INCIPIENT
Intraventricular CARv3-TEAM-E T Cells in Patients with Glioblastoma (INCIPIENT) study
Year of Publication: 2024
Authors: Bryan D. Choi, Elizabeth R. Gerstner, Matthew J. Frigault, ..., Marcela V. Maus
Journal: New England Journal of Medicine
Citation: N Engl J Med 2024;390:1290-8
PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...hms-1991558.pdf
PDF: Clinical Question
Can intraventricular CARv3-TEAM-E T cells safely and effectively treat recurrent glioblastoma by targeting both EGFRvIII and wild-type EGFR simultaneously?
Bottom Line
Intraventricular infusion of dual-targeting CARv3-TEAM-E T cells produced dramatic rapid tumor regression in all 3 participants within days, with durable response in 1/3 patients and acceptable safety profile.
Major Points
- Dramatic radiographic tumor regression occurred within days in all 3 participants after intraventricular infusion
- One participant maintained durable response >150 days while 2 had transient responses
- No dose-limiting toxicities observed, only grade 3 encephalopathy (3 days) and grade 3 fatigue (8 days)
- Novel dual-targeting approach using CAR for EGFRvIII and secreted TEAM molecules for wild-type EGFR
- Liquid biopsy showed decreased EGFRvIII and EGFR copy numbers corresponding to radiographic responses
- Participant 1 received a SECOND infusion on day 37 (cycle 2); Participants 2 and 3 received a single infusion
- Cyclic fevers (peaking by day 2) were managed with the IL-1 receptor antagonist anakinra (100 mg every 6 hours)
Design
Study Type: First-in-human, investigator-initiated, open-label, single-site phase 1 study
Randomization:
Blinding: Open-label
Enrollment Period: March 2023 through July 2023
Follow-up Duration: Up to 150+ days reported
Centers: 1
Countries: US
Sample Size: 3
Analysis: Safety run-in cohort with prespecified interim analysis
Inclusion Criteria
- Age 18 years or older
- Pathologically documented World Health Organization grade 4 recurrent glioblastoma
- EGFRvIII-positive tumor
- Measurable disease defined as at least one lesion ≥10 mm diameter on MRI
Exclusion Criteria
- Previous receipt of EGFRvIII-targeted therapy
Baseline Characteristics
Participant 1:
- Age: 74 years
- Sex: Male
- Handedness: Right-handed
- Tumor Location: Left insula
- IDH Status: Wild-type
- MGMT Status: Methylated
- EGFRvIII Status: Positive
- EGFR Copy Number: Gain present
- Time to Recurrence: 12 months
Participant 2:
- Age: 72 years
- Sex: Male
- Handedness: Right-handed
- Tumor Location: Left posterior temporal lobe
- IDH Status: Wild-type
- MGMT Status: Methylated
- EGFRvIII Status: Positive
- Time to Recurrence: 20 months
Participant 3:
- Age: 57 years
- Sex: Female
- Handedness: Right-handed
- Tumor Location: Left parietal
- IDH Status: Wild-type
- MGMT Status: Unmethylated
- EGFRvIII Status: Positive at initial diagnosis, lost at recurrence
- EGFR Status: Wild-type EGFR amplified nuclei present
- Time to Recurrence: 6 months
Arms
| Field | CARv3-TEAM-E T cells |
|---|---|
| Intervention | Intraventricular infusion of 10×10⁶ CAR-positive CARv3-TEAM-E T cells through Ommaya reservoir |
| Duration | Single infusion (Participant 1 received a second infusion on day 37, cycle 2) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Safety and dose-limiting toxic effects | Primary | No dose-limiting toxic effects in any participant | |||
| Radiographic tumor regression - Participant 1 | Secondary | Rapid regression on day 1 MRI, ultimately transient | |||
| Radiographic tumor regression - Participant 2 | Secondary | 18.5% decrease in cross-sectional area by day 2, 60.7% decrease by day 69, sustained >150 days | |||
| Radiographic tumor regression - Participant 3 | Secondary | Near-complete tumor regression by day 5, recurrence within 1 month | |||
| Grade 3 encephalopathy | Adverse | 1/3 participants (3 days duration, Participant 1) | |||
| Grade 3 fatigue | Adverse | 1/3 participants (8 days duration, Participant 3) | |||
| Cyclic fevers | Adverse | 3/3 participants, peaked by day 2; managed with the IL-1 receptor antagonist anakinra (100 mg q6h) | |||
| Transient pulmonary nodules and ground-glass opacities | Adverse | 2/3 participants (Participants 2 and 3), asymptomatic, resolved in 4-6 weeks |
Subgroup Analysis
Analysis by EGFRvIII expression status showed that CARv3-TEAM-E T cells demonstrated antitumor activity even in the absence of EGFRvIII expression (Participant 3), suggesting TEAM-mediated effects against wild-type EGFR. Liquid biopsy analysis showed corresponding decreases in EGFRvIII and EGFR copy numbers in all participants.
Criticisms
- Very small sample size (n=3) limits generalizability
- Responses were transient in 2 of 3 participants
- Limited persistence of CARv3-TEAM-E T cells over weeks after infusion
- Heterogeneous disease and tissue sampling limitations may affect interpretation of EGFRvIII expression results
- Short-term follow-up period
- Single-arm design without control group
- Participants had different EGFRvIII expression patterns at recurrence
Funding
Gateway for Cancer Research, Mass General Cancer Center, Mass General Brigham, National Gene Vector Biorepository, philanthropic gifts
Based on: INCIPIENT (New England Journal of Medicine, 2024)
Authors: Bryan D. Choi, Elizabeth R. Gerstner, Matthew J. Frigault, ..., Marcela V. Maus
Citation: N Engl J Med 2024;390:1290-8
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