Antibody Treatment In Patients Research Articles

Anti-C5 monoclonal antibody treatment showing pathological resolution of complement-mediated atypical hemolytic uremic syndrome: a case report

BackgroundNo reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies.Case presentationA 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening.ConclusionsThis is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment.

Persistent effectiveness of CGRP antibody therapy in migraine and comorbid medication overuse or medication overuse headache - a retrospective real-world analysis

BackgroundManagement of patients with migraine who have concomitant medication overuse (MO) or medication overuse headache (MOH) is a major problem in clinical practice. Detoxification of acute analgesics before or during initiation of prophylactic therapy has long been recommended although this concept has recently been questioned. Additionally, relapse after detoxification is a common problem. This real-world study analyses the initial and sustained effectiveness of prophylactic migraine therapy with CGRP (receptor) antibodies without prior detoxification in patients with comorbid MO or MOH for up to one year.MethodsA retrospective real-world analysis was performed on 291 patients (episodic migraine (EM) with MO (EM-MO; n = 35), EM without MO (EM-noMO; n = 77), chronic migraine (CM) with MOH (CM-MOH; n = 109), CM without MOH (CM-noMOH; n = 70). All patients began treatment with either erenumab (n = 173), fremanezumab (n = 70) or galcanezumab (n = 48) without prior detoxification. Data were available for up to 12 months of treatment. Responder rates for monthly headache days (MHD), monthly migraine days (MMD) and monthly acute medication intake (AMD) were analysed.ResultsAll groups showed a significant reduction in MHD, MMD and AMD at the last observed time point compared to baseline. In patients with CM and MOH, 60.6% (66/109) no longer fulfilled the definition of MO or MOH and a further 13.8% (15/109) had only EM-MO. In the EM cohort, 89% (31/35) of MO patients lost their MO during therapy. MHD and AMD 30% responder rates were comparable for CM-MOH and CM-noMOH (MHD: CM-MOH: 56.0% vs. CM-noMOH: 41.4%, p = 0.058, AMD: CM-MOH: 66.1% vs. CM-noMOH: 52.9%, p = 0.077). MMD responder rate did not differ significantly (after Bonferroni adjustment) (CM-MOH: 62.4% vs. CM-noMOH: 47.1%, p = 0.045, α = 0.017). After successful initiation of therapy, 15.4% of the initial CM-MOH patients relapsed and met the criterion for CM-MOH at the end of follow-up. There were no antibody specific differences in response to therapy.ConclusionsOur data confirms the effectiveness of CGRP antibody treatment in migraine patients with additional MOH or MO in a real-world setting. Low relapse rates after initial successful therapy support an early start of CGRP antibody treatment in patients with MOH or MO.Trial registrationNo registration, retrospective analysis.Graphical

Add-on multiple submucosal injections of the RNA oligonucleotide GUT-1 to anti-TNF antibody treatment in patients with moderate-to-severe ulcerative colitis: an open-label, proof-of concept study

