Novel CAR T-Cell Therapy Displays Activity in Glioblastoma

Bryan Choi, MD, PhD

The next-generation CAR T-cell therapy CARv3-TEAM-E displayed early activity in a small population of patients with glioblastoma, according to findings from the phase 1 INCIPIENT trial (NCT05660369) published in The New England Journal of Medicine. CARv3-TEAM-E T cells are CAR T cells targeting the EGFR variant III (EGFRvIII) tumor-specific antigen in addition to wild-type EGFR.¹

Preliminary findings from the first-in-human study demonstrated that all 3 patients who were treated with CARv3-TEAM-E T cells between March 2023 and July 2023 experienced dramatic and rapid radiographic tumor regression within days after receiving CARv3-TEAM-E T cells via a single intraventricular infusion. The responses were transient in 2 of the patients, however 1 patient, a 72-year-old man, experienced a decrease in tumor cross-sectional area of 18.5% on day 2 after receiving a single infusion of 10 x 106 CAR-positive CARv3-TEAM-E T cells. Moreover, on day 69 post-infusion the tumor cross-sectional area had further decreased by 60.7% from baseline; the response was sustained and continued to improve at last assessment, which took place over 150 days after the infusion.²

“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,” Bryan Choi, MD, PhD, brain tumor surgeon and associate director, Center for Brain Tumor Immunology and Immunotherapy, Cellular Immunotherapy Program, at Mass General Cancer Center, as well as an assistant professor at Harvard Medical School, both in Boston, Massachusetts, said in a press release. “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."¹

INCIPIENT was a nonrandomized, open-label, single-site study that enrolled adult patients with pathologically documented, World Health Organization grade 4, recurrent, EGFRvIII-positive glioblastoma. Eligible patients also needed to have at least 1 lesion at least 10 mm in diameter on MRI. Those who previously received an EGFRvIII-directed therapy were excluded.²

Following leukapheresis and transduction, the CARv3-TEAM-E T cells were formulated at a target dose of 10 x 106 CAR-positive T cells per vial. The cells were thawed, diluted, and transferred to a syringe for infusion.

The study enrolled 3 patients: participant 1, 2, and 3. Participant 1 was a 74-year-old male with glioblastoma with wild-type IDH and methylated MGMT who experienced disease recurrence at 12 months following standard of care radiation and temozolomide chemotherapy. Participant 2 was a 72-year-old male with IDH wild-type, MGMT-methylated glioblastoma who experienced disease progression at 20 months per surveillance imaging post-standard radiation therapy and temozolomide chemotherapy, as well as tumor-treating field therapy. Participant 3 was a 57-year-old female with IDH wild-type, MGMT-unmethylated glioblastoma who experienced recurrent disease per interval imaging at 6 months following treatment with radiation therapy and temozolomide, which was dose reduced due to thrombocytopenia.

Additional findings from the study showed that participant 1 experienced rapid tumor regression per MRI on day 1 after infusion of 10 x 106 CAR-positive CARv3-TEAM-E T cells; the radiographic improvement was confirmed on subsequent scans over the next 2 weeks but was ultimately transient. Participant 3 experienced a near-complete tumor regression per MRI on day 5 after infusion of 10 x 106 CAR-positive CARv3-TEAM-E T cells, however evidence of recurrence was reported within 1 month of infusion.

All 3 patients experienced a peak absolute count of CAR T cells in the peripheral blood at day 21. The percentage of CAR-positive T cells that had surface-bound TEAM in the blood of participants 1, 2, and 3 at this time was 2.0%, 0.64%, and 0.0%, respectively. The percentages of CAR-positive T cells that had surface-bound TEAM in the cerebrospinal fluid samples were 70.3%, 17.6%, and 56.2%, respectively.

In terms of safety, no dose-limiting toxicities were observed in any of the patients. All 3 patients experienced fevers peaking by day 2 post-infusion, which were managed with anakinra 100 mg every 6 hours. Participant 1 experienced grade 3 encephalopathy for 3 days and participant 3 experienced grade 3 fatigue for 8 days; both events were deemed to be probably related to treatment by an investigator. At day 63 following study discontinuation, participant 1 died due to progressive disease due to gastrointestinal perforation while the patient was being treated with bevacizumab (Avastin) and dexamethasone; the death was not attributed to CARv3-TEAM-E infusion. Participants 2 and 3 developed transient pulmonary nodules and ground-glass opacities, however these were asymptomatic and completely resolved spontaneously within 4 to 6 weeks.

“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,” Marcela V. Maus, MD, PhD, director, Cancer Center Program in Cellular Immunotherapy, and the Paula J. O’Keeffe Endowed Chair in Thoracic Oncology, at Mass General Cancer Center as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts, said in the press release. “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.”¹

“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,” Elizabeth Gerstner, MD, neuro-oncologist, Department of Neurology, at Mass General Cancer Center, added in the press release.

References

1. Preliminary clinical trial results show ‘dramatic and rapid’ regression of glioblastoma after next generation CAR-T Therapy. News release. Massachusetts General Hospital. March 13, 2024. Accessed March 13, 2024. https://www.massgeneral.org/news/press-release/clinical-trial-results-show-dramatic-regression-of-glioblastoma-after-next-generation-car-t-therapy
2. Choi BD, Gerstner ER, Frigault MJ, et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N Engl J Med. Published online March 13, 2024. doi:10.1056/NEJMoa2314390