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Original Investigation
April 20, 2017

HER2-Specific Chimeric Antigen Receptor–Modified Virus-Specific T Cells for Progressive GlioblastomaA Phase 1 Dose-Escalation Trial

Author Affiliations
  • 1Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston
  • 2Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston
  • 3Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  • 4now with Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
  • 5now with Immatics, Houston, Texas
  • 6now with Cell Medica, Houston, Texas
  • 7now with Baylor University Medical Center, Dallas, Texas
  • 8now with Columbia University Medical Center, New York, New York
  • 9Biostatistics Shared Resource Dan L Duncan Center, Baylor College of Medicine, Houston, Texas
  • 10Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas
  • 11Department of Medicine, Baylor College of Medicine, Houston, Texas
  • 12now with Department of Microbiology and Immunology, University of North Carolina, Chapel Hill
  • 13Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas
  • 14Department of Pathology, Houston Methodist Hospital, Houston, Texas
  • 15Department of Medicine, Houston Methodist Hospital, Houston, Texas
  • 16Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany
JAMA Oncol. Published online April 20, 2017. doi:10.1001/jamaoncol.2017.0184
Key Points

Question  What is the safety and antitumor efficacy of autologous HER2-specific chimeric antigen receptor (CAR)–modified virus-specific T cells (VSTs) in patients with progressive glioblastoma?

Findings  This phase 1 dose-escalation study established the safety of autologous HER2-CAR VSTs in 17 patients with progressive glioblastoma with no serious adverse events. Eight patients had a clinical benefit, with a median overall survival of 11.1 months after T-cell infusion and 24.5 months after diagnosis, and 3 patients were alive with no disease progression at the last follow-up.

Meaning  Infusion of autologous HER2-CAR VSTs is safe, with some indication of clinical benefit, and evaluation in a phase 2b study is warranted.

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.

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