PDF: INCIPIENT
(2024)Objective
To evaluate the safety of CARv3-TEAM-E T cells in patients with recurrent or newly diagnosed glioblastoma
Study Summary
• Response was durable >150 days in 1/3 participants but transient in 2/3 participants
• No dose-limiting toxicities observed, only grade 3 encephalopathy (3 days) and grade 3 fatigue (8 days)
Intervention
Intraventricular infusion of 10×10⁶ CAR-positive CARv3-TEAM-E T cells through Ommaya reservoir targeting both EGFRvIII tumor-specific antigen and wild-type EGFR protein via secreted T-cell engaging antibody molecules (TEAMs). Participant 1 received a second infusion on day 37 (cycle 2); Participants 2 and 3 received a single infusion.
Inclusion Criteria
Age ≥18 years with pathologically documented WHO grade 4 recurrent EGFRvIII-positive glioblastoma, measurable disease (≥10mm diameter on MRI), no previous EGFRvIII-targeted therapy
Study Design
Arms: Single arm: CARv3-TEAM-E T cells 10×10⁶ CAR-positive cells intraventricularly
Patients per Arm: 3
Outcome
• Radiographic response: Tumor regression within days in 3/3 patients (18.5% reduction by day 2 in Patient 2, near-complete regression by day 5 in Patient 3)
• Durability: 1/3 participants maintained response >150 days, 2/3 had transient responses
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)
Study Design
- Study Type
- First-in-human, investigator-initiated, open-label, single-site phase 1 study
- Randomization
- No
- Blinding
- Open-label
- Sample Size
- 3
- Follow-up
- Up to 150+ days reported
- Centers
- 1
- Countries
- US
Primary Outcome
Definition: Safety and dose-limiting toxic effects
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| No dose-limiting toxic effects in any participant | - |
Limitations & 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
Citation
N Engl J Med 2024;390:1290-8