# Harnessing Dendritic Cells as a Novel Therapy in Pancreatic Ductal Adenocarcinoma

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2020 · $31,454

## Abstract

Project Summary / Abstract
Checkpoint therapies such as aPD-1 and aCTLA-4 represent a paradigm shift in cancer therapy. Their success
in previously terminal diagnoses such as metastatic melanoma, prompt two conclusions 1) that the immune
system is a constitutive element of the body’s defense against neoplasia and 2) that the immune system is a
targetable tool to treat disease. However, the successes of checkpoint therapy have not translated to pancreatic
ductal adenocarcinoma (PDAC), which remains a deadly disease with fewer than 10% of patients surviving
beyond 5 years9. This resistance to checkpoint therapies can be partly explained by a paucity of conventional
dendritic cells (cDCs) within the PDAC tumor microenvironment (TME). cDCs are uniquely specialized for
priming anti-tumor T cell responses, expanding a population of cytotoxic T lymphocytes (CTLs) that are the target
of therapies such as aPD-1. To combat this deficit in cDCs, we have employed a novel strategy of treating with
the cDC differentiation factor Flt3L to expand cDC numbers, and an agonistic antibody against CD40 (aCD40)
to license cDCs, augmenting their cancer-antigen presentation capacity. Surprisingly, this dual therapy
generates a synergistic increase in intra-tumoral cDCs and T cells, compared to either monotherapy alone.
Additionally, this combination leads to disease stabilization and renewed responsiveness to radiation therapy.
These promising observations lack a mechanistic explanation, as the method of action of either drug alone does
not justify their combined phenotype. Through this proposal, I aim to elucidate the cellular pathways underlying
the increased numbers of cDCs and T cells within the PDAC TME, which largely mediate the efficacy of aCD40
+ Flt3L in PDAC. I hypothesize that the synergistic benefit of aCD40 + Flt3L is mediated through enhanced
recruitment of cDCs to the PDAC microenvironment, enabling effective downstream priming and
mobilization of a tumor specific T cell response. Preliminary data indicate that the expanded pool of tumor
infiltrating CTLs assumes an exhausted-like profile, suggesting that aCD40 + Flt3L dual therapy may render
PDAC sensitive to checkpoint therapies. Clarifying the mechanisms driving the improved outcomes in aCD40 +
Flt3L treated PDAC, will help optimize future treatment protocols and spur translation of this therapy to the clinic.
These proposed aims are highly aligned with my personal goal of becoming a physician-scientist specializing in
immuno-oncology. I am confident that this proposal will provide me with the skills and experience needed to
succeed as an independent investigator endeavoring to bring emerging immunotherapies from my lab to patients
suffering from debilitating malignancies.

## Key facts

- **NIH application ID:** 10065932
- **Project number:** 1F30CA254087-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Graham Douglas Hogg
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,454
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065932

## Citation

> US National Institutes of Health, RePORTER application 10065932, Harnessing Dendritic Cells as a Novel Therapy in Pancreatic Ductal Adenocarcinoma (1F30CA254087-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065932. Licensed CC0.

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