BackgroundCarbohydrate sulfotransferase 15 (CHST15) is an enzyme biosynthesizing matrix glycosaminoglycan that modulates tissue remodeling. We evaluated the efficacy of add-on submucosal injections of GUT-1, the RNA oligonucleotide inhibitor of CHST15, to ongoing anti-tumor necrosis factor (TNF) antibody treatment in patients with moderate-to-severe ulcerative colitis (UC).MethodsThis was an open-label study of 250 nM of GUT-1 by endoscopic submucosal injections at weeks 0, 2, 4 in five UC patients who lost response during maintenance treatment to anti-TNF antibodies. The primary endpoint was the rate of endoscopic improvement at week 6 and secondary endpoints included the rates of clinical remission by modified Mayo Score (mMS). Patients received follow-up observation with continuous maintenance treatment by the same anti-TNF antibody till the time of clinical recurrence or for overall 52 weeks.ResultsAt week 6, rates of endoscopic improvement and clinical remission were 80% (n = 4/5) and 60% (n = 3/5), respectively. The mean Endoscopy Subscore was reduced from 2.4 (95%CI: 1.7 to 3.1) at baseline, to 1.0 (95%CI: 0.1 to 1.9) at week 6. The mean mMS was reduced from 7.8 (95%CI: 6.2 to 9.4) to 1.3 (95%CI: 2.9 to 4.3). GUT-1 was well tolerated. Three patients did not show clinical recurrence for 52 weeks. All three corticosteroid-dependent patients showed no corticosteroid exposure for at least 24 weeks after achieving clinical remission. Multiple dosing was also well tolerated.ConclusionsAdd-on multiple injections of GUT-1 to ongoing anti-TNF antibody was able to induce rapid and durable clinical responses in UC patients who lost response to anti-TNF therapy.Trial registrationClinical trial Registration Number (Japan): UMIN000020900.

P546 Endoscopic findings related to the long-term response to anti-TNF-α antibody treatment in patients with Crohn's disease

Abstract Background Anti-TNF-α antibody treatment in Crohn's disease patients has been established, but loss of treatment response has become a problem in recent years. No studies have investigated the endoscopic findings related to loss of response particularly in the long-term treatment. In this study, we investigated the endoscopic findings associated with diminished efficacy of anti-TNF-α antibodies in Crohn's disease patients treated over a long period of time. Methods A total of 79 patients with Crohn's disease who were observed for at least 1 year after the anti-TNF-α antibody treatment was initiated at our hospital were included in this study. These patients were stratified into cases with and without loss of response to the anti-TNF-α antibody treatment, and the endoscopic findings were compared between the two groups. A case with loss of response was defined as one in which the dose was increased or the duration of treatment was shortened during the anti-TNF-α antibody treatment or the anti-TNF-α antibody preparation was changed to another due to lack of response to the initial preparation. The findings examined were aphtha, erosion, cobblestone-like mucosa, fistula, multiple ulcer, longitudinal ulcer, and anal lesion. Mann-Whitney's U test, χ2 test, and logistic regression analysis were used for statistical analysis, and differences with p < 0.05 were considered significant. Results The mean observation period for all patients was 85.5 months, and the longest period was 188 months. Of the 79 patients included, 29 met the criteria with loss of response, and 50 did not (loss of response rate 37%). Comparisons between the loss of response group and the no loss of response group by univariate analysis showed that anal lesions (66% vs 42%, p = 0.028), stenosis (75% vs 48%, p = 0.021), and multiple ulcers (82% vs 53%, p = 0.011) were significantly more frequent in the loss of response group. The multivariate analysis on these items identified anal lesions (OR: 3.06, 95% CI 1.04-9.04, p = 0.042) and multiple ulcers (OR: 5.33, 95% CI 1.59-17.9, p = 0.0068) as independent risk factors for loss of response. Conclusion In this study, Crohn's disease patients with endoscopic findings of anal lesions and multiple ulcers were prone to loss of response to the anti-TNF-alpha antibody treatment after long-term administration. This result is considered to be very useful for developing a treatment strategy for patients requiring long-term anti-TNF-α antibody treatment.

Efficacy of Chimeric Antigen Receptor T-Cell Therapy Is Not Impaired By Previous Bispecific Antibody Treatment in Patients with Large B-Cell Lymphoma

