HER2-Specific Chimeric Antigen Receptor–Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial
Creators: name: Landi, Daniel
name: Ahmed, Nabil
name: Gottschalk, Stephen
name: Kalra, Mamta
name: Zhang, Yi Jonathan
name: Bielamowicz, Kevin
name: Yi, Zhongzhen
name: Stojakovic, Milica
name: Brenner, Malcolm K.
name: Grossman, Robert
name: Heslop, Helen E.
name: Diouf, Oumar
name: Kew, Yvonne
name: New, Pamela
name: Dotti, Gianpietro
name: Su, Jack
name: Wakefield, Amanda
name: Ghazi, Alexia
name: Gray, Tara L.
name: Gerken, Claudia
name: Ashoori, Aidin
name: Grilley, Bambi
name: Gee, Adrian
name: Powell, Suzanne Z.
name: Hegde, Meenakshi
name: Brawley, Vita
name: Wels, Winfried S.
name: Hicks, John
name: Wu, Meng-Fen
name: Rooney, Cliona
name: Robertson, Catherine
name: Baskin, David
name: Liu, Hao
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. 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. 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). 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). Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. 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. 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.