- Chimeric antigen receptor (CAR) T-cells that target single antigens in glioblastoma have demonstrated initial efficacy, but disease recurrence and immune escape were eventually noted
- Researchers at Massachusetts General Hospital have developed a novel CAR T-cell that simultaneously targets EGFRvIII and IL-13Rα2, two antigens frequently found on glioblastoma cells and absent or expressed at low levels in healthy brain tissue
- TanCART, as the transgene construct is known, was superior to monospecific CAR T-cells in vitro and in murine models of heterogeneous tumors, including patient-derived glioblastoma
- Clinical trials of TanCART are planned
Because of the remarkable success of chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, CAR T-cells that target a single antigen are being trialed in glioblastoma. Unfortunately, despite initial responses, this approach has been associated with tumor progression and immune escape. Targeting multiple antigens simultaneously has the potential to mitigate this effect.
Subscribe to the latest updates from Neuroscience Advances in Motion
Researchers at Massachusetts General Hospital have developed a novel tandem CAR T-cell (TanCART) with dual specificity for EGFRvIII and IL-13Rα2, housed in a single transgene construct. In preclinical studies, TanCART was effective against heterogeneous tumors in the brain, as the team reports in Neuro-Oncology Advances.
The study was led by senior author Bryan D. Choi, MD, PhD, associate director of the Center for Brain Tumor Immunology and Immunotherapy and attending neurosurgeon in the Pappas Center for Neuro-Oncology. Co-authors include Bob S. Carter, MD, PhD, chief of the Department of Neurosurgery, William T. Curry, MD, chief medical officer of Mass General, and Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Cancer Center, among several others.
EGFRvIII and IL-13Rα2 are unique among glioblastoma-associated surface antigens in being completely absent or expressed only negligibly in healthy brain tissues. Targeting them minimizes the risks of off-tumor toxicity.
Moreover, a recent study published in Nature Communications showed EGFRvIII and IL-13Rα2 can be co-expressed in the same cell and intracellular crosstalk between the two molecules confers a growth advantage to tumors. That makes the two antigens an especially favorable combination for concomitant targeting.
Promising Preclinical Results
In preclinical testing of TanCART, the principal observations were:
- In vitro—TanCART displayed enhanced cytotoxicity against heterogeneous glioblastoma populations, including patient-derived tumor cultures (P<0.05)
- In vivo—TanCART treatment was associated with complete and durable responses in murine models of heterogeneous glioblastoma, including patient-derived xenografts
The anti-tumor activity of TanCART was superior to that of monospecific CAR T-cells (P<0.05), suggesting the construct warrants investigation in glioblastoma clinical trials.
Learn more about the Stephen E. and Catherine Pappas Center for Neuro-Oncology
Refer a patient to the Department of Neurosurgery at Mass General