Introduction: Potential T-cell exhaustion after bispecific antibody (BsAb) treatment remains an open question, raising the theoretical concern that prior BsAb exposure could affect subsequent chimeric antigen receptor (CAR) T-cell efficacy. Clinical data on CAR T-cell outcomes after prior BsAb treatment in the setting of large B-cell lymphoma (LBCL) are scarce and highly awaited to better define treatment sequencing in relapsed/refractory (R/R) patients. Methods: We conducted a retrospective, international study including R/R LBCL patients treated with CD19-targeted CAR T-cells at 15 centers between July 2018 and January 2023 who had been exposed to BsAbs prior to apheresis. Then, we identified a control cohort from patients included in the DESCAR-T Registry (n=764). We carried out a 1:1 propensity score matching (PSM) to achieve balance between cohorts; 13 baseline covariates were included in the PSM. We compared response rates, survival outcomes and toxicity after CAR T-cell therapy, according to previous BsAb exposure. Results: We identified 47 LBCL patients who received BsAb therapy prior to CAR T-cell apheresis. Median age was 65 years (range 31-82), with a male predominance (66%), and median prior lines of therapy before BsAb were 2 (IQR 2-3) (Table). The BsAbs targeted CD20/CD3 (91%) or CD22/CD3 (9%), either in monotherapy (n=41, 87%) or in combination with other agents (n=6, 13%) (lenalidomide [n=2], polatuzumab [n=1], chemotherapy [n=2], missing [n=1]). The median time on BsAb treatment was 98 days (IQR 56-160) with a best overall (complete) response rate (ORR [CRR]) of 47% (19%). Median progression-free survival (PFS) and duration of response (DOR) were 3.1 months (95% CI 2.7-4.4 months) and 8.8 months (95% CI 2.2-NR), respectively. Cytokine release syndrome (CRS) occurred in 59% of patients (grade 3 in 4%). No neurologic toxicity (NT) was reported. In 26 (55%) patients, bispecific antibody was the last line before CAR T-cell therapy. Median washout between the last BsAb dose and lymphocyte apheresis for CAR T-cell manufacturing was 43 days (range 34-103 days). In terms of the subsequent CAR T-cell therapy, patients received axi-cel (n=22, 47%), tisa-cel (n=20, 43%) or liso-cel (n=5, 11%). Most patients developed CRS after infusion (79%, 6% grade >2), with a low rate of NT (23%, 2% grade >2). Neutropenia and thrombocytopenia grade >2 were reported in 66% and 45% of patients, respectively. Regarding efficacy, ORR after infusion was 83% (CR 43%). Median PFS and overall survival (OS) were 6.6 months (95% CI 2.6-not reached [NR]) and NR (95% CI 9.0-NR), respectively. The rate of overall (complete) response was similar between patients who had previously responded (CR or PR) or not (SD or PD) to BsAb therapy (82% [41%] vs 84% [44%], respectively, p=0.64). However, all 9 patients achieving CR after BsAb achieved subsequent response to CAR T-cells. Given the wide variability in the washout between last BsAb dose and lymphocyte apheresis, we evaluated the impact of this interval on CAR T-cell efficacy. The 6-month PFS and OS of patients previously exposed to BsAb within 45 days of lymphocyte apheresis was similar to patients who had a longer washout (59% vs 47% [p=0.25] and 83% vs 67% [p=0.21], respectively). In the second part of the analysis, we matched our cohort with a control group of CAR T-cell recipients not previously exposed to BsAbs. The final analysis included 2 sets of 42 patients with comparable characteristics. Median follow-up from CAR T-cell infusion was 11.5 months for the BsAb cohort (CI 95% 6.4-19.0 months) and 18.8 months for the control cohort (CI 95% 10.9-23.0 months). Patients with previous BsAb exposure showed a similar PFS (p=0.10, Figure) and OS (p=0.08) after CAR T-cell infusion in comparison to the control group. In terms of toxicity, there were no differences in the incidence of CRS (p=0.41) or NT (p=1.0) after infusion. Conclusions: Previous exposure to bispecific antibody treatment targeting different antigens does not have a negative impact on survival outcomes after CAR T-cell therapy. Lack of response to a previous BsAb does not predict for lower response rates after CAR T-cell infusion.

