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

作者：Ahmed, Nabil; Brawley, Vita; Hegde, Meenakshi; Bielamowicz, Kevin; Kalra, Mamta; Landi, Daniel; Robertson, Catherine; Gray, Tara L.; Diouf, Oumar; Wakefield, Amanda; Ghazi, Alexia; Gerken, Claudia; Yi, Zhongzhen; Ashoori, Aidin; Wu, Meng-Fen; Liu, Hao; Rooney, Cliona; Dotti, Gianpietro; Gee, Adrian; Su, Jack; Kew, Yvonne; Baskin, David; Zhang, Yi Jonathan; New, Pamela; Grilley, Bambi; Stojakovic, Milica; Hicks, John; Powell, Suzanne Z.; Brenner, Malcolm K.; Heslop, Helen E.; Grossman, Robert

来源：JAMA Oncology, 2017, 3(8): 1094-1101.

DOI：10.1001/jamaoncol.2017.0184

• STEM
• IMMUNOTHERAPY
• VACCINATION
• REGRESSION
• RESPONSES
• CHILDREN
• SURVIVAL
• THERAPY
• ESCAPE
• GLIOMA

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.zeta-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 x 10(6)/m(2) to1 x 10(8)/m(2)) 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.

• 出版日期2017-8