvasive or minimally invasive adenocarcinoma. Given that 
NS nodules can progress to invasive adenocarcinoma (solid nodules), intercepting progression is considered an 
urgent clinical priority. However, the cellular and molecular alterations that accompany disease progression are
poorly understood. NS nodules exhibit lower rates of HLA deletions than invasive/metastatic lung cancer, and 
our integrated clinical and preclinical investigations have recently uncovered T cell-enriched immune 
microenvironments, including elevated activated T regs in NS nodules. Global genomic analysis of NS nodules 
identified high tumor-associated antigen (TAA) XAGE-1b and several HLA-restricted neoantigens. These 
findings have led to the hypothesis that RNA-based vaccination against NS nodule-associated antigens and or 
neoantigens can drive activation of T helper and cytotoxic CD8+ T cells while reducing tumor-infiltrating Tregs to 
impair NS nodule progression to invasive adenocarcinoma.
We will test this hypothesis through two Specific Aims. Aim 1 will determine the potential of lipo-nanoparticle 
RNA (LNP RNA) XAGE-1b vaccination in intercepting NS nodule progression in preclinical syngeneic models of 
NSCLC. A state-of-the-art LNP-XAGE-1b RNA vaccine will be manufactured and optimized in collaboration with 
the LNP-RNA shared resource facility. A novel physiologically relevant mouse model recapitulating the 
progression of human NS nodules will be used to determine the efficacy of the XAGE-1b vaccine in intercepting 
the progression of NSN to invasive carcinoma. Mechanisms associated with LNP RNA vaccine immune 
interception will be elucidated with comprehensive immune profiling approaches. Aim 2 will delineate the most 
immunogenic and cytotoxic patient lung NS nodule antigens and neoantigens identified in a multi-ethnic cohort
of clinically annotated NS nodules for vaccine payloads. Human class I MHC (HLA) transgenic mice will identify
the most immunogenic lung NSN vaccine cargo in vivo. Patient-specific tumoroid/autologous T-cell cocultures 
and immunopeptidomics will be used to confirm immunogenicity and antigenic presentation on autologous 
patient HLA. Finally, the cytotoxic potential of NS nodule patient neoantigen-specific T-cells against autologous 
tumoroids will be used to rank neoantigens.
We expect to delineate the most immunogenic vaccine cargo together with informative correlative studies for 
NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials and provide 
critical mechanistic insights into effective patient LNP RNA immune interception vaccines.

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