Real-World Outcomes of Neutralizing Monoclonal Antibody Treatment in Patients Affected by Nosocomial Coronavirus Disease 2019

Introduction Neutralizing monoclonal antibodies (NmAbs) are a treatment option in patients with early SARS-CoV-2 infection. In this study, we examined the role of NmAbs therapies in a cohort of patients affected by nosocomial COVID-19 infection and high risk of illness progression. Methods A retrospective, single-center analysis was performed including all patients affected by nosocomial SARS-CoV-2 infection receiving NmAbs treatment between April 2021 and March 2022. Results The overall included patients were 75. Mortality rate was 13.3%; disease progression was observed in 22 patients (29.3%); clinical improvement was reported in 49 subjects (65.3%). In multivariate logistic regression, the presence of immunosuppression risk factor and late administration of therapies were recognized as independent predictors of treatment failure. Conclusions In this real-world analysis, the treatment with NmAbs was safety and effectiveness in high-risk patients with nosocomial COVID-19 infection, but the timing of administration and the role of viral variants are the main limiting factors of this approach.

Abstract 4155: The RAF/MEK clamp avutometinib (VS-6766) induces an immunogenic tumor microenvironment and potentiates the efficacy of anti-PD-1

Abstract The RAS/RAF/MEK/ERK (MAPK) pathway is one of the most commonly mutated oncogenic pathways in human cancers. Although RAS, RAF and MEK have been validated as anticancer targets with approval of KRAS G12C, BRAF and MEK inhibitors, combination strategies with chemotherapy, targeted therapies and/or immune checkpoint inhibitors may be optimal for deep and durable response. Avutometinib (avuto, VS-6766) is a unique RAF/MEK clamp that potently inhibits MEK kinase activity and induces a dominant negative RAF/MEK complex preventing phosphorylation of MEK by ARAF, BRAF and CRAF. Preclinically, avuto has shown strong anti-proliferative potency across tumor cell lines carrying various MAPK pathway alterations. Clinically, avuto monotherapy has shown responses in gynecological cancers and KRAS mutant non-small cell lung cancer. Here, we tested the immune modulatory effects of avuto on tumor cells and tumor-infiltrating immune cells and assessed anti-tumor efficacy in mice treated with avuto in combination with an anti-PD1 antibody. In a panel of KRAS and BRAF mutant human tumor cell lines, avuto treatment increased the expression of MHC-I complex genes, including B2M, HLA-A and TAP1. In the CT26 KRAS G12D syngeneic colorectal cancer model, upregulation of B2M and TAP1 by avuto was confirmed in vivo, suggesting that avuto may increase antigen presentation. Furthermore, avuto upregulated the expression of markers of T cells (CD8, PDCD1), NK cell activation (NCR1) and interferon response (IFNG, IRF7, IL12) in the CT26 model. Interestingly, all these pro-immune changes observed with avuto were stronger than those observed with an equivalent dose level of the MEK-only inhibitor trametinib. Avuto also increased expression of B2M, CD8A, PDCD1, NCR1 and IRF7 in a KPARG12C orthotopic lung cancer model. Flow cytometry analysis showed that avuto also significantly increased MHC-II expression by tumor cells and the numbers of CD8 T cells and M1 macrophages, and significantly decreased monocytic and granulocytic MDSCs. These immune changes indicate that avuto induces an immunogenic tumor microenvironment that may potentiate the efficacy of immuno-oncology agents such as anti-PD-1. Accordingly, in the CT26 model, whereas avuto and anti-PD-1 each delayed tumor growth, combination of avuto with anti-PD-1 increased antitumor efficacy and prolonged survival. Furthermore, all complete responders in the avuto + anti-PD-1 group were able to reject a re-challenge with CT26 tumor cells and showed increased CD8 and CD4 effector memory T cells relative to untreated naïve control mice, indicating that avuto + anti-PD-1 treatment induces durable immune memory. These results support clinical evaluation of avutometinib in combination with an anti-PD-1 antibody for treatment of patients with solid tumors harboring MAPK pathway alterations such as KRAS or BRAF mutations. Citation Format: Silvia Coma, Miriam Molina Arcas, Julian Downward, Jonathan A. Pachter. The RAF/MEK clamp avutometinib (VS-6766) induces an immunogenic tumor microenvironment and potentiates the efficacy of anti-PD-1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4155.

