Basis for Immunotherapy for Treatment of Meningiomas.

Meningiomas are common tumors that account for approximately one third of CNS tumors diagnosed every year. They are classified by the World Health Organization in grades I-III. Higher grades have an increased rate of growth, invasiveness, rate of recurrence, and worse outcomes than lower grades. Most meningiomas are grade I, while ~18% of meningiomas are grade II and III in hospital-based series. Meningiomas are typically "benign" tumors that are treated with surgery and radiation. However, when they recur or are unresectable, treatment options are very limited, especially since they are chemotherapy-resistant. Recent advances in the treatment of cancers with immunotherapy have focused on checkpoint blockade as well as other types of immunotherapy. There is emerging evidence supporting the use of immunotherapy as a potentially effective treatment strategy for meningioma patients. The immune microenvironment of meningiomas is a complex interplay of genetic alterations, immunomodulatory protein expression, and tumor-immune cell interactions. Meningiomas are known to be infiltrated by immune cells including microglia, macrophages, B-cells, and T-cells. Several mechanisms contribute to decreased an ti-tumor immune response, allowing tumor growth and evasion of the immune system. We discuss the most current knowledge on the immune micro-environment of meningiomas, preclinical findings of immunotherapy in meningiomas, meningioma immunotherapy clinical trials, and also offer insight into future prospects for immunotherapies in meningiomas.

Targeting macrophages by an aza-anthrapyrazole to ameliorate experimental autoimmune encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease in the central nerve system, in which both innate and adaptive immune cells are involved. BBR3378, an aza-anthrapyrazole prevents experimental autoimmune encephalomyelitis (EAE), an inflammatory condition similar to MS, by antagonizing T cell autoimmune responses. Here, we report BBR3378's regulatory effect on macrophages. METHODS: EAE was induced in ten-week-old female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptides followed by BBR3378 or sham treatment administered intraperitoneally, and clinical signs were assessed using a 0-5 scoring system. These mice were subjected to serum ELISA for cytokine IFNγ and TNFα levels, RT qPCR analysis of macrophage markers in isolated monocytes, and flow cytometry analysis for macrophage infiltration in the brain. Macrophages derived from primary monocytes and macrophage cell line RAW 264.7 were used to investigate BBR3378's effect on LPS-stimulated pro-inflammatory cytokine induction. RAW 264.7 cells expressing NF-κB-driven luciferase reporter were treated with LPS with or without BBR3378, and luciferase assays performed to assess the inhibition on NF-κB activation. LPS-induced activation of mitogen-activated protein kinases (MAPKs) with or without the presence of BBR3378 was also investigated by Western blot analysis. RESULTS: BBR3378 down-regulated cytokine-induced macrophage differentiation and activation in EAE mice, contributing to protection against macrophage infiltration in the brain and clinical symptoms from EAE. Treating macrophages with BBR3378 counteracted LPS-induced cytokine production via blocking activation of key signal molecules mediating inflammatory responses, such as NF-κB and MAPKs. CONCLUSIONS: These data suggest that in addition to T cells, BBR3378 can also target macrophages to attenuate the inflammation associated with EAE.

Risk Factors Associated With Early vs Delayed Dementia After Intracerebral Hemorrhage.

IMPORTANCE: Patients who have experienced intracerebral hemorrhage (ICH) appear to develop cognitive impairment at high rates, both early after ICH and over the long term. OBJECTIVE: To identify and compare risk factors for early and delayed dementia after ICH. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study enrolled patients who had experienced ICH from January 1, 2006, to December 31, 2013. A total of 738 participants 18 years or older, without pre-ICH dementia, who presented to a tertiary care academic institution with primary ICH were included in the analyses of early post-ICH dementia (EPID). After accounting for incident dementia and mortality at 6 months, 435 participants were included in the analyses of delayed post-ICH dementia (DPID). EXPOSURES: Intracerebral hemorrhage. MAIN OUTCOMES AND MEASURES: Cognitive performance was captured using the modified Telephone Interview for Cognitive Status test. Outcomes included EPID, diagnosed within 6 months after ICH, and DPID, diagnosed beyond 6 months after ICH. RESULTS: Among 738 patients who had experienced ICH (mean [SD] age, 74.3 [12.1] years; 384 men [52.0%]), 140 (19.0%) developed dementia within 6 months. A total of 435 patients without dementia at 6 months were followed up longitudinally (median follow-up, 47.4 months; interquartile range, 43.4-52.1 months), with an estimated yearly incidence of dementia of 5.8% (95% CI, 5.1%-7.0%). Larger hematoma size (hazard ratio [HR], 1.47 per 10-mL increase; 95% CI, 1.09-1.97; P < .001 for heterogeneity) and lobar location of ICH (HR, 2.04; 95% CI, 1.06-3.91; P = .02 for heterogeneity) were associated with EPID but not with DPID. Educational level (HR, 0.60; 95% CI, 0.40-0.89; P < .001 for heterogeneity), incident mood symptoms (HR, 1.29; 95% CI, 1.02-1.63; P = .01 for heterogeneity), and white matter disease as defined via computed tomography (HR, 1.70; 95% CI, 1.07-2.71; P = .04 for heterogeneity) were associated with DPID but not EPID. CONCLUSIONS AND RELEVANCE: Incident dementia early after ICH is strongly associated with hematoma size and location. Delayed incident dementia is frequent among patients who have experienced ICH and is not prominently associated with acute characteristics of ICH. These findings suggest the existence of heterogeneous biological mechanisms accounting for early vs delayed cognitive decline among patients who have experienced ICH.