# Re-wiring PDAC Tumor Immunity Through Dendritic Cells

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $551,987

## Abstract

PROJECT SUMMARY
 The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. This is likely due to the
presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most PDAC. Our data
suggest immune priming by conventional dendritic cells (cDCs) may be a necessary barrier to overcome to
generate lasting immunity in PDAC patients. cDCs are central for generating tumor antigen–specific T cell
responses. Our new data show that cDCs are severely dysfunctional in patients with PDAC. This dysfunction is
driven by two mechanisms: 1) We recently reported that PDAC patients have impaired cDC development in
their bone marrow, and this leads to functional depletion of circulation pre-DCs, and poor response to
checkpoint inhibitors. 2) We recently showed that even when cDC development is not fully impaired, cDC1s
are physically/biochemically excluded from the PDAC TME. These mechanisms to the loss of stereotactic body
radiation therapy (SBRT)-induced priming of tumor antigen-specific T cell responses and ultimately failed
tumor control in animal models. We overcame both of these dysfunctional barriers by targeting cDC1s using a
combination of systemic treatment with FMS-like tyrosine kinase 3 ligand (FLT3L) and CD40 agonists. Our pre-
clinical data are exceptionally strong and have placed us in a unique position to translate these findings into
PDAC patients. Our central hypothesis is that targeting cDC can unlock responsiveness to RT by
generating lasting anti-tumor immunity. We will expand test this hypothesis in three specific aims.
Aim 1. Determine the safety and efficacy of the combination of CDX-301 plus CDX-1140 and SBRT in
locally advanced PDAC patients
Aim 2. Determine the mechanisms by which FLT3L plus a CD40 agonist induce anti-tumor immunity.
Aim 3. Determine if FLT3L plus CD40 agonists improves responsiveness to checkpoint
immunotherapy.
Impact. PDAC patient responses to conventional radiation therapy have been disappointing. Our data strongly
support the use of FLT3L and CD40 agonist to enhance patient responsiveness to RT and generate long-term
anti-tumor immunity. Our team is well-positioned to test our central hypothesis directly in clinical and
experimental studies.

## Key facts

- **NIH application ID:** 10280010
- **Project number:** 1R01CA262506-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David G DeNardo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $551,987
- **Award type:** 1
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280010

## Citation

> US National Institutes of Health, RePORTER application 10280010, Re-wiring PDAC Tumor Immunity Through Dendritic Cells (1R01CA262506-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10280010. Licensed CC0.

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