19. A Phase I Clinical Trial of Autologous HER2 CMV Bispecific CAR T Cells for Progressive Glioblastoma

INTRODUCTION: Glioblastoma (GBM) remains virtually incurable. T-cell therapy holds the promise to improve outcomes for GBM patients since it does not rely on the cytotoxic mechanisms of conventional therapies. We have shown in preclinical studies that HER2 and CMV are potential T-cell therapy targets for GBM. METHODS: We report the results of the Phase I clinical study, NCT01109095, administering autologous CMV.pp65 cytotoxic T lymphocytes (CTL) expressing a HER2-specific CD28.zeta second generation chimeric antigen receptor (CAR; HER2/CMV biCTLs) to patients with progressive GBM. RESULTS: Sixteen CMV-seropositive patients, aged 11-70 years (median 49 years) with HER2-positive GBM and radiological evidence of active tumor were enrolled. Autologous HER2/CMV biCTLs were successfully generated for all patients from a peripheral blood draw (maximum 90mL). HER2/CMV biCTLs expressed HER2-CAR at a median of 67% (range: 46-82), and exhibited CMV. pp65 T cell receptor-mediated reactivity as judged by IFN-g Elispot assays (median 985.5 (range 390 to 1292) SFC/105 T cells). Infusions of 1×106/m2, 3×106/m2, 1×107/m2, 3×107/m2 or 1×108/m2 HER2/CMV biCTLs were well tolerated without systemic side effects and no dose limiting toxicity was observed. HER2/CMV biCTLs were detected in the peripheral blood for up to 12 weeks post infusion as judged by real-time PCR of a CAR-specific amplicon. Out of fifteen evaluable patients 10 had progressive disease. 5/15 patients had objective responses: 1 patient had a partial response with a ~62% reduction in tumor volume lasting 8 months, 1 patient had stable disease lasting 4 months and 3 patients have stable disease and are currently alive with a follow up of 18 to >26 months, after T cell infusion. CONCLUSION: This initial evaluation of the safety and efficacy of autologous HER2-CAR CMV bispecific T cells in patients with progressive GBM shows that infusions are safe and that cells could persist for up to 12 weeks in the peripheral blood. Clinical benefit was observed in 33% of patients setting the stage for studies that combine HER2-CAR CMV T cells with other immunomodulatory approaches to enhance their expansion and anti-GBM activity.