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HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1
Nabil Ahmed1,2,3, Vita Brawley1,2,3, Meenakshi Hegde1,2,3
1Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston.
Importance:
Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited.
Objective:
To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity.
Design, Setting, And Participants:
In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months).
Interventions:
Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs).
Main Outcomes And Measures:
Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity.
Results:
A total of 17 patients (8 females and 9 males; 10 patients ≥18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 106/m2 to 1 × 108/m2) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis.
Conclusions And Relevance:
Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.
Insights
This study shows that chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) are safe for treating glioblastoma. HER2-CAR VSTs demonstrated antiglioblastoma activity in patients with progressive disease.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Glioblastoma is an aggressive brain tumor with limited treatment options.
- Developing novel therapeutic strategies is crucial for improving patient outcomes.
Purpose of the Study:
- To assess the safety and efficacy of systemically administered HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) in patients with glioblastoma.
- To evaluate the antiglioblastoma activity of these engineered T cells.
Main Methods:
- An open-label, phase 1 dose-escalation study involving 17 patients with progressive HER2-positive glioblastoma.
- Patients received monotherapy with autologous VSTs engineered to express HER2-CARs (HER2-CAR VSTs).
- Primary endpoints were feasibility and safety; secondary endpoints included T-cell persistence and antiglioblastoma activity.
Main Results:
- HER2-CAR VST infusions were well-tolerated, with no dose-limiting toxic effects observed.
- T cells persisted in peripheral blood for up to 12 months post-infusion.
- One partial response, stable disease in seven patients (three alive with no progression at 24-29 months), and disease progression in eight patients were observed.
Conclusions:
- Systemic administration of autologous HER2-CAR VSTs is a safe approach for glioblastoma treatment.
- This therapy shows potential for clinical benefit in patients with progressive glioblastoma.
- Further investigation in a phase 2b study is warranted for HER2-CAR VSTs as a single agent or in combination therapies.