Multi-engineered CAR-T confers significant, rapid reduction of aggressive brain tumor
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Key takeaways:
- Multi-engineered CAR-T drastically reduced tumor size of glioblastoma in a phase 1 trial.
- Future research aims to extend response time.
A novel chimeric antigen receptor T-cell therapy produced significant tumor reductions in patients with glioblastoma, results from a phase 1 trial published in The New England Journal of Medicine showed.
The treatment, labeled CARv3-TEAM-E T cells, showed almost complete tumor regression in a 57-year-old woman, and a 72-year-old man had response for more than 150 days, although cancer progression eventually occurred in all three patients treated in the trial.
“This was our safety run-in cohort, where we planned to give a single dose of CARv3-TEAM-E cells and then monitor for toxicity. We honestly didn’t expect much to happen, though of course we were nervous and hopeful,” Marcela V. Maus, MD, PhD, director of the cellular immunotherapy program at Massachusetts General Hospital General Cancer Center and Healio | HemOnc Today Associate Medical Editor, told Healio.
“Within 12 hours of giving the cells into the fluid around the brain, the patients developed fever and then altered mental status,” she added. “We were very surprised to see those changes in the tumor on the MRI as early as 24 hours after treatment, especially without any steroids or bevacizumab or any other reason to expect that the imaging might change at all. We saw these imaging changes in all three patients, and in one, the tumor continued to appear to get smaller on imaging over the course of several months.”
Background and methodology
No effective treatments exist for glioblastoma, “the most aggressive primary brain tumor,” Maus and colleagues wrote.
CAR-T has been approved to treat hematologic malignancies, but studies are ongoing regarding solid tumors.
Maus believes CAR-T can be a solution for solid tumors in the brain.
“Unlike small molecules or protein therapeutics, which can only passively diffuse into tissues and have a particularly hard time getting past the blood-brain barrier, T cells are living drugs that can actively migrate into tissues,” she said. “Natural immune responses are also not very efficient when it comes to the brain — it is an immune-privileged site. CAR T cells can theoretically overcome several of these barriers. We can redirect to a specific antigen, thus bypassing ‘natural’ immune responses, and in this case, we can put them in the fluid around the brain, thereby increasing their chances of getting to the brain tumor itself.”
Maus and colleagues previously developed CAR T cells that targeted the cancer mutation EGFRvIII, and while they “mediated on-target effects,” radiographic responses did not occur, they wrote.
The new CARv3-TEAM-E T cells (CAR-TEAM), which combine CAR T cells and bispecific antibodies, target wild-type EGFR, which appears in more than 80% of glioblastoma cases, a press release stated.
“The trick is that it’s also expressed in other healthy tissues, like the skin, lungs and gut,” Maus said. “We devised a system to have CAR T cells target a very specific mutated antigen in glioblastoma (EGFRvIII) but also secreting a T-cell engager antibody molecule (TEAM); this allowed us to open a therapeutic window where the TEAM molecules target the brain tumor but quickly fall off any T cells that enter the blood and ultimately get cleared by the kidneys. We had evidence of this from mouse models, but this is our first in-human experience.”
They tested the cells in three adults, who had already been unsuccessfully treated for grade 4, recurrent, EGFRvIII-positive glioblastoma with radiation and chemotherapy, in an open-label study between March and July 2023.
Results and next steps
Patient 1: A 74-year-old man had rapid tumor reduction one day after a single injection, which continued for 2 weeks, although it did not last. He received a second dose and at multiple points of his treatment, his EGFRvIII and EGFR copy numbers became almost “undetectable,” researchers wrote.
Patient 2: A 72-year-old man had his tumor decrease by 18.5% 2 days after receiving treatment, which rose to 60.7% after 69 days. His response lasted more than 150 days.
Patient 3: A 57-year-old woman had “near-complete tumor regression,” according to an MRI 5 days after treatment. Recurrence occurred at 1 month.
All the patients’ cancers progressed over time, but researchers viewed the results positively and are looking at ways to extend response.
Grade 3 adverse events included encephalopathy for 3 days in one patient and fatigue for 8 days for another.
“We are continuing to enroll on this clinical trial, and future cohorts will include low-dose chemotherapy as a conditioning regimen, which has generally made T-cell therapies work better across both blood cancer and solid tumors or give multiple infusions to improve the durability of the responses,” Maus said.
“We are hopeful that this kind of multi-engineering of T cells will also be able to have therapeutic effects in other solid tumors,” she added. “There are various CAR-Ts that are already approved in lymphoid malignancies, but this kind of ‘standard’ design has not been as effective in solid tumors. Further engineering of the T cells offers that hope.”
References:
- Choi BD, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2314390.
- Preliminary clinical trial results show ‘dramatic and rapid’ regression after next generation CAR-T therapy (press release). Available at: https://www.massgeneral.org/news/press-release/clinical-trial-results-show-dramatic-regression-of-glioblastoma-after-next-generation-car-t-therapy. Posted March 13, 2024. Accessed March 13, 2024.
For more information:
Marcela V. Maus, MD, PhD, can be reached at mvmaus@mgh.harvard.edu.
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