# Tumor Stroma Breaking System for Efficient Delivery of Therapeutic Agents

> **NIH NIH R41** · MIGRA-THERAPEUTICS, LLC · 2020 · $105,503

## Abstract

Cancer immunotherapy using adoptive T cell transfer has shown its promises in the treatment of hematological
malignancies. Despite tremendous efforts, results of clinical trials using tumor infiltrating lymphocytes or
engineered CAR-T cells in human solid tumors have not produced desired therapeutic responses. In solid
tumors, there are multiple barriers that prevent cytotoxic T cells reaching tumor cells. First, abnormal blood
vessels limit T cell delivery into solid tumors, especially tumor center. The presence of dense tumor stromal cells
and extracellular matrix create a physical barrier that traps T cells in an immunosuppressive stroma
microenvironment. Therefore, there is an unmet need to develop novel approaches to improve delivery efficiency
of cytotoxic T cells in solid tumors. The translational goal of the proposed phase I research is to develop
and validate a stroma-breaking therapeutic T cell delivery system for immunotherapy in human solid
tumors with a focus on pancreatic and colon cancers. We have developed a receptor targeted and stroma
breaking drug delivery platform with novel designs to overcome tumor stromal cellular and extracellular matrix
barriers. We have demonstrated its ability to deliver nanoparticle-drug crossing tumor vessels, migrating through
tumor stroma, and penetrating the basement membrane to reach tumor cells. This recombinant targeting ligand
consists of urokinase plasminogen activator receptor (uPAR) binding domain of uPA fused with the catalytic
domain of matrix metalloproteinase-14 (ATFmmp14). Our preliminary results showed that co-delivery of T cells
with ATFmmp14 ligands led to significant increases in the numbers of T cells delivered in tumors following
intravenous delivery in mouse colon and pancreatic tumor models as well as a human colon cancer patient
derived xenograft (PDX) model. In this phase I project, we aim to determine the effect of ATFmmp14-T cell
delivery system on intratumoral delivery and distribution using the MHC-non-restricted cytotoxic ɣδ T cells as a
T cell model system in human colon and pancreatic cancer PDX models. First, we will develop the best
formulation of ATFmmp14 conjugated T cell delivery platform using ɣδ T cells obtained from healthy donors in
human pancreatic and colon PDX models (Aim1). Next, we will determine whether ATFmmp14 ligand can
improve selective delivery of ɣδ T cells into pancreatic and colon PDX tumors and promote cell migration through
stroma and basement membrane barriers to reach tumor cells (Aim 2). Biodistribution and systemic toxicity in
normal organs and tissues will also be evaluated (Aim 2). Finally, the therapeutic efficacy of targeted delivery of
ɣδ T cells without or with the combination of a chemotherapy drug will be determined in pancreatic and colon
PDX models (Aim 3). Results of the above proposed studies should allow us building a strong foundation for
conducting further translational studies in the Phase II research project to bring this ap...

## Key facts

- **NIH application ID:** 10261732
- **Project number:** 3R41CA247165-01A1S1
- **Recipient organization:** MIGRA-THERAPEUTICS, LLC
- **Principal Investigator:** H TRENT SPENCER
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $105,503
- **Award type:** 3
- **Project period:** 2020-06-23 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261732

## Citation

> US National Institutes of Health, RePORTER application 10261732, Tumor Stroma Breaking System for Efficient Delivery of Therapeutic Agents (3R41CA247165-01A1S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10261732. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*