# Research Testbed 1

> **NIH NIH U54** · UNIVERSITY OF MINNESOTA · 2024 · $340,570

## 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 physical and molecular basis for native and
engineered T cell infiltration and defining strategies to further enhance their infiltration, migration throughout
tumor masses, and function in cancer will inform cell engineering strategies for improved treatment. Here, we
test a number of focused hypotheses using advanced optical imaging with state-of-the-art in vivo systems,
engineered environments, genome engineering, and mathematical modeling to better define how T cells
successfully move through some environments but are impeded by others. We hypothesize that by defining
design criteria that can be employed to help engineer T cells to move throughout tumor volumes we can
profoundly improve therapeutic efficacy and employ combinations therapies to improve disease outcomes.
Therefore, here, through advanced imaging and quantitative analysis we will dissect physical and molecular
mechanisms governing migration and function of both native and engineered T cells. We will define the roles of
both matrix architecture and immunosuppressive cells populations, and the links between the two. This
information will provide tookits to engineer T cells that most effectively move throughout the entire tumor mass.
Our goals are aligned with the TECH unit, where we will perform iterations between experiments, analysis, and
technology development, and RTB-2 to define approaches to improve therapy in poor prognosis cancers.
Collectively, we seek to elucidate fundamental mechanisms of immune cell migration and define approaches to
transform cell engineering therapies to eradicate cancer.

## Key facts

- **NIH application ID:** 10782990
- **Project number:** 5U54CA268069-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Paolo Provenzano
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $340,570
- **Award type:** 5
- **Project period:** 2021-12-09 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782990

## Citation

> US National Institutes of Health, RePORTER application 10782990, Research Testbed 1 (5U54CA268069-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10782990. Licensed CC0.

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