Intraventricular Meningiomas: Clinical-Pathological and Genetic Features of a Monocentric Series

Intraventricular meningiomas (IVMs) are rare (0.5–5%) and usually low-grade (90% grade I) brain neoplasms. Their recurrence rate is lower than that of extra-axial meningiomas, but their surgical resection can be burdened with life-threatening complications, which represent the major cause of the reported 4% mortality. The aim of this study is to characterize the molecular portrait of IVMs to identify potential therapeutic targets. For this, we explored mutations and copy number variations (CNV) of 409 cancer-related genes and tumor mutational burden (TMB) of six cases, using next-generation sequencing. Five IVMs were grade I and one was grade II; none recurred, in spite of partial surgical resection in one case. NF2 mutation was the only recurring alteration and was present in three of the six IVMs, in association with SMARCB1 mutation in one case. None of the cases was hypermutated (TMB > 10 mutations/Mb). NF2-mutant progressing or recurring IVMs could potentially be treated with targeted therapies applied to other NF2-mutant tumors, as an alternative to surgery or radiosurgery, while in view of their low TMB they are unlikely candidates to immune check-point inhibition.

Investigation of The Effects of The Toll-Like Receptor 4 Pathway on Immune Checkpoint Vista in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors of the pancreas. Preclinical studies show that it evades the immune system with immune checkpoints and promotes tumor development. V-domain Ig suppressor of T cell activation (VISTA) is a new immune-check point from the B7 family and is highly expressed in cancer cells. Overexpression of toll like receptor 4 (TLR4) in pancreatic adenocarcinoma is associated with inducing tumorigenesis, tumor growth and resistance to chemotherapy. Naloxone is an opioid and inhibits TLR4-ligand association. In this study, we investigated the connection of TLR4 and downstream pathway with immune-check point VISTA in pancreatic cancer proliferation. We first collected pancreatic cancer-related datasets using the GEPIA2 and UALCAN databases. Based on the data obtained the effect of different concentrations and incubation times of Naloxone were used on PANC-1 cells proliferation. Combination of Naloxone and VISTA-siRNA were applied, and effect of both Naloxone and combined reatment on TLR4, Interleukin 1 receptor associated kinase 4 (IRAK4) and VISTA gene expression were analysed in pancreatic cancer cells. As a result of analysis with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), gene expression levels of TLR4, IRAK4 and VISTA were significantly suppressed and cell proliferation was significantly reduced. We found that administration of Naloxone and VISTA-siRNA in combination to PDAC cells suppressed signaling. Therefore, we considered that the relationship between VISTA and TLR4 signaling pathways and the other possible associated signal molecules may be an important marker in determining the response of immune checkpoint inhibitors in cancer treatment.

Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear.Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors.Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit.Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

Ruxolitinib Plus Nivolumab in Patients with R/R Hodgkin Lymphoma after Failure of Check-Point Inhibitors: Preliminary Report on Safety and Efficacy

Background: Recent studies demonstrated that classical Hodgkin lymphoma (cHL) is characterized by chromosome 9p24.1 amplification with associated overexpression of PD-1 ligands as well as JAK2 tyrosine kinase activation. Immune evasion mediated by the PD-1/PD-1 ligand axis can be inhibited with IgG4 agonist antibody specific for human PD-1 nivolumab which has shown excellent overall response rate (ORR) of over 60% in relapsed cHL. JAK2 induces PD-1 ligand expression and augments tumor cell proliferation. JAK2 signaling can be inhibited with clinical grade small molecules (i.e. ruxolitinib). Given this biology, we designed a Phase I/II study to target both pathways in cHL patients who had failed PD-1 blocking agents. Methods: This is a Phase I/II, multicenter, open-label, dose escalation/dose-expansion study to evaluate the safety and tolerability of ruxolitinib when combined with nivolumab (fixed dose 3mg/kg IV every 2 weeks) in patients with relapsed or refractory (R/R) cHL (NCT03681561). Eligible patients had to fail prior check-point inhibitor (CPI; nivolumab or pembrolizumab). Three dose levels of ruxolitinib were tested: 10 mg orally twice a day (bid), 15 mg bid, and 20 mg bid. Planned duration of therapy was 2 years. The primary objective was to find the maximum tolerated dose (MTD) of ruxolitinib when given with nivolumab and characterize the safety and tolerability of this combination. The phase 2 objective was to evaluate the overall response rate (ORR). Results: We enrolled 19 patients. Median age was 38 years (range 22-76); 68% were males. Patients were a median of 3.4 years from the initial diagnosis (range 0.9-16.7 years), 89% had stage III-IV disease and all had experienced progressive disease following CPI. 17 (89%) had prior autologous HCT and 1 had prior allogeneic HCT. All patients received nivolumab combined with ruxolitinib, and the highest ruxolitinib dose 20mg BID (MTD) was reached without DLTs. The combination was well tolerated; most AEs were grade 1 and 2. Only 3 patients required hospitalization (2 had pneumonia, one for disease progression). Three patients experienced immune mediated adverse events (LFT elevation: 1 Gr 1 and 1 Gr 2; 1 Gr 3 pneumonitis) and all were reversible. Three subjects were not evaluable for response (2 patients who received < 1 month of therapy due to rapid disease progression and Gr 2 immune hepatitis and 1 patient with short follow-up is not yet evaluable for response). Median follow-up was 13 months (range 3-27 months). In 16 patients evaluable for response, best ORR was 75% (12 of 16); including 3 CRs (19%), 2 PRs (13%), 6 patients had stable disease (SD, 44%) with tumor bulk reduction ranging from 10-45%. One patient had indeterminate response (negative biopsy of new PET-avid site). Duration of responses were 12.5 months (ranged from 3.7 to 20.4 months); 5 responders continue study therapy and 2 completed 2 years; 1 went on to autologous HCT in PR, and 3 progressed while on therapy after 6, 6 and 23 months. One patient died after later experimental therapy. Progression-free survival at 1 year was 64% (95%CI 34-84%). Conclusions: Inhibition of JAK2 combined blockade of the PD-1 pathway represent complementary rational therapeutic targets in cHL. Therapy combining ruxolitinib with nivolumab is well tolerated and yield encouragingly high remission rates and durable responses in patients who had all failed previous CPI. Pharmacodynamic and correlative analyses on the mechanism of synergism are underway. Disclosures Bachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Janakiram: ADC Therapeutics: Research Funding; FATE Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Kyowa Kirin Therapeutics: Honoraria. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Farooq: Kite, a Gilead Company: Honoraria. OffLabel Disclosure: ruxolitinib for Hodgkin lymphoma

Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6-dependent pathway

Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper-layer cortical projection neurons during postnatal corticogenesis. We used this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we found Bcl6, previously shown to be involved in transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major check point regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6-dependent molecular pathway in regulation of developmental cell death during corticogenesis.