NEW YORK – A new type of autologous cell therapy, dubbed CARv3-TEAM-E, may benefit patients with recurrent glioblastoma, according to an encouraging, albeit extremely small, first-in-human trial conducted at Massachusetts General Hospital.
Early results from the first three patients treated with CARv3-TEAM-E were published Wednesday in the New England Journal of Medicine.
"This is something we're very excited about," Bryan Choi, a neurosurgeon at Mass General, said during a press conference to discuss the early results on Thursday morning. "We think that there's a lot of optimism here about the study [although] it's still very early."
The treatment approach involved what Marcela Maus, director of Mass General's Cellular Immunotherapy Program, called a "two-in-one tumor fighter." The researchers took patients' harvested immune cells and engineered them not only to express an EGFR variant III (EGFRvIII)-targeted chimeric antigen receptor (CAR) but also to secrete a T-cell engaging antibody molecule (TEAM) against wild-type EGFR.
"This allows us to target a second molecule on the glioblastoma," Maus said. "And it also recruits other immune cells to join in the fight against the tumor."
Maus, Choi, and colleagues decided to engineer this new type of cell therapy to address the overwhelming need for efficacious treatments against glioblastoma, a highly heterogeneous cancer. In a prior clinical study, Maus and her colleagues had tried to treat patients with EGFR-directed CAR T-cell therapy with limited success. When patients' cancers recurred, the tumors expressed wild-type EGFR and were heavily infiltrated by suppressive regulatory T cells.
These earlier experiments drove the researchers to develop the CARv3-TEAM-E approach.
In the safety run-in cohort within the Phase I study, dubbed INCIPIENT, three patients received CARv3-TEAM-E. They all had advanced, EGFRvIII-mutated glioblastoma for which they had previously received standard-of-care radiation and temozolomide chemotherapy.
After harvesting patients' cells and engineering them to express the CAR and secrete the TEAM, patients received infusions of CARv3-TEAM-E directly into their brain via an Ommaya reservoir.
Although the study's primary goal was to establish the new treatment's safety and tolerability, the researchers also tracked early signs of response using MRI and liquid biopsy assessments.
"We didn't expect to see any sort of improvement in their tumors on imaging at all," Maus said. "We were just hoping to show safety and then to continue to accrue data … but we were surprised and happy to see that this seems to be having an impact on their tumors."
To the researchers' surprise, all three patients experienced dramatic tumor regression within days of their CARv3-TEAM-E infusions. One patient experienced near-complete tumor regression. "The radiographic progressions of the tumor are remarkable, unprecedented, and unlike what we see with currently available therapies," Choi said.
Although two of these patients' responses were transient and they eventually started progressing, Maus believes there may be an opportunity to extend the response durability, for example, by giving patients lymphodepleting chemotherapy prior to the CARv3-TEAM-E infusions. "This helps the incoming immune cells stick around longer," she said. The researchers are also considering serial dosing strategies in which they'd infuse CARv3-TEAM-E repeatedly as opposed to just once.
In terms of safety, the researchers noted that none of the patients experienced dose-limiting toxicities, and although one patient died several months after discontinuing the study, the death wasn't attributable to the cell therapy.
Given these early responses, Maus, Choi, and colleagues are looking forward to continuing their Phase I study and are enrolling up to 21 patients.
"We're hopeful that if we continue to see this level of initial response, and continue to see this safety, then we'll be able to open a larger study," Maus said, adding that she and her colleagues are also planning to bring similarly designed CAR-TEAM therapies to clinical trials for patients with other difficult-to-treat cancers, including pancreatic cancer, renal cell carcinoma, and acute myeloid leukemia.
Maus and Choi acknowledged that Mass General's ability to advance the new cell therapy approach could hinge on industry support. So far, this has been an academic research project, funded through grants and philanthropy without any industry collaboration. Additional support will likely be necessary to conduct larger studies of the cell therapy.
"This probably needs commercial partners. We're one institution," Maus said. "In the long run, if we want to be able to make a difference in the disease, [a trial] will have to be offered in multiple cities around the world."
For now, Maus and Choi are viewing the rapid progression seen in the three glioblastoma patients with cautious optimism. "It's too early to really understand … how much impact we're having on overall survival," Maus said.
But the fact an autologous cell therapy has brought on tumor regression in an advanced, heterogeneous solid tumor — and one deep inside the brain at that — is an encouraging sign. Choi, for one, believes this cell therapy approach may have a place in the new era of immunotherapy in solid tumors.
"We're seeing a mini-renaissance in how our hematologic CAR Ts may be translated into a solid tumor setting," Choi said.