# Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2024 · $341,650

## Abstract

ABSTRACT
We have made important contributions to the immunobiology of cancer neoantigens, and have developed a
robust, publically available, and frequently downloaded suite of software tools for neoantigen prediction. With
support from our previous SPORE in Pancreatic Cancer and SU2C, we have now completed enrollment to two
phase 1 clinical trials in PDAC testing neoantigen DNA vaccines (NCT03122106) and synthetic long peptide
(SLP) vaccines (NCT03956056). Preliminary analyses confirm that both neoantigen vaccine platforms can
induce robust immune responses, and suggest that PDAC patients treated with neoantigen vaccines have
better than predicted clinical outcomes. We recently developed algorithms for the prioritization of class II
neoantigens and demonstrated that optimized vaccines incorporating both class I and II neoantigens improve
the success of neoantigen vaccines. With funding from Leidos Biomedical Research, we are currently testing
optimized neoantigen SLP vaccines in PDAC patients using a window trial design (NCT05111353).
Aim 1: Test the hypothesis that optimized neoantigen vaccines can increase the number and improve
the function of neoantigen-specific T cells in PDAC. We are currently testing optimized neoantigen
vaccines in PDAC patients following neoadjuvant chemotherapy in the window prior to surgery
(NCT05111353). The window clinical trial design provides the opportunity to study neoantigen-specific T cell
responses in the tumor microenvironment (TME) after vaccination. In Aim 1, we will use biospecimens from the
trial to rigorously assess the functional biology of neoantigen-specific T cells present in the TME using coupled
single-cell RNA sequencing (scRNA-seq) and TCR sequencing.
Aim 2: Test innovative strategies to address the paucity of cDC1 in PDAC. We have made important
contributions to understanding the development and biology of cDC1. We recently demonstrated that cDC1
orchestrate CD4 and CD8 immune responses in cancer, and that PDAC impairs development of cDC1,
restraining antitumor immunity. We are currently testing an innovative strategy to expand and license cDC1 in
PDAC (NCT04536077). We will test innovative strategies to enhance neoantigen vaccine therapy in PDAC by
expanding and licensing cDC1 in vivo. We will also test biospecimens from NCT05111353 and NCT04536077
to evaluate the impact of cDC1 paucity on the response to neoantigen vaccines.
Aim 3: Test the hypothesis that the TIGIT pathway restrains the response to optimized neoantigen
vaccines in PDAC. We and others have generated data using human specimens and preclinical models
suggesting that the TIGIT pathway restrains antitumor immune responses in PDAC. We propose correlative
studies to determine if TIGIT signaling also restrains neoantigen-specific T cell responses in human PDAC.
These studies have immediate translational relevance given that anti-TIGIT and anti-PD-1 antibodies are
currently being tested in early phase clinical trials

## Key facts

- **NIH application ID:** 10916347
- **Project number:** 5P50CA272213-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** WILLIAM G HAWKINS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $341,650
- **Award type:** 5
- **Project period:** 2023-08-28 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916347

## Citation

> US National Institutes of Health, RePORTER application 10916347, Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC (5P50CA272213-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10916347. Licensed CC0.

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