HER2-Specific Chimeric Antigen Receptor–Modified Virus-Specific T Cells for Progressive Glioblastoma

By N. Ahmed, V. Brawley, M. Hegde, K. Bielamowicz, M. Kalra, D. Landi, C. Robertson, T. Gray, O. Diouf, Amanda Wakefield and 23 more. JAMA Oncology, 2017

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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.&zgr;-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.

Subfields: Genetics, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/835086389ca8947c30be6f7327280555e75d9c41

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Citations in the corpus

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment (2019, methodology): “Clinically, a HER2/CD28ζ CAR was used to treat progressive glioblastoma in a phase I trial that showed efficacy in some patients (38).”
Gene therapy clinical trials worldwide to 2017: An update (2018, background): “The number of reports targeting solid tumours such as glioblastoma, which are more challenging to treat, is also increasing.(31-33)”
Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia (2015, background): “Central nervous system toxicity has also been associated with other T cell–engaging therapies such as blinatumomab (22, 23), supporting the concept that T cell activation leads to these neurologic events (12).”