Diffuse gliomas comprise the most common malignant brain tumors in adults and include glioblastomas (GBM) and World Health Organization (WHO) grade II and grade III tumors, sometimes referred to as lower-grade gliomas (LGGs). Genetic tumor profiling is used for disease classification and to guide therapy 1 , 2 , but involves brain surgery for tissue collection and repeated tumor biopsies may be necessary for accurate genotyping over the course of the disease 3 – 10 . While detection of circulating tumor DNA (ctDNA) in blood remains challenging for patients with primary brain tumors 11 , 12 , sequencing of cerebrospinal fluid (CSF) ctDNA may provide an alternative to genotype glioma at lower morbidity and cost 13 , 14 . We therefore evaluated the representation of the glioma genome in CSF from 85 glioma patients who underwent a lumbar puncture for evaluation of neurological signs or symptoms. Tumor-derived DNA was detected in CSF from 42/85 (49.4 %) patients and was associated with disease burden and adverse outcome. The genomic landscape of glioma in CSF contained a broad spectrum of genetic alterations and closely resembled the genome in tumor biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2 1 , 2 , were shared in all matched ctDNA-positive CSF/tumor pairs, whereas we observed considerable evolution in growth factor receptor signaling pathways. The ability to monitor evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

He was a co-founder of Seragon, purchased by Genentech/Roche in 2014. J.M. is a science advisor and owns company stock in Scholar Rock. H.C. is an inventor on several patents related to organoid technology. S.W.L. is a co-founder and scientific advisory board member for ORIC Pharm, Blueprint, and Mirimus. He also serves on the scientific advisory board for Constellation, Petra, and PMV and has recently served as a consultant for Forma, Boehringer Ingelheim, and Aileron. J.G.-A. has received support from Medtronic (honorarium for consultancy with Medtronic), Johnson & Johnson (honorarium for delivering a talk), and Intuitive Surgical (honorarium for participating in a webinar by Intuitive Surgical). P.B.R. has received honorarium from Corning to discuss 3D cell culture techniques, has served as a consultant for AstraZeneca, and is a consultant for EMD Serono for work on radiation sensitizers.

Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.

PURPOSE Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.