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?
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.
Infusion of autologous HER2-CAR VSTs is safe, with some indication of clinical benefit, and evaluation in a phase 2b study is warranted.
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.
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).
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.
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.
Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, Robertson C, Gray TL, Diouf O, Wakefield A, Ghazi A, Gerken C, Yi Z, Ashoori A, Wu M, Liu H, Rooney C, Dotti G, Gee A, Su J, Kew Y, Baskin D, Zhang YJ, New P, Grilley B, Stojakovic M, Hicks J, Powell SZ, Brenner MK, Heslop HE, Grossman R, Wels WS, Gottschalk S. HER2-Specific Chimeric Antigen Receptor–Modified Virus-Specific T Cells for Progressive GlioblastomaA Phase 1 Dose-Escalation Trial. JAMA Oncol. Published online April 20, 2017. doi:10.1001/jamaoncol.2017.0184