# Gamma delta T-cell immunotherapy for T-cell acute lymphoblastic leukemia

> **NIH NIH K08** · EMORY UNIVERSITY · 2024 · $224,496

## Abstract

Project Summary
My long-term career goal is to become an independent physician-scientist with a research focus in developing
novel cellular immunotherapeutics for pediatric blood cancers, especially T-cell acute lymphoblastic leukemia
(T-ALL). My clinical experiences as a pediatric oncologist have driven my research interest to develop better
therapies for these patients. This proposal outlines a series of preclinical experiments, which in combination
with complementary didactics and interdisciplinary mentorship, will provide a promising platform to advance my
training in immunology, cancer animal models, and cellular therapy development. This work will be completed
under the exceptional mentorship team of Drs. H. Trent Spencer, Edmund K. Waller and Douglas K. Graham,
given their collective expertise in cell and gene therapy, translational immunology and leukemia biology.
Survival for patients with relapsed T-ALL remains extremely poor. Although allogeneic hematopoietic stem cell
transplant (HSCT) provides a chance of cure, attaining disease remission is necessary prior to HSCT, but is
seldom achieved. In this research, we capitalize on the promise of gamma delta (γδ) T cells which unlike the
more predominant alpha beta (αβ) T cells, do not require antigen presentation and identify their targets in a
major histocompatibility complex independent manner. Allogeneic γδ T cells, thus have a minimal risk of
causing graft-versus-host disease and can be used to create ‘off-the-shelf’ cellular therapeutics. This is ideal to
target T-ALL given the aggressive nature of relapsed disease. Inherent cytotoxic mechanisms used by γδ T
cells include recognition of cellular stress molecules such as NKG2D and DNAM-1 receptor ligands and
interactions with death pathway receptors Fas and TRAIL-R1/R2 on target cells. Our promising data shows
that these markers are overexpressed in T-ALL, making them susceptible to γδ T-cell mediated killing.
Furthermore, stress ligand expression can be upregulated by proteasome inhibition, epigenetic modification,
and through use of traditional chemotherapeutic agents. We also predict that malignant T-ALL cells can be
directly targeted by γδ T cells using CD5-directed chimeric antigen receptors (CARs). CAR T-cell therapy has
been challenging in T-ALL given the lack of a specific target antigen on cancerous T cells. However, we have
shown that expression of a CAR directed against the pan surface T-cell marker CD5, results in surface CD5
downregulation, thereby reducing the fratricidal effect among CD5-CAR T cells. Additionally, the limited
persistence of γδ T cells negates the possibility of life-threatening immune suppression from T-cell aplasia,
which may be seen with a CAR-based approach using αβ T cells. Thus, our overarching hypothesis is that the
intrinsic cytotoxic activity of γδ T cells can be enhanced and directed towards cancerous T-ALL cells. In Aim 1,
we will utilize cellular stress modulation by three distinct mechanisms t...

## Key facts

- **NIH application ID:** 10813751
- **Project number:** 5K08CA248962-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sunil Sudhir Raikar
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $224,496
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813751

## Citation

> US National Institutes of Health, RePORTER application 10813751, Gamma delta T-cell immunotherapy for T-cell acute lymphoblastic leukemia (5K08CA248962-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10813751. Licensed CC0.

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