# Project 2

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2022 · $544,481

## Abstract

Pancreatic ductal adenocarcinoma is an extremely lethal disease with the lowest 1-year and 5-year survival
rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells and
their extreme resistance to both chemical and radiotherapies. Importantly, we now know that a strong, but
nevertheless unique, fibrotic and immunosuppressive stromal response is present in PDA. This intense
fibroinflammatory, or desmoplastic, response is essentially pathognomonic for PDA and limits infiltration of
anti-tumor immune cells and also their ability to move throughout and sample the tumor volume. Indeed,
immunotherapies with immune checkpoint blockade or infusion of genetically modified cells are producing
remarkable clinical responses in other advanced malignancies, but to date, success has been much more
limited in PDA. However, focused preclinical strategies to disrupt the stroma or specifically engineer T cell
therapies have shown promise in PDA. Thus, understanding the molecular basis for engineered T cell
infiltration and identifying strategies to further enhance their infiltration, migration throughout tumor masses,
and persistence and function in cancer will inform cell engineering strategies for improved treatment. Here, we
test a number of focused hypotheses using integrated experiments, advanced imaging, and mathematical
modeling to elucidate engineered T cell migratory mechanisms both in vivo and in engineered platforms in vitro
and utilize genome editing and overexpression to engineer T cells that can maximally infiltrate and move
throughout complex tumor microenvironments. We hypothesize that by enhancing the ability of engineered T
cells to move throughout tumor we can profoundly improve their efficacy and employ combinations of stroma
targeting and T cell therapies to improve disease outcomes. We will dissect mechanisms governing infiltration,
longevity and functionality of engineered T cells and determine how engineered T cell migrate within the
physically complex tumor environments. This information will be used engineer T cells that most effectively
move throughout the entire tumor mass. Using these cells, we will perform rigorous preclinical evaluation of
our engineered T cell approach in concert with rational stroma re-engineering. Our goals are aligned with
Projects 1 and 3 where we seek to collectively elucidate fundamental mechanisms of immune cell migration
and to innovate novel cell engineering approaches to eradicate cancer.

## Key facts

- **NIH application ID:** 10489762
- **Project number:** 5P01CA254849-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Paolo Provenzano
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $544,481
- **Award type:** 5
- **Project period:** 2021-09-16 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489762

## Citation

> US National Institutes of Health, RePORTER application 10489762, Project 2 (5P01CA254849-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489762. Licensed CC0.

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