Intracranial injection of natural killer cells engineered with a HER2-targeted chimeric antigen receptor in patients with recurrent glioblastoma
Michael C. Burger, Marie-Thérèse Forster, A Romański, F Straßheimer, Jadranka Macas, Pia S. Zeiner, Eike Steidl, Stefanie Herkt, Katharina J. Weber, Jonathan Schupp, Jennifer H. Lun, Maja Strecker, Karolin Wlotzka, Pinar Cakmak, Corinna Opitz, Rosemol George, Iris Mildenberger, Paulina Nowakowska, Congcong Zhang, Jasmin Röder, Elvira Müller, Kristina Ihrig, Karl‐Josef Langen, Michael A. Rieger, Eva Herrmann, Halvard Bonig, Patrick N. Harter, Yvonne Reiss, Elke Hattingen, Franz Rödel, Karl H. Plate, Torsten Tonn, Christian Senft, Joachim P. Steinbach, Winfried S. Wels
Abstract
BACKGROUND: Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas. METHODS: Nine patients with recurrent HER2-positive GB were treated with single doses of 1 × 107, 3 × 107, or 1 × 108 irradiated CAR-NK cells injected into the margins of the surgical cavity during relapse surgery. Imaging at baseline and follow-up, peripheral blood lymphocyte phenotyping and analyses of the immune architecture by multiplex immunohistochemistry and spatial digital profiling were performed. RESULTS: There were no dose-limiting toxicities, and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Five patients showed stable disease after relapse surgery and CAR-NK injection that lasted 7 to 37 weeks. Four patients had progressive disease. Pseudoprogression was found at injection sites in 2 patients, suggestive of a treatment-induced immune response. For all patients, median progression-free survival was 7 weeks, and median overall survival was 31 weeks. Furthermore, the level of CD8+ T-cell infiltration in recurrent tumor tissue prior to CAR-NK cell injection positively correlated with time to progression. CONCLUSIONS: Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 × 108 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells.