# Project 3: Exploit Immune Consequences of U1 Mutations in Sonic Hedgehog (Shh) Medulloblastoma

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $340,888

## Abstract

SUMMARY: PROJECT 3
Medulloblastoma (MB), the most common malignant pediatric brain tumor, is responsible for significant morbidity
and mortality in the United States. Of the different subtypes of MB, Sonic Hedgehog (Shh) is the most common
and patients with Shh-α (mostly adolescents) who have TP53 mutations have nearly 100% mortality, and those
with Shh-δ (mostly adults) experience significant morbidity from standard treatment with craniospinal radiation,
and have extremely poor outcomes with limited treatment options once the tumor recurs. How best to treat these
Shh MBs remains a significant problem in brain tumor therapeutics. In this context, we recently identified a unique
somatic point mutation in a non-coding small nuclear RNA (snRNA) called U1 in 50% of Shh medulloblastomas.
This mutation, U1 (r.3A>G), is found in 97% of Shh-δ tumors and >65% of Shh-α tumors with TP53 mutations.
The U1 snRNA is an essential component of the spliceosome, and tumors with this mutation exhibit a unique
form of post-transcriptional hypermutation which results in the expression of thousands of novel epitopes that
are not expressed in normal human tissue. Because hypermutant cancers are often responsive to immune
checkpoint inhibitors (ICI) therapy, we hypothesize that U1 mutant Shh MBs will be similarly responsive to ICIs.
In addition, because novel tumor-specific antigenic epitopes arise from aberrant splicing in U1-mutant Shh MBs,
we hypothesize that the novel intron-derived epitopes in U1 mutants constitute excellent targets for the
development of selective immunotherapies, particularly CAR T cells. To test these hypotheses we will: conduct
a phase II clinical trial of nivolumab and ipilimumab in patients with Shh MB and correlate the clinical outcomes
with U1 mutation status (Aim 1); identify novel tumor antigenic epitopes, characterize the tumor
microenvironment and delineate the molecular biology of cells along the differentiation hierarchy in U1-mutant
Shh MBs through state-of-the-art transcriptomic profiling and analysis (Aim 2); and prioritize U1-mutation driven
tumor antigenic epitopes and use these epitopes to design, develop and test CAR T cells in preclinical models
of Shh MB (Aim 3). These aims will be achieved through collaborations across multiple institutions to facilitate
accrual to the proposed clinical trial and for the development of targeted U1 Shh MB-specific CAR T cells.

## Key facts

- **NIH application ID:** 10847569
- **Project number:** 2P50CA127001-16
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael D. Taylor
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $340,888
- **Award type:** 2
- **Project period:** 2008-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847569

## Citation

> US National Institutes of Health, RePORTER application 10847569, Project 3: Exploit Immune Consequences of U1 Mutations in Sonic Hedgehog (Shh) Medulloblastoma (2P50CA127001-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10847569. Licensed CC0.

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