Management of Alzheimer’s disease in the next ten years

Since the inception of clinical neuroscience, scientific breakthroughs have enhanced our knowledge of how certain pathologies impair the function of the nervous system. Alzheimer’s disease (AD) is a perpetual challenge in modern clinical neuroscience due to the ageing population, which makes individuals increasingly susceptible to AD. On a global scale, AD is the most common form of dementia and the number of people living with dementia worldwide has more than doubled from 1990 to 2016, which warrants prompt development of effective interventions that may halt or delay disease progression. This narrative review recommends further investigation into the effectiveness of monoclonal antibody treatment in patients with early AD and the utilisation of several laboratory tools to understand the complex aetiology of AD. In the next ten years, it is hoped that the recommendations in this article may come to fruition and facilitate further advancements in clinical neuroscience to develop therapies that delay the onset and even reverse the clinical manifestation of AD that currently has a poor prognosis.

Prospective observational study of monitoring gene alterations in plasma cell-free DNA using droplet digital PCR system during anti-EGFR antibody treatment in patients with RAS wild-type advanced colorectal cancer.

172 Background: Anti-EGFR antibody is recommended as one of the standard treatments in patients with RAS wild-type advanced colorectal cancer (CRC). Few reports have evaluated low-frequency subclones of alterations in EGFR signaling pathway genes in plasma cell-free DNA (cfDNA) during anti-EGFR treatment in prospective cohort of advanced CRC patients. Methods: Key inclusion criteria of this study was as follows: 20 years old and over, performance status 0 to 2, metastatic or recurrent CRC (adenocarcinoma), RAS wild-type CRC diagnosed by PCR-rSSO using tumor tissue, no prior use of anti-EGFR antibody. Plasma samples were prospectively collected at pre-treatment, at 4, 10 weeks, every 10 weeks thereafter, and at the end of the anti-EGFR treatment. With QX200 Droplet Digital PCR platform, we analyzed hotspot mutations of KRAS, NRAS, BRAF, and PIK3CA and copy number (CN) variant of HER2 and MET using plasma samples of pre- and post-treatment as well as during treatment (limited to patients with any gene alterations at pre- and post-treatment). Results: Total 50 patients were registered in this study, but 3 patients were excluded because inclusion criteria were not met. Finally, 47 patients were included in full analysis set. In 15 patients (31.9%), genetic alterations including KRAS (G12G13: 10.1%, A59Q61: 2.2%), NRAS (G12G13: 2.2%, Q61: 2.1%), BRAF (V600: 6.4%) , PIK3CA (E545: 4.3%, H1047: 4.3%) , and HER2 (amplification: 6.5%) were detected in pre-treatment samples. Analysis of pre-treatment samples showed that response rates of patients with any gene alterations (N = 13) and that without any gene alterations (N = 29) were 30.8% and 58.6%, respectively (p = 0.095). When the cut-off of variant allele frequency (VAF) was set as 0.5% in patients with any gene mutations, the response rates for cases with VAF ≥0.5% (N = 6) and those with VAF < 0.5% (N = 7) were 0% and 57.1%, respectively (p = 0.049). Among 41 patients with detectable target lesions by CT scan, there was significant difference in percentage of best tumor shrinkage between patients with gene alterations and those without gene alterations (32.1% vs 10.5%, p = 0.037), when cut-off VAF of any gene mutations was set as 0.5% and cut-off CN of HER2 or MET was set as 4 at pre-treatment. Due to dynamics of each gene alteration in cfDNA during treatment, mutations of KRAS A59Q61, NRAS Q61, and MET amplification were characterized as acquired alterations which were newly detected after the administration of anti-EGFR antibodies. Conclusions: Our study demonstrated the clinical relevance of minor mutant subclones in EGFR signaling pathway genes in plasma for predicting response to anti-EGFR treatment. Although sample size of this study was small, preferable threshold for distinguishing responders from non-responders may be 0.5% as VAF of these gene mutations. Clinical trial information: 000034923 .

