# 'Arresting' bone marrow T cell sequestration in patients with GBM

> **NIH NIH P50** · DUKE UNIVERSITY · 2021 · $193,676

## Abstract

ABSTRACT – Project 2
Glioblastoma (GBM) elicits severe local and systemic immune dysfunction, including T cell lymphopenia, which
has remained unexplained and unaddressed for nearly 40 years. Foundational studies characterizing T cell
disappearance from the blood and lymphoid organs of both patients and mice with GBM reveal AIDS-level CD4
counts (< 200 cells/μl), substantial reductions in spleen volume (mean of 30%), and up to 5-fold increases in
naïve T cell counts in bone marrow. Additional work has connected these observations to the loss of sphingosine
1-phosphate receptor 1 (S1P1) from the T cell surface. Specifically, loss of S1P1 results in sequestration of T
cells preferentially in the bone marrow in the context of regressing lymphoid organs such as spleen. In mice,
however, S1P1 can be stabilized on T cells by knocking in a receptor with disrupted cytoplasmic serines to
prevent β-arrestin recruitment, an early step toward receptor internalization. Importantly, β-arrestin-inhibited,
S1P1-stabilized mice implanted with GBM exhibit long-term survival when administered T cell-activating
therapies that were previously ineffective. Likewise β-arrestin2 knockout mice, specifically, prove resistant to T
cell sequestration in the setting of GBM. Building on these findings, Project 2 proposes to set the groundwork for
designing translatable strategies to inhibit β-arrestin2 and stabilize S1P1 as a novel anti-tumor platform. Likewise
the project has an early focus on elucidating biomarkers that correctly identify those patients most likely to benefit
from intervention and when. The project will test the hypothesis that systemically administered β-arrestin2 small
molecule inhibitors developed by the group will effectively hinder S1P1 internalization, stabilize surface T cell
S1P1, free T cells from sequestration, and newly license T cell anti-tumor capacities. This hypothesis will be
tested by the following Specific Aims: Aim 1: Assess in patients the longitudinal variation in T cell sequestration
with tumor resection and treatment and establish predictive biomarkers and contributory mechanisms for T cell
S1P1 loss; Aim 2: Establish the relative contribution of β-arrestin2 to S1P1 internalization and screen candidate
β-arrestin2 small molecule inhibitors for their ability to stabilize S1P1 and abrogate T cell sequestration; Aim 3.
Initiate IND-enabling toxicity and efficacy studies with our leading β-arrestin2 small molecule inhibitor. This study
is expected to provide a foundation for therapeutic approaches enabling T cell release, which our data suggest
would allow immunotherapies to render a more successful antitumor response.

## Key facts

- **NIH application ID:** 10248317
- **Project number:** 5P50CA190991-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Peter Fecci
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,676
- **Award type:** 5
- **Project period:** 2014-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248317

## Citation

> US National Institutes of Health, RePORTER application 10248317, 'Arresting' bone marrow T cell sequestration in patients with GBM (5P50CA190991-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10248317. Licensed CC0.

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