Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma
Related Experiment Video
Updated: Aug 11, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Andrea Schmidts1, Ambike A Srivastava1, Rishab Ramapriyan2
1Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Background:
Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape.
Methods:
Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors.
Results:
Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < .05).
Conclusions:
We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.
Insights
This study introduces a novel dual-specific CAR T-cell therapy (TanCART) that effectively targets multiple antigens in glioblastoma. This approach shows promise for durable responses in heterogeneous brain tumors, overcoming limitations of single-antigen therapies.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematological malignancies but faces challenges in solid tumors like glioblastoma (GBM) due to tumor heterogeneity and single-antigen targeting.
- Strategies engaging multiple antigens simultaneously can enhance therapeutic efficacy and overcome immune escape mechanisms in cancers.
Purpose of the Study:
- To develop and evaluate a novel dual-specific, tandem CAR T (TanCART) cell therapy targeting EGFRvIII and IL-13Rα2 antigens on GBM cells.
- To assess the efficacy of TanCART against heterogeneous GBM models, including patient-derived xenografts.
Main Methods:
- Development of a dual-specific tandem CAR T (TanCART) construct targeting EGFRvIII and IL-13Rα2.
- Evaluation using standard immunological assays and orthotopic preclinical models, including patient-derived xenografts.
Main Results:
- TanCART demonstrated enhanced in vitro cytotoxicity against heterogeneous GBM cell populations.
- Dual antigen targeting via TanCART was essential for achieving complete and durable responses in orthotopic murine models of heterogeneous GBM, outperforming single-antigen CAR T cells.
Conclusions:
- TanCART exhibits efficacy against heterogeneous brain tumors, supporting its further development for GBM treatment.
- Multi-specific CAR T-cell strategies hold significant potential for treating GBM and other complex cancers.
More Related Videos
08:04In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
08:46A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
