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

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.

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

“…In addition to the regional delivery route, our proposed HER2-CAR T-cell immunotherapy also addresses potential toxicity issues by the choice of intracellular costimulatory signaling domain (8)(9)(10)(25)(26)(27). Our data show significant dampening of cytokine production, along with a tendency to require higher HER2 expression for cytokine production by HER2-BBz compared with HER2-28z CAR T cells.…”

“…In contrast, intravenous delivery of HER2-CAR T cells achieved only partial antitumor responses in mice even at 10-fold higher doses compared with local or regional delivery to the brain. Our investigation of the route of administration is timely given the recent clinical trial of HER2-CAR virusspecific T cells for the treatment of recurrent glioblastoma (10). In that study, clinical benefits of intravenously administrated HER2-CAR T cells were observed in approximately 50% of patients.…”

“…Unfortunately, the first CAR T-cell clinical experience with targeting the HER2 antigen resulted in the death of a patient with HER2 þ metastatic colon cancer due to "on-target, off-tumor" toxicities (8). Recent phase I clinical trials evaluating intravenous administration of HER2-CAR T cells have demonstrated safety and antitumor activity in patients with sarcoma (9) and recurrent glioblastoma (10). These three trials have highlighted multiple elements of CAR T-cell therapy that should be addressed, including CAR construct design and T-cell manufacturing considerations, preconditioning prior to CAR Tcell infusion, and CAR T-cell dose; all of which are critical factors in therapeutic outcome.…”

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

“…Ahmed N et al reported the results of a phase I study investigating the use of anti-HER2 CMV-specific CAR T-cells in patients with glioblastoma. They noted one partial response persisting for more than 9 months, stable disease for 8 to 29 months in seven patients, while eight progressed after infusion [36,37].…”

CAR-T cells : indications actuelles en pédiatrie et perspectives de développement

“…Sur 16 patients évaluables, 1 a obtenu une réponse partielle pendant 9 mois, 7 une maladie stable pendant 8 semaines à 29 mois, 8 ont progressé. La survie globale médiane était de 11,1 mois (IC95 %, 4,1-27,2) après l'injection des CAR T cells [33]. L'injection locale de CAR T cells ciblant la sous unité a2 du récepteur de l'interleukine 13 dans les glioblastomes a montré une activité clinique sans toxicité notable (qui aurait pu être attendue après injection par voie systémique) [34].…”