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Objective: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Method(s): In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients' NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed. Result(s): During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS <=2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03-1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome. Conclusion(s): NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE.© Copyright © 2021 Broadley, Wesselingh, Seneviratne, Kyndt, Beech, Buzzard, Nesbitt, D'Souza, Brodtmann, Kalincik, Butzkueven, O'Brien, Monif and Australian Autoimmune Encephalitis Consortium.

Objective: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Method(s): In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients' NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed. Result(s): During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS <=2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03-1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome. Conclusion(s): NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE.© Copyright © 2021 Broadley, Wesselingh, Seneviratne, Kyndt, Beech, Buzzard, Nesbitt, D'Souza, Brodtmann, Kalincik, Butzkueven, O'Brien, Monif and Australian Autoimmune Encephalitis Consortium.

Background: MEDI0680 is a humanised IgG4kappa anti-programmed cell death-1 (PD-1) mAb. We hypothesised that simultaneous blockade of PD-1:PD-L1/PD-L2 with MEDI0680 (M) and PD-1:PD-L1/CD80 with anti-PD-L1 mAb durvalumab (D) would improve efficacy vs blockade of the PD-1:PD-L1/PD-L2 pathway (with nivolumab; N) alone. M+D was well tolerated in the dose-escalation phase of a Phase I/II study in pts with advanced solid tumours, with an ORR of 33% (10/30; including 3/4 RCC pts). In the Phase II portion of the study, we compared M+D to N in a dose-expansion cohort of pretreated, immunotherapy (IO)-naive pts with metastatic ccRCC. Method(s): Eligible pts had received 1-3 prior therapy lines, no prior IO exposure and >=1 measurable lesion. They were randomised 2:1 (stratified by MSKCC risk group and PD-L1 expression) to M 20 mg/kg IV + D 750 mg Q2W or N 240 mg IV Q2W until unacceptable toxicity or disease progression, for <=2 years. Endpoints included investigator-assessed ORR by RECIST v1.1 (primary endpoint), PFS and safety (secondary). Sample size was ~60 to detect a difference of 26.0% (ie, ORR = 47.5%, assuming ORR of 21.5% for N) with 76% power at a 1-sided significance level of 0.10. Result(s): By Feb 24, 2019, 63 pts were randomised. Baseline pt/disease characteristics were generally well balanced, but more pts on N had favourable MSKCC risk (7/21; 33.3%) vs M+D (10/42; 23.8%). ORR was 14.3% (6/42; 2 CR, 4 PR; plus 2 unconfirmed PR) vs 19.0% (4/21; 4 PR, 0 unconfirmed) for M+D and N, respectively. There was no difference between arms in ORR by PD-L1 expression (<1% vs >= 1%). All responses are ongoing. Median PFS was 3.6 months in both arms. Grade 3/4 treatment-related AEs (TRAEs) occurred in 26% on M+D (including 1 case of autoimmune encephalitis) and 19% on N. On M+D, 12% had TRAEs leading to treatment discontinuation, including colitis or diarrhoea (n = 3) and increased ALT/transaminases (n = 2), vs 5% on N (pancreatitis and increased lipase and amylase in 1 pt).

