CAR TEAM Cells Show Dramatic, Short-Lived Responses in Glioblastoma
Transient responses in 2 of 3 participants may be due to limited persistence of CARv3-TEAM-E T-cells in the weeks after infusion.
Marcela Maus, MD, PhD
Credit: Massachusetts General Hospital
CARv3-TEAM-E chimeric antigen receptor (CAR) T-cells show potential in treating glioblastoma, according to data from 3 participants treated in the phase 1 INCIPIENT trial (NCT05660369) published in a paper in the New England Journal of Medicine.1
“We think [CARv3-TEAM-E T cells are] exciting, because it's a modular approach to different kinds of tumors and with different kinds of problems that you might be trying to overcome... In brain tumors, we want to be able to target... wild type EGFR, but it's really hard to target it with antibodies, or bispecifics, or even small molecule drugs, because they don't really get past the blood brain barrier very well. But with CAR T-cells, they can go anywhere, and they do get past the blood brain barrier, they actively traffic. And so, we've been trying to use the T-cells to deliver another drug essentially, to that tumor microenvironment, into the brain tumor,” senior author Marcela Maus, MD, PhD, Associate Professor of Medicine, Harvard Medical School, and director, cellular immunotherapy, Cancer Center, Massachusetts General Hospital, told CGTLive®.
CARv3-TEAM-E T cells are engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM). INCIPIENT was a first-in-human, investigator-initiated, open-label study that treated 3participants with recurrent glioblastoma.1
Investigators found that all 3 participants had remarkable and fast responses with CARv3-TEAM-E T cell treatment, but disease recurrence occurred in 2 of 3 participants, which corresponded in part with limited persistence of CARv3-TEAM-E T cells over the weeks after infusion.No associated dose-limiting toxicities were observed.1
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“The early responses support further research into cell-based therapies in treating advanced glioblastoma in the brain parenchyma through intraventricular administration,” Misty R. Jenkins, PhD, and Katharine J. Drummond, MD, MBBS, both from University of Melbourne, wrote in a related editorial.2 “Although such administration involves a surgical procedure (placement of an injection port called an Ommaya reservoir), it is likely to permit direct traffic of the therapy to the tumor and avoid systemic activity that could result from peripheral administration, especially if the targets of the CAR T cells are expressed outside the central nervous system. Given the devastating nature of glioblastoma, this invasive mode of administration is warranted.”
Investigators observed grade 3 adverse events (AEs) that were at least possibly attributable to therapy of grade 3 encephalopathy for 3 days in Participant 1 and grade 3 fatigue for 8 days in Participant 3. Participant 1 died from gastrointestinal perforation due to disease progression 63 days after study discontinuation, which was not attributed to CARv3-TEAM-E T cells. Participants 2 and 3 developed asymptomatic transient pulmonary nodules and ground-glass opacities, which were observed on chest computed tomography and spontaneously and completely resolved on repeat imaging within 4-to-6 weeks. No participants received glucocorticoids during the study or related to the therapy.1
“Research into enhancing the longevity of the CAR T cell and integrating combination treatments to counter the immunosuppressive nature of the tumor microenvironment are warranted... Overcoming the challenge of brain-tumor heterogeneity is also important,” Jenkins and Drummond wrote.2 “As for CARv3-TEAM-E T cells in the treatment of glioblastoma, the results reported by Choi et al. support a cautious optimism. However, it is only with data collected through the treatment of additional patients that the effect and scalability of this therapy can be evaluated.”
