# Addressing tumor heterogeneity in pediatric gliomas with precision adoptive T cell therapy

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $474,656

## Abstract

Project Summary
Tumor-specific immunotherapy is a promising modality capable of improving clinical outcomes for
children affected with high-grade glioma (HGG). We have pioneered a ‘first-generation’ adoptive
cellular therapy (ACT) platform utilizing total tumor RNA-pulsed dendritic cells (DCs) to expand
polyclonal tumor-specific T cells for the treatment of invasive and refractory brain cancers. We
have demonstrated the safety, feasibility, and promising pre-clinical and early clinical efficacy of
this approach, including prolonged disease-free remission in some treated subjects (>2 to 5 years)
and radiographic and clinical response in first-in-human phase I/II clinical trials treating patients
with medulloblastoma (MB), HGG, and brain stem glioma (FDA INDs 14058 and 17298).
 In this proposal, we will develop a ‘next-generation’ precision ACT approach using a
combination of patient-specific antigen profiling using a novel cancer immunogenomics-based
algorithm developed in our lab, a novel gene enrichment strategy that allows us to target hundreds
of tumor-specific antigens in a single pool of RNA (tsRNA), and the SELEX-CTL (Selective
Expansion of Cytotoxic T Lymphocytes) platform for the stimulation and selective enrichment of
polyclonal tumor-reactive T cells from precursor frequency of 1-3% after stimulation with tsRNA-
pulsed DCs. This powerful approach to generating enriched T cell populations recognizing a
plurality of tumor antigens uniquely addresses the challenge of dealing with tumor antigenic
heterogeneity and confronting the reality of patient-to-patient variation in antigen expression in
the development of antigen targeting strategies. We hypothesize that given the preclinical and
clinical data we have generated demonstrating the capacity to engender a polyclonal T cell
response against HGGs and MB antigens using DCs pulsed with unrestricted total tumor RNA,
the approach studied within this proposal of selectively identifying and amplifying patient-specific
tsRNA and uniquely identifying, sorting, and expanding responding tumor-specific T cells for use
in ACT will constitute a highly significant and highly effective precision immunotherapy approach
for the treatment of pediatric patients with invasive HGG. Our SPECIFIC AIMS will be to:
1. Evaluate the safety, efficacy, and immunologic effects of ACT targeting neoantigens and
 uniquely expressed tumor-associated antigens (TAAs) in preclinical models of pediatric HGG;
2. Determine the capacity to selectively isolate and expand antigen-specific memory T cells in
 vitro from pediatric patients with HGG who have received ACT at our center;
3. Conduct a phase 1 clinical trial of precision ACT targeting tumor-specific antigens in children,
 adolescents, and young adults (AYAs) with invasive HGG.

## Key facts

- **NIH application ID:** 10945623
- **Project number:** 1R01CA293376-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** DUANE A. MITCHELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,656
- **Award type:** 1
- **Project period:** 2024-08-12 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945623

## Citation

> US National Institutes of Health, RePORTER application 10945623, Addressing tumor heterogeneity in pediatric gliomas with precision adoptive T cell therapy (1R01CA293376-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10945623. Licensed CC0.

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