Background: MEDI0680 is a humanised IgG4kappa anti-programmed cell death-1 (PD-1) mAb. We hypothesised that simultaneous blockade of PD-1:PD-L1/PD-L2 with MEDI0680 (M) and PD-1:PD-L1/CD80 with anti-PD-L1 mAb durvalumab (D) would improve efficacy vs blockade of the PD-1:PD-L1/PD-L2 pathway (with nivolumab; N) alone. M+D was well tolerated in the dose-escalation phase of a Phase I/II study in pts with advanced solid tumours, with an ORR of 33% (10/30; including 3/4 RCC pts). In the Phase II portion of the study, we compared M+D to N in a dose-expansion cohort of pretreated, immunotherapy (IO)-naive pts with metastatic ccRCC. Method(s): Eligible pts had received 1-3 prior therapy lines, no prior IO exposure and >=1 measurable lesion. They were randomised 2:1 (stratified by MSKCC risk group and PD-L1 expression) to M 20 mg/kg IV + D 750 mg Q2W or N 240 mg IV Q2W until unacceptable toxicity or disease progression, for <=2 years. Endpoints included investigator-assessed ORR by RECIST v1.1 (primary endpoint), PFS and safety (secondary). Sample size was ~60 to detect a difference of 26.0% (ie, ORR = 47.5%, assuming ORR of 21.5% for N) with 76% power at a 1-sided significance level of 0.10. Result(s): By Feb 24, 2019, 63 pts were randomised. Baseline pt/disease characteristics were generally well balanced, but more pts on N had favourable MSKCC risk (7/21; 33.3%) vs M+D (10/42; 23.8%). ORR was 14.3% (6/42; 2 CR, 4 PR; plus 2 unconfirmed PR) vs 19.0% (4/21; 4 PR, 0 unconfirmed) for M+D and N, respectively. There was no difference between arms in ORR by PD-L1 expression (<1% vs >= 1%). All responses are ongoing. Median PFS was 3.6 months in both arms. Grade 3/4 treatment-related AEs (TRAEs) occurred in 26% on M+D (including 1 case of autoimmune encephalitis) and 19% on N. On M+D, 12% had TRAEs leading to treatment discontinuation, including colitis or diarrhoea (n = 3) and increased ALT/transaminases (n = 2), vs 5% on N (pancreatitis and increased lipase and amylase in 1 pt).

Objective: To perform a systematic review of the current scientific literature in order to identify variables associated with patient prognosis in autoimmune encephalitis. Method(s): We performed a systematic literature search using MEDLINE, Embase, PubMed and PsychInfo databases. We selected studies that explored the correlation between early clinical and paraclinical findings, and patient outcomes. Data was extracted, analyzed and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Result(s): Forty four publications detailing 2823 subjects matched our inclusion criteria. There was considerable heterogeneity in methodology, patient profile, investigation results and clinical outcome measures. Findings were often discrepant for cases of anti-NMDAR encephalitis when compared with other causes of autoimmune encephalitis. Delay in immunotherapy contributed to a variety of worse outcomes for patients with different subsets of autoimmune encephalitis. Altered consciousness, ICU admission and no use of immunotherapy were variables associated with poor prognosis in anti-NMDAR encephalitis. Older age, sex, the presence of status epilepticus, CSF abnormalities and MRI changes were unlikely to have significant prognostic value. The influence of antibody titers, autonomic dysfunction and underlying malignancy was unclear. Conclusion(s): A number of variables were identified to have potential predictive value for outcomes in autoimmune encephalitis. Heterogeneous study design, size and quality were major limiting factors in this review.Copyright © 2018 Elsevier Ltd

Introduction: BGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC-and EGFR-family kinases, and demonstrates favorable pharmacokinetic and pharmacodynamics properties (Tam et al. ASH 2016). BGB-A317, a humanized IgG4 variant monoclonal antibody with no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor and is being developed for the treatment of solid and hematologic malignancies (Friedlander, ASCO, 2017). The combination of PD-1/PD-L1 inhibitors with B-cell receptor pathway inhibitors is being evaluated in different B-cell malignancies with the expectation of greater benefit for patients. Here, we present early safety data from a Phase 1b trial exploring the combination of BGB-3111 and BGB-A317. Method(s): This is an open-label multicenter, phase study to evaluate safety, tolerability, and preliminary efficacy of BGB-3111 in combination with BGB-A317 in subjects with B-cell malignancies, including Waldenstrom's macroglobulinemia (WM), aggressive and indolent non-Hodgkin's lymphoma, and transformed chronic lymphocytic leukemia/follicular lymphoma (FL) amongst other B-cell malignancies. The study includes a standard 3+3 dose escalation phase followed by dose expansion. The dose levels are: Cohort 1, BGB-3111 320 mg once a day (QD) combined with BGB-A317 2.0 mg/kg every 3 weeks (Q3W); Cohort 2, BGB-3111 320 mg QD combined with BGB-A317 5.0 mg/kg Q3W; and Cohort 3, BGB-3111 160 mg BID combined with BGB-A317 200 mg (flat dose) Q3W. Result(s): As of 01 June 2017, 25 pts were enrolled in the dose escalation portion of the trial: 15 pts in Cohort 1 and 10 pts in Cohort 2. Key patient characteristics, safety, and efficacy are shown in the Table. Safety: Median follow-up was 2.8 (range, 0.4-10.7) months. There were no dose-limiting toxicities (DLTs) in Cohort 1. Cohort 2 saw hemolysis in 2 pts, both with WM; one qualified as a DLT. These events were not associ

