# Engineered T cells for improved migration into solid tumor sites

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2024 · $182,325

## Abstract

Adoptive transfer T cell-based immunotherapies and checkpoint inhibitor immunotherapy have shown
significant promise in the treatment of cancers. However, checkpoint inhibitor therapy still fails in a majority of
patients and chimeric antigen receptor (CAR)-T cells are ineffective against most solid tumors. In large part,
these failures are due to the fact that frequently tumors are mostly devoid of T cells or that T cells are present
only in the tumor-surrounding stroma but largely excluded from the tumor mass. Tumors are often surrounded
by extensive collagen-rich extracellular matrix (ECM) structures, which impede the entry of T cells into the
tumor mass. T cell paucity or exclusion from the tumor site correlate with poor prognosis, limited efficacy of
checkpoint inhibitor immunotherapies, and ineffectiveness of CAR-T cell therapy against solid tumors. Most
cellular tumor immunotherapy approaches to date have focused on reversing T cell exhaustion and increasing
persistence of tumor-specific T cells and CAR-T cells. However, these approaches generally do not solve the
issue of recruitment and infiltration of therapeutic T cells into the tumor. The overall goal of this proposal is to
engineer T cells to enhance their migration into tumors to increase their anti-tumor activity in ‘cold’ tumors and
tumors that exclude T cells from the tumor mass. Our exploratory R21 proposal specifically addresses the
unmet need to improve migration of T cells into tumors by creating T cells with increased capacity to migrate
through restrictive environments. We have found that Formin-like-1 (FMNL1) promotes efficient T cell
extravasation, motility through confined environments, and interstitial migration in vivo. Furthermore, our
preliminary data using a melanoma model show that overexpression of FMNL1 significantly increases the
number of tumor-specific T cells present at the tumor site. Thus, we hypothesize that T cells engineered to
overexpress FMNL1, or its active mutants, will have increased trafficking to the tumor site, deeper infiltration
into the tumor mass, and enhanced anti-tumor activity. We will test our hypothesis with the following Aims:
Aim 1. Determine if overexpression of FMNL1 or its active mutants enhances tumor-specific T cell migration
and accumulation within tumors. Aim 2. Determine if T cells engineered to overexpress FMNL1 have increased
anti-tumor activity and improve the efficacy of checkpoint inhibitor therapy. Overall, we will establish and
validate a platform for T cell bioengineering to improve T cell migration into tumor sites that can be applied to
tumor-infiltrating lymphocyte (TIL) transfer therapy and CAR-T cell therapy for solid tumors. Our novel
approach can both improve the ability of T cells to extravasate at the tumor site, and enhance the capacity of T
cells to migrate through restrictive tissue barriers to infiltrate the tumor mass. From a future translational
standpoint, an additional advantage of this system is that t...

## Key facts

- **NIH application ID:** 10862130
- **Project number:** 1R21CA280145-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jordan Jacobelli
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $182,325
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862130

## Citation

> US National Institutes of Health, RePORTER application 10862130, Engineered T cells for improved migration into solid tumor sites (1R21CA280145-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10862130. Licensed CC0.

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