Machine-learning-based approach for predicting response to anti-calcitonin gene-related peptide (CGRP) receptor or ligand antibody treatment in patients with migraine: A multicenter Spanish study.

Several variables have been reported to be associated with anti-calcitonin gene-related peptide (CGRP) receptor or ligand antibody response, but with differing results. Our objective was to determine whether machine-learning (ML)-based models can predict 6-, 9- and 12-month responses to anti-CGRP receptor or ligand therapies among migraine patients. We performed a multicenter analysis of prospectively collected data from patients with migraine receiving anti-CGRP therapies. Demographic and clinical variables were collected. Response rates in the 30% to 50% range, or at least 30%, in the 50% to 75% range, or at least 50%, and response rate of at least 75% regarding the reduction in the number of headache days per month at 6, 9 and 12 months were calculated. A sequential forward feature selector was used for variable selection and ML-based predictive models for the response to anti-CGRP therapies at 6, 9 and 12 months, with model accuracy not less than 70%, were generated. A total of 712 patients were included, 93% were women, and the mean (SD) age was 48(11.6) years. Eighty-four percent of patients had chronic migraine. ML-based models using headache days/month, migraine days/month and the Headache Impact Test (HIT-6) yielded predictions with an F1 score range of 0.70-0.97 and an area under the receiver-operating curve score range of 0.87-0.98. SHAP (SHapley Additive exPlanations) summary plots and dependence plots were generated to evaluate the relevance of the factors associated with the prediction of the above-mentioned response rates. Our results show that ML models can predict anti-CGRP response at 6, 9 and 12 months. This study provides a predictive tool that can be used in a real-world setting.

Cautious Addition of MEK Inhibitors to PD-1 Antibody Treatment in Patients with NRAS or NF1 Mutant Metastatic Melanoma Failing Initial Immunotherapy

Cautious Addition of MEK Inhibitors to PD-1 Antibody Treatment in Patients with NRAS or NF1 Mutant Metastatic Melanoma Failing Initial Immunotherapy

496 - Bamlanivimab Monoclonal Antibody Treatment in Patients with Graft Versus Host Disease (GVHD) Diagnosed with COVID-19 Infection

496 - Bamlanivimab Monoclonal Antibody Treatment in Patients with Graft Versus Host Disease (GVHD) Diagnosed with COVID-19 Infection

Sensitivity of two SARS-CoV-2 variants with spike protein mutations to neutralising antibodies

SARS-CoV-2 infections elicit a humoral immune response capable of neutralising the virus. However, multiple variants have emerged with mutations in the spike protein amongst others, the key target of neutralising antibodies. We evaluated the neutralising efficacy of 89 serum samples from patients, infected with SARS-CoV-2 in the beginning of 2020, against two virus variants isolated from acutely infected patients and harbouring spike protein mutations. One isolate was assigned to lineage B.1.351 (MUC-IMB-B.1.351) whilst the other (MUC-484) was isolated from an immunocompromised patient, sharing some but not all mutations with B.1.351 and representing a transitional variant. Both variants showed a significant reduction in neutralisation sensitivity compared to wild-type SARS-CoV-2 with MUC-IMB-B.1.351 being almost completely resistant to neutralisation. The observed reduction in neutralising activity of wild-type-specific antibodies against both variants suggests that individual mutations in the spike protein are sufficient to confer a potent escape from the humoral immune response. In addition, the effect of escape mutations seems to accumulate, so that more heavily mutated variants show a greater loss of sensitivity to neutralisation up to complete insensitivity as observed for MUC-IMB-B.1.351. From a clinical point of view, this might affect the efficacy of (monoclonal) antibody treatment of patients with prolonged infections as well as patients infected with variants other than the donor. At the same, this could also negatively influence the efficacy of current vaccines (as they are based on wild-type spike protein) emphasising the need to thoroughly surveil the emergence and distribution of variants and adapt vaccines and therapeutics accordingly.

