CAP-IT CRI has two projects:
and one administrative supplement award:
3. Metformin for chemoprevention of lung cancer in obese subjects at high risk
Lynch syndrome (LS) affects approximately 1.2 million Americans and predisposes individuals to colorectal cancer (CRC) and other malignancies. In LS, normal cells acquire somatic second mutations and become DNA mismatch repair deficient (MMRD), leading to microsatellite instability (MSI) in cancer cells. This process results in MSI cancers sharing precisely the same frameshift peptide (FSP) neoantigen pool due to Darwinian selection of driver mutations.
Research has shown 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.
This hypothesis will be evaluated 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)
The research has noted a correlation between metformin use and improved lung cancer outcomes in overweight and obese patients, a connection that appears to be related to metformin-induced immunological changes observed in both human and mouse studies. A clinical trial and mouse experiments are planned to investigate whether metformin's anti-cancer immune effects are specifically evident in obese individuals at high risk for lung cancer, with the aim of potentially using the drug for cancer prevention.
The project is structured around two specific aims to examine this hypothesis:
Aim 1: To examine this preventive potential of metformin, we will conduct a small phase II trial with at- high-risk obese/overweight subjects to establish that months-long oral metformin treatment diminishes markers of immunosuppressive Tregs in lungs and enhances markers local pulmonary and systemic immunosurveillance activity.
Aim 2: To identify mechanisms that underlie the obesity-specific immunomodulatory effects of metformin, we will study the impact of this drug in obese and non-obese mice of two distinct but complementary mouse lung cancer models.
(For additional information, please visit NIH RePORTER)
