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JAMA Oncol. 2017 Aug 1;3(8):1094-1101. doi: 10.1001/jamaoncol.2017.0184.

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

Ahmed N1,2,3, Brawley V1,2,3, Hegde M1,2,3, Bielamowicz K1,2,3,4, Kalra M1,2,3,5, Landi D1,2,3, Robertson C1, Gray TL1, Diouf O1,6, Wakefield A1,2,3, Ghazi A1,2,3,7, Gerken C1,2,3, Yi Z1,2,3, Ashoori A1,2,3,8, Wu MF9, Liu H9, Rooney C1,2,3,10, Dotti G1,2,10,11,12, Gee A1,2,3, Su J2,3, Kew Y13, Baskin D13, Zhang YJ13, New P13, Grilley B1,2,3, Stojakovic M1,2,3, Hicks J10, Powell SZ14,15, Brenner MK1,2,3,10,11, Heslop HE1,2,3,10,11, Grossman R13, Wels WS16, Gottschalk S1,2,3,10.

Author information

1
Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston.
2
Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston.
3
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
4
now with Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
5
now with Immatics, Houston, Texas.
6
now with Cell Medica, Houston, Texas.
7
now with Baylor University Medical Center, Dallas, Texas.
8
now with Columbia University Medical Center, New York, New York.
9
Biostatistics Shared Resource Dan L Duncan Center, Baylor College of Medicine, Houston, Texas.
10
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
11
Department of Medicine, Baylor College of Medicine, Houston, Texas.
12
now with Department of Microbiology and Immunology, University of North Carolina, Chapel Hill.
13
Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas.
14
Department of Pathology, Houston Methodist Hospital, Houston, Texas.
15
Department of Medicine, Houston Methodist Hospital, Houston, Texas.
16
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.

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.

PMID:
28426845
PMCID:
PMC5747970
DOI:
10.1001/jamaoncol.2017.0184
[Indexed for MEDLINE]
Free PMC Article

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