Next-generation CAR-T lymphocytes helped glioblastoma in pilot trial
American researchers have presented preliminary results of the first phase I clinical trial of CARv3-T lymphocytes injected into the ventricles of the brain to treat recurrent glioblastoma. The tumors rapidly and significantly decreased in size in all three patients, but in two of them the effect was temporary. The paper was published in The New England Journal of Medicine.
Glioblastoma is the most aggressive primary malignant neoplasm of the brain with the worst prognosis. There are no really effective methods of its treatment at the moment. Therefore, researchers are pinning their hopes on lymphocytes with chimeric antigenic receptor (CAR-T-lymphocytes), which have shown efficacy in refractory lymphoid and some other neoplasms. However, their use is also difficult due to the heterogeneity of the disease and immunosuppressive tumor microenvironment, which complicates the choice of target antigen and reduces the effectiveness of potential therapy.
Nevertheless, employees of several American universities and Novartis have attempted to use for this purpose CAR-T-lymphocytes targeting mutant variant III of epidermal growth factor receptor (EGFRvIII), which is characteristic of glioblastoma and other human solid tumors. In pilot trials, intravenous administration of such cells (CAR-T-EGFRvIII) demonstrated marked on-target activity but did not result in a significant radiographic response from the tumor. Recurrent neoplasms produced normal EGFR and appeared infiltrated with T-suppressors.
After receiving these results, the head of the work Marcela Maus (Marcela Maus) from Massachusetts General Hospital and Harvard Medical School with colleagues from different research centers in the United States decided to modify the methodology. For this purpose, the researchers developed a CAR-construct, which contains a second-generation receptor to EGFRvIII, and also expresses activator T-cells (T-cell-engaging antibody molecule, TEAM), binding them to the usual EGFR (it is not present in healthy brain tissue, but it is almost always present on glioblastoma cells). Cells expressing this construct were labeled CARv3-TEAM-E. Preclinical modeling confirmed that they secrete TEAM only at sites where CAR recognized the desired antigen. Also, in vitro experiments showed that these molecules can redirect even regulatory T lymphocytes to fight the tumor.
These findings led to the initiation of the INCIPIENT Phase I clinical trial to evaluate the safety of administering autologous CARv3-TEAM-E to adult patients with newly diagnosed or recurrent glioblastoma. These cells are injected once at 10 × 106 into the ventricles of the brain using an Ommaya reservoir. The trial is planned to enroll 21 participants. This publication reports the interim treatment results of the first three: A 57-year-old woman and men aged 72 and 74 with relapsed glioblastoma. They received the drug between March and July 2023.
No dose-limiting toxic effects were identified. All participants experienced a transient increase in body temperature with a peak on the second day after infusion, and interleukin-1 receptor antagonist anakinra was administered intermittently to control it. Levels of markers of systemic inflammation were highest on the second to third week and returned to baseline by day 30. The most severe adverse events potentially related to therapy were grade 3 (events that impaired the ability to perform basic activities such as dressing or eating). These included a three-day encephalopathy in one patient and an eight-day pathologic fatigue in another. On day 21, CAR-T lymphocyte content in peripheral blood was maximal in all patients, but their proportion with TEAM on the surface was negligible (2, 0.64, and 0 percent, respectively). At the same time, their number in cerebrospinal fluid was significant (70.3, 17.6 and 56.2 percent, respectively).
All three patients showed a rapid (within a few days) and marked reduction in tumor size almost to complete disappearance according to MRI. However, in a 74-year-old man and a 57-year-old woman, the neoplasm recurred within a month and expressed virtually no EGFRvIII. The former received another infusion of CARv3-TEAM-E at the same dose on day 37, but with no significant result; he died 63 days after the end of trial participation from gastrointestinal perforation on bevacizumab and dexamethasone. In the 72-year-old patient, the effect was durable and persisted for more than 150 days of follow-up without glucocorticoids or antiangiogenic drugs.
Thus, CARv3-TEAM-E produced a pronounced effect, but in two patients glioblastoma recurred. The authors attribute this to the limited survival of modified cells and intend to further use different strategies to increase their endurance, such as prior chemotherapy or several scheduled infusions of the drug.
Earlier, New Zealand, Australian, American and Chinese researchers reported success in phase I clinical trials of third-generation CAR-T lymphocytes for the treatment of B-cell lymphoma. They were as effective as previous generations, but proved to be much less neurotoxic.