Introduction: BGB-3111 is a potent, highly specific, and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity for BTK vs other TEC-and EGFR-family kinases, and demonstrates favorable pharmacokinetic and pharmacodynamics properties (Tam et al. ASH 2016). BGB-A317, a humanized IgG4 variant monoclonal antibody with no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor and is being developed for the treatment of solid and hematologic malignancies (Friedlander, ASCO, 2017). The combination of PD-1/PD-L1 inhibitors with B-cell receptor pathway inhibitors is being evaluated in different B-cell malignancies with the expectation of greater benefit for patients. Here, we present early safety data from a Phase 1b trial exploring the combination of BGB-3111 and BGB-A317. Method(s): This is an open-label multicenter, phase study to evaluate safety, tolerability, and preliminary efficacy of BGB-3111 in combination with BGB-A317 in subjects with B-cell malignancies, including Waldenstrom's macroglobulinemia (WM), aggressive and indolent non-Hodgkin's lymphoma, and transformed chronic lymphocytic leukemia/follicular lymphoma (FL) amongst other B-cell malignancies. The study includes a standard 3+3 dose escalation phase followed by dose expansion. The dose levels are: Cohort 1, BGB-3111 320 mg once a day (QD) combined with BGB-A317 2.0 mg/kg every 3 weeks (Q3W); Cohort 2, BGB-3111 320 mg QD combined with BGB-A317 5.0 mg/kg Q3W; and Cohort 3, BGB-3111 160 mg BID combined with BGB-A317 200 mg (flat dose) Q3W. Result(s): As of 01 June 2017, 25 pts were enrolled in the dose escalation portion of the trial: 15 pts in Cohort 1 and 10 pts in Cohort 2. Key patient characteristics, safety, and efficacy are shown in the Table. Safety: Median follow-up was 2.8 (range, 0.4-10.7) months. There were no dose-limiting toxicities (DLTs) in Cohort 1. Cohort 2 saw hemolysis in 2 pts, both with WM; one qualified as a DLT. These events were not associ

Epitope mimicry is the theory that an infectious agent such as a virus causes pathological effects via mimicry of host proteins and thus elicits a cross-reactive immune response to host tissues. Weise and Carnegie (1988) found a region of sequence similarity between the pol gene of the Maedi Visna virus (MVV), which induces demyelinating encephalitis in sheep, and myelin basic protein (MBP), which is known to induce experimental allergic encephalitis (EAE) in laboratory animals. In this study, cross-reactions between sera raised in sheep against synthetic peptides of MVV (TGKIPWILLPGR) and 21.5 kDa MBP (SGKVPWLKRPGR) were demonstrated using enzyme-linked immunosorbant assay (ELISA) and thin layer chromatography (TLC) immunoprobing. The antibody responses of MVV-infected sheep were investigated using ELISA against the peptides, and MBP protein, immunoprobing of the peptides on TPC plates and Western blotting against MBP. Slight significant reactions to the 21.5 kDa MBP peptide (P < 0.001) and to a lesser extent sheep MBP (P < 0.004) were detected in ELISA. The MBP peptide evoked stronger responses from more sera than the MVV peptide on immunoprobed TLC plates. On the Western blots, eight of the 23 sheep with Visna had serum reactivity to MBP. This slight reaction to MBP in MVV-infected sheep is of interest because of the immune responses to MBP evident in multiple sclerosis and EAE, but its relevance in Visna is limited since no correlation with disease severity was observed. The cell-mediated immune responses of MVV-infected sheep against similar peptides was assessed. The peptides did not stimulate proliferation of peripheral blood lymphocytes of MVV-infected sheep. Since the MVV peptide was not recognised by antibodies or T lymphocytes from MVV-infected and encephalic sheep, it was concluded that epitope mimicry of this 21.5 kDa MBP peptide by the similar MVV pol peptide was not contributing to the immunopathogenesis of Visna. The slight antibody response to MBP a