P04.05 The CAR2BRAIN study: a monocentric phase I trial with ErbB2-specific NK-92/5.28.z cells in recurrent glioblastoma

Abstract

Recent preclinical studies from our institutions and other researchers suggest that natural killer (NK) cells have the potential for adoptive immunotherapy of GBM. Like T cells, NK cells can be genetically modified to express chimeric antigen receptors (CARs) that recognize tumor-associated cell surface antigens and mediate selective recognition and specific lysis of cancer cells, thereby overcoming endogenous resistance mechanisms in tumor cells. In two previous phase I clinical trials, the continuously expanding human NK cell line NK-92 has been safely applied as an allogeneic cell therapeutic with clinical responses observed in some of the cancer patients treated. To enhance efficiency and specificity, the ErbB2-specific cell clone NK-92/5.28.z carries a codon-optimized CAR (CAR 5.28.z) based on ErbB2-specific antibody FRP5 and CD28 and CD3ζ signaling domains. Elevated ErbB2 protein levels have been reported in a significant proportion of GBM tumors and were correlated with impaired survival. We have previously demonstrated potent antitumor activity of NK-92/5.28.z cells in vitro and in orthotopic GBM models in vivo, suggesting adoptive transfer of these cells as a promising new approach for immunotherapy of ErbB2-positive glioblastoma andother ErbB2-expressing cancers. Based on the convincing preclinical data, we consequently designed the CAR2BRAIN trial, a monocentric phase I dose finding trial investigating the safety and tolerability of NK-92/5.28.z cells in patients with recurrent glioblastoma. The NK-92/5.28.z cells will be repeatedly injected through a Rickham reservoir into the resection cavity or the tumor center. In a dose escalation part of the trial the highest cell number which can be applied safely will be established (maximum tolerated dose = MTD). We plan to escalate the dose up to 1 × 108 cells per injection in four injections. After determination of the MTD, up to twelve injections will be carried out to establish safety of prolonged treatment. Distribution of the injected NK-92/5.28.z cells in the brain, the cerebrospinal fluid and the blood will be monitored. Furthermore, the immune reaction triggered against the target antigen ErbB2 as well as ErbB2-independent immune reactions will be characterized.