The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma

BackgroundImmunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial.MethodsDANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers.DiscussionDANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs.Trial registrationISRCTN15837212, 31 July 2018.

Increasing of Ternary Complex Formation By Predominant Accumulation of Factor (F)X Accompanied By Increase of Fixa Contributes to Enhancement of Clotting Function By Apcc in Combination with Emicizumab

Background: Emicizumab is a novel therapeutic bispecific antibody for treatment of patients with hemophilia A (PWHA) irrespective of FVIII inhibitors. In the phase 3 clinical study of emicizumab focusing on PWHA with inhibitor (-inh) over 12 years old (NEJM2017), several thromboembolic events were reported among participants after multiple infusions of activated prothrombin complex concentrate (APCC) for breakthrough bleeding. We recently reported that the global hemostatic function evaluated by ROTEM was additively enhanced by infusion of APCC under treatment of emicizumab in the Japanese phase 1/2 study (ISTH2017). There exist three forms of emicizumab in the circulating plasma such as i) monomer, ii) binary complex with either FIX(a) or FX, and iii) ternary complex with FIX(a) and FX. According to in vitro experiments, we recently demonstrated that the percent of the ternary complex would be predicted by KD -based simulation based on concentration of emicizumab, FIX(a) and FX (Thromb Haemost. 2017). The in vivo pharmacodynamics of FIX(a) and FX after infusion of APCC in the presence of emicizumab are to be elucidated for confirmation of safety.Aim: To clarify the relationship between pharmacodynamics of FIX(a) and FX after infusion(s) of APCC and hemostatic potential in the presence of emicizumab.Methods: We first examined the hemostatic function by addition of emicizumab (0, 10, 50, 100μg/ml) in the citrated blood samples obtained from seven PWHAs-inh (who do not participate in the clinical study) received APCC (80-100U/kg) by thrombin generation assay (TGA) using tissue factor (0.5pM) and ellagic acid (0.3µM) as trigger reagents. The plasma samples were classified by APCC-dosing at collection as summarized in Table. Class A was defined as single or prophylactic administration while class B was defined as treatment with multiple administrations. For patient 7, intra-individual evaluation was examined before (as class A) and after initiation of treatment by APCC (as class B). We further confirmed the in vivo additional effect by APCC to emicizumab in the samples obtained from one PWHA-inh (patient 8) enrolled in the Japanese phase 1/2 study. This patient received four multiple infusions of APCC (~50U/kg, every 12hr) for a major bleeding.Results: Spike of emicizumab in vitro exhibited a dose-dependent modest increase of PeakTh maximally by ~1.6-fold of that in the absence of emicizumab (212 ± 22.8 nM) in class A. On the other hand in class B, PeakTh augmented dose-dependently on emicizumab (max. to 1,538 ± 38 nM by ~12.5-fold of that in its absence) far beyond normal control (382 nM). As for the samples from patient 8, PeakTh increased from 80.6 nM to 240 nM after 4th infusion of APCC. This increase of PeakTh was less than that in class B (from 122 ± 9.73 nM to 793 ± 29.3 nM) after spike of emicizumab (10µg/ml) which is equivalent to the target concentration in patient 8. To identify the determinant of these different hemostatic enhancing effects, antigen (Ag) levels of FX and FIX(a) in the plasmas were measured by ELISAs. The median values of FX:Ag and FIX(a):Ag were 424nM (~3.1-fold of normal control) and 124nM (~1.4-fold of normal) in class A, and those in class B were 2,000nM (~15-fold of normal) and 278nM (~3-fold of normal), respectively. In the samples of patient 8 from the Japanese phase 1/2 study, FX:Ag increased up to 3.7-fold of normal after 1st administration of APCC and further increased to 7-fold of normal after 4th administration, while FIX(a):Ag was little affected by administrations of APCC different from class B, which would be attributed to that the lower dose of APCC were infused for patient 8 than that for patients in class B. Taken together, dose and/or frequency of APCC infusion(s) seemed to affect the pharmacodynamics of FIX(a) and FX in the plasma. The elevation of both of them, especially FX, resulting in the increase of ternary complex in the presence of emicizumab, contribute to hemostatic enhancement.Conclusion: In conclusion, high-dose and frequent infusions of APCC contribute to the predominant accumulation of FX accompanied by the increase of FIX(a) in the plasma enhancing the hemostatic effect in the presence of emicizumab, in addition to the bypassing reactions. [Display omitted] DisclosuresYada:Chugai Pharmaceutical Co.: Research Funding. Nogami:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Matsumoto:Chugai Pharmaceutical Co.: Research Funding. Kitazawa:Chugai Pharmaceutical Co.: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Distinct Populations of Immune-Suppressive Macrophages Differentiate from Monocytic Myeloid-Derived Suppressor Cells in Cancer

