# Project 3: Novel B-SYNC T cell therapy with CNS-specific expression of CAR as a safe and effective therapy for glioblastoma

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $405,933

## Abstract

Project Summary/Abstract
The development of safe and effective chimeric antigen receptor (CAR)-transduced T cell (CART) therapy for
glioblastoma (GBM) needs to overcome multiple challenges, including heterogeneity of antigen expression, on-
target off-tumor toxicity, and exhaustion of CART cells. To date, there are no GBM-specific antigens that are
uniformly present on all GBM cells. On the other hand, while non-mutant GBM-associated antigens (GAAs),
including Ephrin type A receptor 2 (EphA2) and interleukin-13 receptor α2 (IL-13Rα2), are expressed in the
majority of GBM cells, they are also expressed in some non-central nervous system (CNS) organs, raising the
concern of off-tumor toxicity. As a way to safely and effectively target GAAs, we have adopted a novel synthetic
Notch “synNotch” receptor system and developed innovative “prime-and-kill” T cell circuits. In this system, the
first antigen, which is expressed exclusively on GBM or CNS cells, primes the T cells to induce the expression
of a CAR that recognizes IL-13Rα2 and EphA2, thereby eradicating GBM cells expressing either EphA2 or IL-
13Rα2. The first priming antigen should be restrictedly expressed on CNS cells but not on cells of any (non-
CNS) systemic organs. Then the system should be safe because, within the CNS, EphA2 and IL-13Rα2 are
expressed only on tumor cells and not on normal CNS cells. We found Brevican (BCAN), a proteoglycan localized
to the neuronal and glial cell surface, as the most promising priming antigen. When mice bearing well-established
day 9 intracerebral GBM6 PDX tumors received a single IV infusion of T cells engineered with the α-BCAN
synNotchα-EphA2/IL-13Rα2 CAR (B-SYNC) circuit, all mice demonstrated complete regression of tumor
without attacking EphA2/IL-13Rα2-positive cells outside of CNS. Furthermore, these B-SYNC T cells were
significantly more efficacious than conventional, constitutively expressed EphA2/IL-13Rα2 CART cells, with
superior CNS tumor-homing and less exhausted phenotype compared to control T cells. We will develop a phase
I study to evaluate our hypothesis that B-SYNC T cells can be safely administered as a single IV infusion in
patients with GBM and that B-SYNC T cells are able to infiltrate the GBM tissue, wherein they will be primed to
express the CAR against EphA2 and IL-13Rα2. Concurrently, using syngeneic mouse models, we will evaluate
our 2nd hypothesis that modulation of immunoregulatory mechanisms may further improve the function and
efficacy of B-SYNC T cells. We will evaluate the following two specific aims.
Aim 1. Determine the safety as well as the homing and priming status (i.e., expression of CAR) of the IV-infused
B-SYNC T cells in patients with GBM.
Aim 2. Assess potential resistance mechanisms and integrate mitigation strategies into the B-SYNC regimen in
preclinical syngeneic models. In a prior trial with anti-EGFRvIII CART cells, the CART cells infiltrated the GBM
and induced immunoregulatory molecules, such as progra...

## Key facts

- **NIH application ID:** 10712670
- **Project number:** 2P50CA097257-21
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Hideho Okada
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $405,933
- **Award type:** 2
- **Project period:** 2002-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10712670

## Citation

> US National Institutes of Health, RePORTER application 10712670, Project 3: Novel B-SYNC T cell therapy with CNS-specific expression of CAR as a safe and effective therapy for glioblastoma (2P50CA097257-21). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10712670. Licensed CC0.

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