Imaging immune response in vivo: cytolytic action of genetically altered T cells directed to glioblastoma multiforme.

Abstract

Clinical trials have commenced to evaluate the feasibility of targeting malignant gliomas with genetically engineered CTLs delivered directly to the tumor bed in the central nervous system. The objective of this study is to determine a suite of magnetic resonance imaging (MRI) measurements using an orthotopic xenograft murine model that can noninvasively monitor immunologically mediated tumor regression and reactive changes in the surrounding brain parenchyma. Our preclinical therapeutic platform is based on CTL genetic modification to express a membrane tethered interleukin-13 (IL-13) cytokine chimeric T-cell antigen receptor. This enables selective binding and signal transduction on encountering the glioma-restricted IL-13 alpha2 receptor (IL-13Ralpha2). We used MRI to visualize immune responses following adoptive transfer of IL-13Ralpha2-specific CD8+ CTL clones. Based on MRI measurements, several phases following IL-13Ralpha2-specific T-cell adoptive transfer could be distinguished, all of which correlated well with glioblastoma regression confirmed on histology. The first detectable changes, 24 hours post-treatment, were significantly increased T2 relaxation times and strongly enhanced signal on T1-weighted postcontrast images. In the next phase, the apparent diffusion coefficient was significantly increased at 2 and 3 days post-treatment. In the last phase, at day 3 after IL-13Ralpha2-specific T-cell injection, the volume of hyperintense signal on T1-weighted postcontrast image was significantly decreased, whereas apparent diffusion coefficient remained elevated. The present study indicates the feasibility of MRI to visualize different phases of immune response when IL-13Ralpha2-specific CTLs are administered directly to the glioma tumor bed. This will further the aim of better predicting clinical outcome following immunotherapy.