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Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific ‘GBM-on-a-Chip’ microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients. 

We present a methodology for identifying security critical properties for use in the dynamic verification of a processor. Such verification has been shown to be an effective way to prevent exploits of vulnerabilities in the processor, given a meaningful set of security properties. We use known processor errata to establish an initial set of security-critical invariants of the processor. We then use machine learning to infer an additional set of invariants that are not tied to any particular, known vulnerability, yet are critical to security. We build a tool chain implementing the approach and evaluate it for the open-source OR1200 RISC processor. We find that our tool can identify 19 (86.4%) of the 22 manually crafted security-critical properties from prior work and generates 3 new security properties not covered in prior work.