TY - JOUR
T1 - HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma
T2 - A phase 1 dose-escalation trial
AU - Ahmed, Nabil
AU - Brawley, Vita
AU - Hegde, Meenakshi
AU - Bielamowicz, Kevin
AU - Kalra, Mamta
AU - Landi, Daniel
AU - Robertson, Catherine
AU - Gray, Tara L.
AU - Diouf, Oumar
AU - Wakefield, Amanda
AU - Ghazi, Alexia
AU - Gerken, Claudia
AU - Yi, Zhongzhen
AU - Ashoori, Aidin
AU - Wu, Meng Fen
AU - Liu, Hao
AU - Rooney, Cliona
AU - Dotti, Gianpietro
AU - Gee, Adrian
AU - Su, Jack
AU - Kew, Yvonne
AU - Baskin, David S.
AU - Zhang, Yi Jonathan
AU - New, Pamela
AU - Grilley, Bambi
AU - Stojakovic, Milica
AU - Hicks, John
AU - Powell, Suzanne Zein-Eldin
AU - Brenner, Malcolm
AU - Heslop, Helen
AU - Grossman, Robert G.
AU - Wels, Winfried S.
AU - Gottschalk, Stephen
N1 - Funding Information:
Funding/Support: This study was funded by the Alliance for Cancer Gene Therapy, Cancer Prevention and Research Institute of Texas grant RP110553, Alex’s Lemonade Stand Pediatric Cancer Foundation, Stand Up To Cancer/St Baldrick’s Pediatric Dream Team Translational Research grant SU2C-AACR-DT1113, the Clinical Research Center at Texas Children’s Hospital, the Dan L. Duncan Institute for Clinical and Translational Research at Baylor College of Medicine, and by shared resources through grant P30CA125123 from the National Institutes of Health. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.
Publisher Copyright:
© 2017 American Medical Association. All rights reserved.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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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U2 - 10.1001/jamaoncol.2017.0184
DO - 10.1001/jamaoncol.2017.0184
M3 - Article
C2 - 28426845
AN - SCOPUS:85021976256
VL - 3
SP - 1094
EP - 1101
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
IS - 8
ER -