247. Phase I Study of Second Generation Chimeric Antigen Receptor-Engineered T Cells Targeting IL13Rα2 for the Treatment of Glioblastoma
Authors: Christine E. Brown, Renate Starr, Lihong Weng, Darya Alizadeh, Jamie R. Wagner, Julie Kilpatrick, Todd L. Harshbarger, Massimo D'Apuzzo, Julie A. Ressler, Michael C. Jensen, Jana Portnow, Michael E. Barish, Stephen J. Forman, Behnam Badie
Journal: Molecular Therapy (2016)

T cell immunotherapy is emerging as a powerful strategy to treat cancer, and may offer new opportunities to improve outcomes for patients with glioblastoma (GBM), the most aggressive of primary brain tumors and among the most lethal of human cancers. We have optimized a chimeric antigen receptor (CAR) T cell therapy targeting the tumor associated antigen IL13Rα2 for the treatment of GBM. This T cell product utilizes CD62L-enriched central memory T cells (Tcm), engineered by lentiviral transduction to express a second-generation 4-1BB-containing CAR (IL13BBζ. We report here initial findings from our first-in-human clinical trial [NCT02208362], evaluating the safety, feasibility and bioactivity of weekly intracranial infusions of autologous IL13BBζ Tcm in patients with recurrent IL13Rα2+ GBM. Enrolled patients undergo leukapheresis to collect autologous PBMC and, concurrent with IL13BBζ Tcm manufacturing, tumor biopsy or resection is performed, with placement of a reservoir/catheter device. Following baseline MR and PET imaging and recovery from surgery, patients are treated on a 4-week therapeutic regimen consisting of 3-weekly intracranial infusions of IL13BBζ Tcm followed by one rest week for toxicity and disease assessment. To date, we have completed treatment of the first low dose cohort of three resection patients, and find that local delivery of IL13BBζ Tcm post surgical resection is safe and well-tolerated with no grade 3 or higher toxicities attributed to the therapy observed. Importantly, we have also obtained early evidence for antitumor activity following CAR T cell administration. For all patients in which sample was available, CAR T cells were detected in the tumor cyst fluid or cerebral spinal fluid (CSF) by flow cytometry for a minimum of 7 days post treatment. One patient of particular interest presented with a recurrent multifocal GBM, including one metastatic site in the spine and extensive leptomeningeal disease. This patient was initially treated per protocol with six local infusions of IL13BBζ Tcm into the resection cavity of the largest recurrent tumor focus in the posterior temporal-occipital region. Encouragingly, this CAR T cell injection site remained stable without evidence of disease recurrence for over 7-weeks, while other disease foci distant from the CAR T cell injection site continued to progress. Based on our preclinical laboratory experiments showing the efficacy of intraventricular delivery of CAR T cells, this patient was then treated on a compassionate use protocol with five weekly intraventricular infusions of IL13BBζ Tcm without any other therapeutic interventions. One week following the final intraventricular CAR T cell infusion, all intracranial and spinal tumors had regressed with most decreasing more than 75% by volume, and this patient remains clinically stable four months following the start of CAR T cell treatment. These early clinical findings suggest that intracranial delivery of second-generation IL13Rα2-targeted CAR T cells is safe and well-tolerated, and that after adoptive transfer, CAR T cells survive and maintain activity, capable of eliciting potent antitumor responses against recurrent multifocal glioblastoma.