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Clinical Trial
. 2017 Aug 1;3(8):1094-1101.
doi: 10.1001/jamaoncol.2017.0184.

HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial

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Free PMC article
Clinical Trial

HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial

Nabil Ahmed et al. JAMA Oncol. .
Free PMC article

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Ahmed, Hegde, Bielamowicz, Dotti, Brenner, Heslop, Wels, and Gottschalk and Ms Brawley have patents and/or patent applications pertaining to adoptive cell therapy. No other disclosures were reported.

Figures

Figure 1
Figure 1
CONSORT Flow Diagram
Figure 2
Figure 2. Clinical Outcome After HER2–Chimeric Antigen Receptor Virus-Specific T-Cell (HER2-CAR VST) Infusions
A, Magnetic resonance imaging (MRI) scan of the brain before and 6 weeks after HER2-CAR VST infusion. The MRI scan of patient 4 shows a partial response (PR); MRI scans of patients 9 and 15 show increased edema after HER2-CAR VST infusions (yellow arrowheads outline the margin of edema). B, Swimmer plot showing disease status and overall survival in 17 patients treated with HER2-CAR VSTs. DL indicates dose level; PD, progressive disease; PR, partial response; and SD, stable disease. aAlive.

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