CAR T-cell therapy shrinks glioblastoma tumors in days

Mass General Cancer Center researchers reported on March 13, 2024 that an experimental CAR-T therapy produced rapid tumor shrinkage in the first three patients treated for recurrent glioblastoma, according to a paper in the New England Journal of Medicine and a related hospital release. The treatment, called CARv3-TEAM-E, is being tested in the phase 1 INCIPIENT trial at Mass General Brigham. The early responses included one patient whose tumor showed near-complete regression within five days of a single infusion. The researchers also said the responses were not uniformly durable, and tumor progression later returned in the patients described. ### Which therapy produced the rapid scans that circulated online? CARv3-TEAM-E is a next-generation CAR-T product engineered to target EGFRvIII, a tumor-specific mutation found in some glioblastomas, while also secreting a T-cell engager directed at wild-type EGFR, the Mass General and NEJM reports said. The design is meant to address a central problem in glioblastoma: tumor cells within the same cancer can differ from one another, leaving single-target therapies with gaps. (massgeneral.org) The March 2024 paper described the treatment as an intraventricular infusion, meaning the engineered cells were delivered into the brain’s ventricular system rather than through a standard intravenous route. The trial is designed to evaluate safety in patients with recurrent glioblastoma. (massgeneral.org) ### What exactly happened in the first three patients? The New England Journal of Medicine paper said all three patients had recurrent glioblastoma and all three showed radiographic tumor reductions within days after treatment. Participant 1, a 57-year-old woman, had near-complete tumor regression five days after infusion, according to the paper and the hospital release. (massgeneral.org) Participant 2, a 72-year-old man, showed tumor regression on MRI by day 2 after infusion, and the NEJM slide deck said the regression was sustained at later time points. Participant 3, a 74-year-old man, also had rapid imaging changes after a single infusion, the paper reported. The hospital release said the first three patients experienced “dramatic responses within days,” but it also said the researchers later observed tumor progression. (massgeneral.org) The paper framed the findings as preliminary case data from an ongoing phase 1 study rather than proof of long-term benefit. (nejm.org) ### Why is glioblastoma a hard target for CAR-T therapy? Glioblastoma has long been difficult for cell therapy because the tumors are biologically heterogeneous and can change under treatment pressure, Bryan Choi, a Mass General neurosurgeon and study author, said in the hospital release. Choi said solid tumors such as glioblastoma have remained challenging because “not all cancer cells are exactly alike and cells within the tumor vary.” (massgeneral.org) A 2016 NEJM report had already shown that CAR-T therapy could induce regression in a patient with recurrent multifocal glioblastoma, but broader and more durable activity has remained difficult to establish. The new Mass General approach combines a mutation-specific CAR with a secreted engager against EGFR, aiming to widen the number of tumor cells that can be attacked. ### What should readers be careful not to overstate? (massgeneral.org) The March 2024 paper involved three reported cases from an early-stage safety trial, not a randomized study, and the authors said tumor progression eventually occurred after the initial regressions. The trial’s stated goal is safety evaluation, and the researchers said they planned to pursue ways to extend the durability of response. (nejm.org) The images that spread on social media reflected real trial data, but they did not by themselves show that the therapy is a proven treatment for glioblastoma. The evidence so far is early clinical evidence from a small number of patients under close monitoring in a specialized research setting. (massgeneral.org) ### What comes next in this research? The INCIPIENT study protocol says enrollment in recurrent glioblastoma arms precedes enrollment in newly diagnosed disease, with dose levels for newly diagnosed patients tied to what is shown to be safe in earlier arms. The protocol also says the cell product is manufactured over roughly three to four weeks before release to the study site, if safety requirements are met. (massgeneral.org) Mass General Brigham said in its March 2024 release that the team would pursue strategies to improve durability after the early responses. The named investigators on the effort include Bryan Choi, Marcela Maus, Elizabeth Gerstner, Matthew Frigault and William Curry. (massgeneral.org) (nejm.org)