# Mutant KRAS targeted vaccines for the interception of pancreatic cancer development

> **NIH NIH R37** · JOHNS HOPKINS UNIVERSITY · 2024 · $659,090

## Abstract

ABSTRACT
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing, and despite the use of conventional
therapies, including immune checkpoint inhibitors, 5–year survival remains dismal, at ~12%1. Late detection and
therapeutic resistance constitute the two cardinal challenges in PDAC management. However, it is now clear
that, following the initial KRAS mutation, it takes over a decade for overt cancer to develop from premalignant
lesions, called pancreatic intraepithelial neoplasia (PanIN). Recent studies have also identified individuals at a
high risk of PDAC who have a strong family history or harbor pathogenic variants of cancer susceptibility genes.
Imaging further identifies premalignant pathologies, such as intrapapillary mucinous neoplasia (IPMN). Both
advances––genetic testing and imaging––together with the exceptionally protracted, >10–year–long, window of
silent PDAC progression underscore the opportunities to intercept progression. Here, we have targeted
mutated KRAS (mKRAS) that drives up to 90% PDACs. We found previously that a KrasG12D vaccine halts PanIN
progression in 40% of KPC mice that harbor a heterozygous KrasG12D mutation. This study provided the premise
for testing our mKRAS vaccine comprising six peptides corresponding to the most common KRAS mutations in
patients with resected PDAC (NCT04117087). We provide evidence for safety, induction of mKRAS–specific
predominantly CD4 T cells, and improved disease–free survival. These data prompted us to initiate a study to
evaluate the safety and immunogenicity of vaccine in genetically predisposed individuals (NCT05013216, Aim
1). Promising preliminary data establish conceptual and technological feasibility. We hypothesize that the
mKRAS vaccine will (a) trigger mKRAS–specific anti–tumor immunity in individuals with premalignant lesions––
PanINs or IPMN––and (b) slow progression of PanINs to PDAC with a survival benefit in KPC mice when given
prior to the induction of the KrasG12D mutation. Aim 1 (already initiated) and Aim 2 will study the safety and
immunogenicity of mKRAS vaccine in individuals with genetic predisposition and high–risk IPMN, respectively.
We will study mKRAS–specific T cells in terms of memory, exhaustion, and polyfunctionality, as well as clonality
and richness of the T cell repertoire. In Aim 1, we will also identify TCR clones with cytotoxic gene signatures
and validate their function by knocking in the selected TCRs into human T cells. Aim 2 will allow us to examine
the effect of vaccine on premalignant IPMN tissue using image mass cytometry. In the spirit of bidirectional
translation, we will move back, in Aim 3, to the inducible version of the KPC mouse to determine the optimal
timepoints for vaccine interception, characterize longitudinal changes in the immune compartment of PanIN
lesions, and investigate the role of CD4 T cells in preventing PanIN–to–PDAC progression. Establishing vaccine
effects in high–risk cohorts, together with murine s...

## Key facts

- **NIH application ID:** 10940953
- **Project number:** 1R37CA292056-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Neeha Zaidi
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,090
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940953

## Citation

> US National Institutes of Health, RePORTER application 10940953, Mutant KRAS targeted vaccines for the interception of pancreatic cancer development (1R37CA292056-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10940953. Licensed CC0.

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