Autologous HER2 CMV bispecific CAR T cells for progressive glioblastoma: Results from a phase I clinical trial.

3008 Background: 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 initial results of the phase I clinical study, NCT01109095, administering autologous CMV.pp65 T cells grafted with a second generation HER2 chimeric antigen receptor (CAR; with a CD28.zeta signaling domain) to patients with progressive GBM. Results: Sixteen CMV-seropositive patients with HER2-positive GBM and radiological evidence of progression aged 11-70 (median age 49) were enrolled. Autologous HER2-CAR CMV T cells were successfully generated for all patients from a peripheral blood draw (maximum 90mL). T-cell products contained HER2-CAR expressing T cells as judged by FACS analysis (median: 67% (range: 46-82) %), and CMV.pp65-specific T cells as judged by IFN-gamma Elispot assays (median 985.5 (range 390 to 1292) SFC/105 T cells). Infusions of 1x106/m2, 3x106/m2, 1x107/m2, 3x107/m2 or 1x108/m2HER2-CAR.CMV-T cells were well tolerated without systemic side effects and no dose limiting toxicity was observed. HER2-CAR CMV T cells 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. Five out of fifteen 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 >24 months, after T cell infusion. Conclusions: 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. Clinical trial information: NCT01109095.