CAP-IT CRI has two projects:
and one administrative supplement award:
Lynch syndrome (LS) affects ~1.2 million Americans and predisposes them to colorectal cancer (CRC) and other malignancies.
LS normal cells acquire somatic second mutations and become DNA mismatch repair deficient (MMRD), which leads to microsatellite instability (MSI) in cancer cells.
Due to Darwinian selection of driver mutations, MSI cancers share precisely the same frameshift peptide (FSP) neoantigen pool.
Previously, we showed that:
a. 100% of MMRD CRC patients have CD8+ T cells reactive against MMRD recurrent (broadly shared) frameshift peptides (rFSPs),
b. performed first-in-human trials showing that peptide vaccination robustly upregulates T-cell immunity against rFSP in advanced MMRD cancer patients, and
c. demonstrated functionally in LS mouse models that vaccination with only four mouse recurrent neoantigens increases CD8+ killer and CD4+ helper T-cell immune response, reduces CRC burden and prolongs cancer-free survival.
This project will identify the most immunogenic recurrent neoantigens with two Specific Aims.
Aim 1: Test the hypothesis that LNP-RNA rFSP vaccination drives LS mouse immune responses, reduces tumor burden, and increases survival.
Aim 2: Delineates the most immunogenic cytotoxic Lynch syndrome patient recurrent neoantigens.
(For additional information, please visit NIH RePORTER)
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: Determine the potential of lipo-nanoparticle RNA (LNP RNA) XAGE-1b vaccination in intercepting NS nodule progression in preclinical syngeneic models of NSCLC.
Aim 2: 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.
(For additional information, please visit NIH RePORTER)
To test our hypothesis this project has two Specific Aims.
Specific Aim 1: Evaluate SurVaxM as a cancer prevention agent for mouse lung carcinogenesis
Specific Aim 2: Evaluate SurVaxM as a cancer interception agent for mouse lung cancer progression.
