Case Series: Intraventricular Infusion of Dual-targeting CAR T-Cells for Glioblastoma

Chimeric antigen receptor (CAR) T-cells have become standard care for lymphoid malignancies, but the utility of this approach in solid tumors is unproven. For patients with glioblastoma, CAR T-cells have been used to target only single antigens and have been limited by tumor heterogeneity, emergence of antigen loss, and eventual immune escape.

Subscribe to the latest updates from Neuroscience Advances in Motion

Thank you for subscribing!

Error: Please enter a valid email address.

Email Address Submit

A novel CAR T-cell therapy for glioblastoma has been co-engineered by Bryan D. Choi, MD, PhD, associate director of the Center for Brain Tumor Immunology and Immunotherapy at Massachusetts General Hospital and a neurosurgeon in the Stephen E. and Catherine Pappas Center for Neuro-Oncology, and Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at Mass General Cancer Center, and the Paula O'Keefe professor of Oncology at Harvard Medical School.

Called CARv3-TEAM-E, the therapy targets the EGFR variant III tumor-specific antigen (EGFRvIII) through a CAR while secreting T-cell–engaging antibody molecules (TEAMs) against wild-type EGFR protein, which is nearly always expressed in glioblastoma.

In The New England Journal of Medicine, the researchers present data from a prespecified interim analysis of the first three patients treated with CARv3-TEAM-E. They report proof of principle that CAR T-cells can target multiple surface antigens simultaneously and confirm EGFR as a suitable immunotherapeutic target in glioblastoma.

Methods

The team is conducting the INCIPIENT trial (Intraventricular CARv3-TEAM-E T Cells in Patients with Glioblastoma), a first-in-human, nonrandomized, open-label, single-site phase 1 study evaluating the safety of CARv3-TEAM-E in patients with recurrent or newly diagnosed glioblastoma.

Participants in the safety run-in cohort were adults with grade 4 recurrent EGFRvIII-positive glioblastoma. The first three were enrolled between March and July 2023. The protocol called for them to receive 10×10⁶ CAR-positive CARv3-TEAM-E T cells as a single intraventricular infusion.

MRI Results

Tumor regression, as evaluated radiographically, was dramatic and rapid:

• Participant 1, a 74-year-old man—MRI on day 1 after infusion showed rapid tumor regression, which was confirmed on additional scans over the next two weeks but was ultimately transient. This patient received a second infusion of CARv3-TEAM-E on day 37.
• Participant 2, a 72-year-old man—MRI on day 2 showed a decrease in tumor area by 18.5% from the pre-infusion baseline, and by day 69, the decrease was 61%. The response continued to improve and remained durable at the latest assessment, more than 150 days after the single infusion, in the absence of glucocorticoid or antiangiogenic therapy.
• Participant 3, a 57-year-old woman—MRI on day 5 showed nearly complete tumor regression, but evidence of recurrence appeared within one month after infusion.

Adverse Events

The TEAMs secreted by the CAR T-cells were safe despite widespread expression in systemic tissues. Grade 3 events considered at least possibly related to treatment were encephalopathy for three days in participant 1 and fatigue for eight days in participant 3 (both deemed probably related).

Commentary

The eventual tumor progression in two study participants corresponded partly with the limited persistence of CARv3 TEAM-E T cells over the weeks after infusion. CARv3-TEAM-E should be evaluated with strategies designed to enhance durability, such as preconditioning with chemotherapy or scheduling additional infusions.

For more information, you can contact the study team by email.

view original journal article Subscription may be required

Learn more about the Stephen E. and Catherine Pappas Center for Neuro-Oncology

Refer a patient to the Department of Neurosurgery at Mass General