# Bioactivity of CAR T cells secreting T cell engager-anitbodies in humans with glioblastoma

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $652,725

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM) is a deadly brain tumor with limited treatment options. We have developed a promising new
treatment for GBM using chimeric antigen receptor (CAR)-T cells. CAR-T cells are derived from the patient’s
own T cells and genetically modified to express a receptor that will target the cancer cells through a specific
antigen. We first developed CAR-T cells targeting epidermal growth factor receptor variant III (EGFRvIII), a
mutated form of EGFR that is uniquely expressed in GBM. Treating patients with EGFRvIII-CAR-T cells resulted
in decreased EGFRvIII-expressing cells, while EGFR expression remained the same or increased. With
EGFRvIII-CAR-T cell treatment, there was also infiltration of T regulatory cells (Tregs), which are known to
suppress T cell function and may have limited CAR-T cell killing of tumor cells. To improve this therapy, we
engineered the EGFRvIII-CAR-T cell to secrete a T cell-engaging antibody molecule (TEAM) that binds to EGFR
and CD3 (CARv3.TEAM-E cells). The TEAM allows the CAR-T cell to target more than one antigen while also
activating other (non-CAR) T cells within the tumor, including converting Tregs to killer cells. We tested
CARv3.TEAM-E cells in vitro and in mouse xenograft models and found they safely and effectively target
EGFRvIII+EGFR+ and EGFRvIII–EGFR+ GBM. When these cells were injected into the mouse brain for direct
access to the tumor, very few escaped into the peripheral circulation, which protected normal tissues with EGFR
expression from being targeted by the TEAM. Based on these preclinical results, we are initiating a phase I
clinical trial of the CARv3.TEAM-E cells for the treatment of primary or recurrent GBM. The CARv3.TEAM-E cells
will be injected into the cerebrospinal fluid (CSF) via an Ommaya reservoir. We will measure the safety of this
treatment by monitoring patients for adverse events related to CAR-T treatment and EGFR targeting.
Additionally, we will perform correlative studies to monitor CAR-T cell expansion, persistence, and phenotype in
the CSF and peripheral blood as well as infiltration into the tumor. We will examine the tumor for changes in
antigen expression (EGFRvIII, EGFR, etc.) with CARv3.TEAM-E cell infiltration and changes in other immune
cells that could be influencing CARv3.TEAM-E cell function, including Tregs and myeloid cells. We will correlate
these parameters with responses to treatment or toxicities that we observe in each patient. Overall, these studies
will inform us about the safety and feasibility of CARv3.TEAM-E cells for treating GBM, as well as provide insights
into future modifications that could improve the efficacy of these CAR-T cells or lessen their side effects.
CARv3.TEAM-E cells hold promise for improving the outcome of this dismal disease.

## Key facts

- **NIH application ID:** 10979322
- **Project number:** 1R01CA294071-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Bryan Choi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $652,725
- **Award type:** 1
- **Project period:** 2024-09-19 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979322

## Citation

> US National Institutes of Health, RePORTER application 10979322, Bioactivity of CAR T cells secreting T cell engager-anitbodies in humans with glioblastoma (1R01CA294071-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979322. Licensed CC0.

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