In an an early phase I, first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with intraventricularly delivered CARv3-TEAM-E T-cells, which are chimeric antigen receptor (CAR) T-cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumour-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 (DLT) effects. Radiographic tumour regression was rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. The findings from a prespecified interim analysis of the INCIPIENT study are published by Associate Professor Marcela V. Maus of the Massachusetts General Hospital and Harvard Medical School in Boston, MA, US and colleagues on 13 March 2024 in The New England Journal of Medicine.
In an interim analysis of another ongoing first-in-human, phase I study of CAR T-cells targeting EGFR and interleukin-13 receptor alpha 2 (IL13Ra2) conducted in patients with multifocal, recurrent glioblastoma, intratechal delivery is feasible and well tolerated with observed reductions in tumour size. The findings are published by Dr. Stephan J. Bagley of the Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine and Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine in Philadelphia, PA, US and colleagues on 13 March 2024 in the Nature Medicine.
The use of CAR T-cells in solid tumours such as glioblastomas has been limited to date, largely due to the challenge in targeting a single antigen in a heterogeneous disease and to immunosuppressive mechanisms associated with the tumour microenvironment.
Findings from the INCIPIENT study with CARv3-TEAM-E T-cells
The same group of investigators who conduct the INCIPIENT study previously found that peripheral infusion of CART-EGFRvIII safely mediated on-target effects in patients with glioblastoma. Despite this activity, no radiographic responses were observed, and recurrent tumour cells expressed wild-type EGFR protein and showed heavy intratumoural infiltration with suppressive regulatory T-cells.
To address these barriers, the study team developed an engineered T-cell product CARv3-TEAM-E that targets EGFRvIII through a second-generation CAR while also secreting TEAMs against wild-type EGFR, which is not expressed in the normal brain but is nearly always expressed in glioblastoma.
Based on data from preclinical models, the study team initiated a first-in-human, phase I clinical study, the Intraventricular CARv3-TEAM-E T Cells in Patients with Glioblastoma (INCIPIENT), to evaluate the safety of CARv3-TEAM-E T-cells in patients with recurrent or newly diagnosed glioblastoma. Eligible participants were 18 years of age or older with pathologically documented, WHO grade 4, recurrent, EGFRvIII-positive glioblastoma.
Participants had to have measurable disease, defined as at least one lesion at least 10 mm in diameter on magnetic resonance imaging. Previous receipt of EGFRvIII-targeted therapy was an exclusion criterion. Participants in the safety run-in cohort received 10×106 CAR-positive CARv3-TEAM-E T-cells as a single infusion through an Ommaya reservoir. Participants were monitored for toxic effects throughout the study.
From March 2023 through July 2023, three participants with recurrent glioblastoma were enrolled in the safety run-in cohort of the INCIPIENT study at Massachusetts General Hospital. No associated DLT effects were noted among the participants. Grade 3 events that were at least possibly attributable to the investigational product included grade 3 encephalopathy for 3 days in participant 1 and grade 3 fatigue for 8 days in participant 3. Participant 1 died from disease progression 63 days after study discontinuation; the cause of death was gastrointestinal perforation while the participant was receiving bevacizumab and dexamethasone.
In the work-up of cyclic fevers in participants 2 and 3, development of transient pulmonary nodules and ground-glass opacities was observed on chest computed tomography. These findings were otherwise asymptomatic and had spontaneously and completely resolved on repeat imaging within 4 to 6 weeks. None of the participants received glucocorticoids during the initial post-treatment phase or for any therapy-related indication.
The authors underlined radiographic responses observed in participants within days after a single intraventricular infusion of dual-targeting CARv3-TEAM-E T-cells. These effects were transient in two of three participants, and one participant had a durable regression through a short-term follow-up period. Findings from liquid biopsy with the use of cerebrospinal fluid and peripheral-blood samples are reported as a correlative study in these participants.
This study of CARv3-TEAM-E T-cells provides proof of principle that multiple surface antigens can be targeted simultaneously with the use of CAR T-cells and confirms that EGFR is a suitable immunotherapeutic target in glioblastoma. Moreover, the secreted T-cell–engaging antibody made by the CAR T-cells was safe despite widespread expression of its target in systemic tissues. It is also notable that CARv3-TEAM-E T-cells showed signs of antitumour activity in the absence of EGFRvIII expression.
Despite the remarkable responses in this case series, the study team observed tumour progression in two of the three participants, which corresponded in part with limited persistence of CARv3-TEAM-E T-cells over the weeks after infusion. As such, these data warrant future evaluation of CARv3-TEAM-E T-cells alongside strategies specifically designed to enhance durability, perhaps through preconditioning with chemotherapy or additional scheduled infusions.
The study was supported by a grant from Gateway for Cancer Research, grants from the Mass General Cancer Center and Mass General Brigham, the National Gene Vector Biorepository at Indiana University, which is funded under the US National Cancer Institute contract, and philanthropic gifts directed to the Cellular Immunotherapy Program.
Findings from a study with CART-EGFR-IL13Rα2 cells
In an article published on 13 March 2024 in the Nature Medicine, Dr. Stephan J. Bagley and colleagues reported the first six patients with recurrent glioblastoma treated in a phase I study of intrathecally delivered bivalent CAR T-cells targeting EGFR and IL13Rα2. The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria.
All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome, and managed with high-dose dexamethasone and anti-IL1R. One patient in dose level 2 experienced a DLT of grade 3 anorexia, generalised muscle weakness and fatigue.
Reductions in enhancement and tumour size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T-cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients.
The authors emphasized that these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in patients with recurrent glioblastoma. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up.
This work was funded by Kite Pharma (a Gilead company), the Abramson Cancer Center Glioblastoma Translational Center of Excellence, the Templeton Family Initiative in Neuro-Oncology, the Maria and Gabriele Troiano Brain Cancer Immunotherapy Fund, the US National Institutes of Health grants and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
References
- Choi BD, Gerstner ER, Frigault MJ, et al. Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma. NEJM; Published online 13 March 2024. DOI: 10.1056/NEJMoa2314390
- Bagley SJ, Logun M, Fraietta JA, et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nature Medicine; Published online 13 March 2024. DOI: https://doi.org/10.1038/s41591-024-02893-z