Summary: Researchers demonstrated significant initial success using CAR-T therapy for glioblastoma, a notoriously deadly brain cancer. They detailed the outcomes of the first three patients in a Phase 1 clinical trial who experienced dramatic tumor reductions shortly after treatment.
This innovative approach combines CAR-T cells with bispecific antibodies to more effectively target the heterogeneous cell populations within solid tumors. While the initial results show promise, the team is exploring ways to enhance the longevity of the therapy’s effectiveness.
Key Facts:
- The study observed rapid tumor regression in patients following a single treatment with the newly developed CAR-TEAM therapy, marking a significant breakthrough in glioblastoma treatment.
- The innovative therapy combines CAR-T cell technology with bispecific antibodies, aiming to address the challenge of tumor cell heterogeneity in solid tumors.
- Despite initial success, researchers noted tumor progression over time, prompting ongoing efforts to improve the durability of the therapy’s effects.
Source: Harvard
A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment.
In a paper published Wednesday in The New England Journal of Medicine, researchers from Mass General Cancer Center shared the results for the first three patient cases from a Phase 1 clinical trial evaluating a new approach to CAR-T therapy for glioblastoma.
Just days after a single treatment, patients experienced dramatic reductions in their tumors, with one patient achieving near-complete tumor regression. In time, the researchers observed tumor progression in these patients, but given the strategy’s promising preliminary results, the team will pursue strategies to extend the durability of response.
“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 co-author Bryan Choi, a neurosurgeon at Harvard-affiliated Mass General and an assistant professor at Harvard Medical School.
“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.”
The new approach is a result of years of collaboration and innovation springing from the lab of Marcela Maus, director of the Cellular Immunotherapy Program and an associate professor at the Medical School.
Maus’ lab has set up a team of collaborating scientists and expert personnel to rapidly bring next-generation genetically modified T cells from the bench to clinical trials in patients with cancer.
“We’ve made an investment in developing the team to enable translation of our innovations in immunotherapy from our lab to the clinic, to transform care for patients with cancer,” said Maus.
“These results are exciting, but they are also just the beginning — they tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease. We haven’t cured patients yet, but that is our audacious goal.”
CAR-T (chimeric antigen receptor T-cell) therapy works by using a patient’s own cells to fight cancer — it is known as the most personalized way to treat the disease. A patient’s cells are extracted, modified to produce proteins on their surface called chimeric antigen receptors, and then injected back into the body to target the tumor directly.
Cells used in this study were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.
CAR-T therapies have been approved for the treatment of blood cancers, but the therapy’s use for solid tumors is limited. Solid tumors contain mixed populations of cells, allowing some malignant cells to continue to evade the immune system’s detection even after treatment with CAR-T. Maus’ team is working to overcome this challenge by combining two previously separate strategies: CAR-T and bispecific antibodies, known as T-cell engaging antibody molecules.
The version of CAR-TEAM for glioblastoma is designed to be directly injected into a patient’s brain.
In the new study, the three patients’ T cells were collected and transformed into the new version of CAR-TEAM cells, which were then infused back into each patient. Patients were monitored for toxicity throughout the duration of the study. All patients had been treated with standard-of-care radiation and temozolomide chemotherapy and were enrolled in the trial after disease recurrence.
- A 74-year-old man had his tumor regress rapidly but transiently after a single infusion of the new CAR-TEAM cells.
- A 72-year-old man was treated with a single infusion of CAR-TEAM cells. Two days after receiving the cells, an MRI showed a decrease in the tumor’s size by 18 percent. By day 69, the tumor had decreased by 60 percent, and the response was sustained for more than six months.
- A 57-year-old woman was treated with CAR-TEAM cells. An MRI five days after the infusion showed near-complete tumor regression.
The authors note that despite the remarkable responses among the first three patients, they observed eventual tumor progression in all the cases, though in one case, there was no progression for over six months.
Progression corresponded in part with the limited persistence of the CAR-TEAM cells over the weeks following infusion. As a next step, the team is considering serial infusions or 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, a Mass General neuro-oncologist.
In addition to Choi, Maus, and Gerstner, other authors are Matthew J. Frigault, Mark B. Leick. Christopher W. Mount, Leonora Balaj, Sarah Nikiforow, Bob S. Carter, William T. Curry, and Kathleen Gallagher.
Funding: The study was supported in part by the National Gene Vector Biorepository at Indiana University, which is funded under a National Cancer Institute contract.
About this brain cancer research news
Author: Haley Bridger
Source: Harvard
Contact: Haley Bridger – Harvard
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma” by Bryan D. Choi et al. NJEM
Abstract
Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma
In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM).
Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects.
Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants.
(Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.)