SUMMARYHere, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPβ. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

BackgroundWhile the BRAF V600E mutation occurs in 5%–15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model.Trial designThe BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m2 and subsequently 250 mg/m2, once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort.Trial registration numbersUMIN000031857 and 000031860.

High Numbers of Circulating CD57+ NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2+ Primary Breast Cancer.

Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57+ NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2+ breast cancer cells was comparable in patients with high and low proportions of CD57+ NK cells. However, circulating CD57+ NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro Presence of CD57+ NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57+ were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57+ NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer.

Clinical Impact of Sonographic Transmural Healing After Anti-TNF Antibody Treatment in Patients with Crohn's Disease.

To assess the clinical benefits of transmural healing (TH) shown on intestinal ultrasound (IUS) after treatment with tumor necrosis factor-alpha antibodies (anti-TNF) in patients with Crohn's disease. This prospective study included consecutively 36 patients who underwent IUS in the week prior to start anti-TNF treatment, at 12weeks, and 1year after starting treatment. The clinical response to treatment was assessed using the Crohn's disease activity index and C-reactive protein (CRP) values. TH was defined as the normalization of bowel wall thickness on IUS. Treated patients were considered to have a good outcome if none of the following situations presented: need to reintroduce corticosteroids or intensify maintenance therapy and/or need for surgery. After the induction regimen, 29 patients (80.6%) achieved clinical remission, and serum CRP values returned to normal in 20 patients (55.6%). In the IUS at 12weeks, treatment induced a statistically significant reduction in the wall thickness (p < 0.001) and color Doppler grade (p < 0.001), as well as resolution of complications in 66.7% of patients (p < 0.03). IUS after 1year of biological therapy showed TH in 14/33 patients (42.4%). During the follow-up (median 48.5months), 23 of the 33 (69.7%) patients in remission or response after induction therapy presented a good outcome. Sonographic TH was significantly related with better outcomes, with only 1/14 patients having a poor outcome compared to 9/19 without TH (OR 11.7, 95% CI 1.2-108.2 p = 0.01, Chi-squared test). Patients who achieve TH on IUS with biological treatment have better clinical outcomes.

Serum eosinophil cationic protein concentrations do not predict response to anti-interleukin 5 antibody treatment in patients with severe uncontrolled eosinophilic asthma

Serum eosinophil cationic protein (ECP) has been described as a marker reflecting the degree of activation of eosinophils in asthma, therefore indirectly measuring the degree of airway inflammation.