A novel CAR-T cell therapy has demonstrated remarkable early success in treating patients with recurrent glioblastoma (GBM), a highly aggressive form of brain cancer. The Phase 1 clinical trial, known as INCIPIENT (NCT05660369), evaluated the safety and efficacy of CARv3-TEAM-E T cells in three patients with recurrent GBM, revealing dramatic tumor regression in all cases following a single infusion. The study, published in The New England Journal of Medicine, offers a promising new avenue for treating this challenging disease.
CAR-TEAM Strategy Targets Glioblastoma Heterogeneity
Traditional CAR-T therapies have shown limited success in solid tumors like glioblastoma due to the heterogeneous nature of cancer cells within the tumor. To overcome this challenge, researchers at Mass General Cancer Center developed a CAR-TEAM approach that combines CAR-T cells with bispecific antibodies, known as T-cell engaging antibody molecules (TEAMs). This innovative strategy targets both EGFRvIII, a common cancer mutation, and wild-type EGFR, which is expressed in over 80% of GBM cases but not typically found in normal brain tissue.
Rapid Tumor Regression Observed
In the INCIPIENT trial, three patients with recurrent GBM who had previously undergone standard-of-care radiation and temozolomide chemotherapy were enrolled. Following a single infusion of CAR-TEAM cells, patients experienced rapid and significant tumor regression. One patient achieved near-complete tumor regression, while another showed an 18.5% decrease in tumor size just two days post-infusion, which further decreased to 60.7% by day 69 and was sustained for over six months. The third patient also experienced rapid tumor regression, although transiently.
Clinical and Translational Significance
"This is a story of bench-to-bedside therapy, with a novel cell therapy designed in the laboratories of Massachusetts General Hospital and translated for patient use within five years, to meet an urgent need," said Bryan Choi, MD, PhD, neurosurgeon and associate director of the Center for Brain Tumor Immunology and Immunotherapy, Cellular Immunotherapy Program, Mass General Cancer Center and Department of Neurosurgery. The CAR-T platform has revolutionized how we think about treating patients with cancer, but solid tumors like glioblastoma have remained challenging to treat because not all cancer cells are exactly alike and cells within the tumor vary. Our approach combines two forms of therapy, allowing us to treat glioblastoma in a broader, potentially more effective way."
Durability and Future Directions
Despite the initial success, researchers observed eventual tumor progression in all three patients, which correlated with the limited persistence of CAR-TEAM cells. To address this, the team is exploring strategies such as serial infusions and preconditioning with chemotherapy to prolong the response. "We report a dramatic and rapid response in these three patients. Our work to date shows signs that we are making progress, but there is more to do," said co-author Elizabeth Gerstner, MD, a neuro-oncologist in the Department of Neurology at Massachusetts General Hospital.
The study was supported by grants from Gateway for Cancer Research, the Mass General Cancer Center, Mass General Brigham, and philanthropic gifts. The CAR-T cells were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.
