# Engineering CD4+ T cells to develop a novel immunotherapy for pancreatic cancer

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary:
Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor with limited treatment options and a dismal five-year
survival rate of only 12%, necessitating the development of improved therapeutics for this malignancy. While
cancer immunotherapy has shown promise in hematological malignancies and some solid tumors, the
application of chimeric antigen receptor (CAR) T cell therapy in PDAC faces obstacles due to its unique
characteristics, including desmoplastic stroma and poor T cell infiltration (work by Dr. Lesinski, sponsor). To
overcome these challenges, we propose a groundbreaking approach: using CD4+ T cells expressing high levels
of the enzymatically active molecule CD26 and engineering them with a mesothelin-directed CAR. Previous work
from the Paulos lab (co-sponsor) has demonstrated that CD26 marks T cells with favorable properties, making
them an ideal template for CAR engineering. CD26's enzymatic activity in degrading immunosuppressive
peptides holds promise for remodeling the tumor microenvironment and limiting the myeloid-dominant features
in PDAC. We hypothesize that by engineering CD26+CD4+CAR T cells with a mesothelin-targeted CAR (Meso-
CAR), we can enhance PDAC immunotherapy efficacy. Preliminary data support this hypothesis, with
CD26+CD4+Meso-CAR T cells showing robust activity against PDAC and other mesothelin-positive tumors in
mice. Aim 1 of this grant will focus on assessing the impact of CD26+CD4+Meso-CAR T cells upon remodeling
the tumor microenvironment (TME), including chemokines and myeloid cells that are likely altered by the CD26
enzyme. We will use systemic inhibition and genetic knockout of CD26 to determine the importance of its
enzymatic activity in TME modulation. Aim 2 will elucidate how CD26+CD4+Meso-CAR T cells engage the
endogenous immune response and enhance the efficacy of co-administered, purified CD8+CAR T cells in both
immune-competent and immune-deficient mouse models. The rationale for both aims lies in understanding the
interactions between CD26+CD4+Meso-CAR T cells and the endogenous immune response within the complex
PDAC microenvironment. We propose to deepen this understanding by using congenic orthotopic mouse models
to systematically evaluate the efficacy of CD26+CD4+Meso-CAR T cells and/or CD8+Meso-CAR T cells with
variable CD26 activity (Aim 1) and with alterations in the endogenous host immune system presence (Aim 2).
The anticipated impact of our findings is significant, providing proof-of-principle pre-clinical data supporting the
development of CD26+CD4+ based cell therapy approaches for PDAC patients. Because CD26's enzymatic
action on immunosuppressive peptides may mitigate myeloid-dominant features in PDAC tumors, this approach
offers a promising avenue to improve outcomes in other challenging solid tumors. While we utilize mesothelin
as the target antigen in this proposal, the approach is adaptable to other antigens or neoantigens in PDAC and
other solid tumors. Collecti...

## Key facts

- **NIH application ID:** 10998579
- **Project number:** 1F31CA294972-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Delaney Kate Geitgey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998579

## Citation

> US National Institutes of Health, RePORTER application 10998579, Engineering CD4+ T cells to develop a novel immunotherapy for pancreatic cancer (1F31CA294972-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10998579. Licensed CC0.

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