# HORMAD-specific TGF-beta resistant memory T cells for treatment of patients with Gastro-esophageal Cancer

> **NIH NIH UG3** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $1,310,673

## Abstract

Project Summary
This proposal addresses three major challenges in adoptive cellular therapy: 1) T cell persistence; 2) Tumor
immune resistance and 3) Target epitope identification for solid tumors, bringing together the expertise of Dr.
Yee in T cell therapy, Dr. Rai in epigenetics and Dr. Morelli in clinical trials. We have established a strategy for
generating memory T cells from peripheral blood of patients, via an ACT modality known as Endogenous T Cell
(ETC) therapy pioneered in the Yee lab, allowing us to target HORMAD1, a cancer testis antigen broadly
expressed in gastric and esophageal cancer, which in its advanced stages represents a significant unmet need.
By applying rationally designed combinations of epigenetic modulators we plan to optimize the replicative
capacity and memory properties of HORMAD1-specific CTL (HMD-CTL) generate ex vivo to address the
challenge of limited in vivo T cell persistence (UG3 Aim 1). One of the dominant extrinsic factors mediating tumor
immune resistance in gastric and esophageal cancer is the influence of TGF-β in the tumor microenvironment.
In addressing this challenge, we propose the use of a dominant negative TGF-β receptor to sequester TGF-β by
engineering expression of the TGFBDNR2 gene into HORMAD1-specific CTL using a retroviral transduction
strategy that is well-established in the Cell Therapy Manufacturing Center (UG3 Aim 2). Finally, addressing the
challenge of targeting gastric and esophageal cancers was borne out of an ongoing antigen discovery pipeline
developed over 5 years examining the portfolio of tandem mass spectrometric defined epitopes eluted from MHC
of over 30 tumor samples. From this pipeline we have empirically validated both an HLA-A2 and HLA-A11
epitopes of HORMAD1, demonstrated high affinity with CTL generated using the ETC workflow and propose the
use of HORMAD1-specific CTL for this trial, allowing us to cover more than 25% of all gastric and esophageal
patients given the prevalence of HORMAD1 expression in these tumors (> 40%) and HLA allele expression (>
65%). At completion of the UG3 portion of this proposal, we will identify an optimal epigenetic program (Aim 1)
and TGFBDNR2 transduction workflow (Aim 2) that fulfills the metrics for a Go/ No-Go decision. In the clinical
trial component (UH3) these strategies will be assembled to allow us to evaluate safety and duration of in vivo
persistence, comparing HORMAD1-specific CTL and TGFBDNR2-engineered HORMAD-1-specitic CTL in two
cohorts, while assessing for preliminary efficacy in an Expansion arm.
 The ETC platform provides greater flexibility than other ACT modalities in its agility to direct specificity to
almost any desired target epitope, demonstrated evidence of antigen-spreading, minimal toxicities, and has an
established memory potential proven to be sustained in several clinical trials. We anticipate, that with an
enhanced epigenetic memory program and, endowed with a mechanism to undermine at least one feature of
...

## Key facts

- **NIH application ID:** 10931656
- **Project number:** 5UG3CA283615-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Maria Pia Morelli
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,310,673
- **Award type:** 5
- **Project period:** 2023-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931656

## Citation

> US National Institutes of Health, RePORTER application 10931656, HORMAD-specific TGF-beta resistant memory T cells for treatment of patients with Gastro-esophageal Cancer (5UG3CA283615-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931656. Licensed CC0.

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