Antibody Treatment Research Articles

Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) pathology (PS2APP) or combined Aβ and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.

Changing Characteristics of Treg/Th17 Cells in the Nasal Mucosa of a Mouse Model of Allergic Rhinitis and the Effect of Intervention with Anti-IL-17 Antibody.

The incidence rate of allergic rhinitis (AR) is on the rise, which seriously affects the quality of life, work efficiency, mental state of patients, and sleeping in AR sleep. This experiment aimed to investigate the changes in Treg/Th17 cells in the nasal mucosa of an AR mouse model and the intervention effect of an Anti-IL-17 antibody. A mouse model of AR was induced by intraperitoneal ovalbumin (OVA) injection for sensitization and stimulation with nasal drops. The times of rubbing, sneezing, and symptomatology scores were counted and analyzed. Pathological damage to the nasal mucosa was observed by Hematoxylin-Eosin (HE) staining. Peripheral blood CD4+CD25+CD127- Treg cell levels and the content of Th17 cells were measured by flow cytometry (FCM). ELISA kits were used to detect the levels of relevant cytokines (IL-10 and TGF-β1) secreted by Treg cells. The intervention effect of Anti-IL-17 antibody was observed by giving Anti-IL-17 antibody treatment. The times of rubbing, sneezing, and symptomatology scores were significantly higher in mice in the OVA group than in the Control group (p < 0.001). The percentage of CD4+CD25+CD127- Treg cells in CD4+CD25+ T cells (p < 0.05) and the levels of IL-10 (p < 0.001) and TGF-β1 (p < 0.001) were significantly decreased. After OVA induction, the continuity of the nasal mucosa of mice was interrupted, the percentage of Th17 cells, IL-17, and IL-4 levels were increased, and IFN-γ levels were significantly reduced (p < 0.001). And protein expression of RORγt was significantly upregulated (p < 0.001). In addition, all of these results were reversed by Anti-IL-17 antibody treatment, significantly improving AR-related symptoms (p < 0.05). Anti-IL-17 antibodies may regulate the body's immune response by promoting CD4+CD25+CD127- Treg cell differentiation, thereby ameliorating the symptoms associated with AR.

Effect of blocking CD96 on CD8+ T cell–mediated elimination of tumor dormancy.

e14679 Background: Dormant tumor cells, characterized by quiescent state, exhibit superior tumorigenic capacity, chemotherapy resistance, and expression of stemness genes, along with reduced immune infiltration. Tumor recurrence frequently emerges from persistent dormant tumor cells, posing a formidable challenge for targeted intervention. Methods: In this study, we established a reporter gene system to isolate dormant tumor cells from implanted tumors and reimplanted them into C57BL/6 mice. The effectiveness of the anti-CD96 antibody against dormant tumor cells was assessed by measuring tumor volumes and survival. Subsequently, anti-EpCAM CAR-T cells with CD96 knockout were administered to NSG mice with established dormant tumor cells to evaluate their efficacy and toxicity in vivo. Results: In this study, we identify a novel therapeutic target for dormant tumor cells. Administering anti-CD96 antibodies, rather than anti-PD-1 antibodies, in a systemic treatment of mice effectively eradicates dormant tumor cell-mediated recurrence in a CD96 T cell-dependent manner. Notably, dormant tumor cells exhibit resistance to adoptive cell transfer therapy. Consequently, the blockade of CD96 in anti-EpCAM CAR-T cells, either through antibody treatment or knock-out approaches, holds promise for eliminating dormant tumor cells in colorectal cancer (CRC). Furthermore, knockout CD96 in CAR-T cells enhances CAR-T cell memory formation via regulating mitochondria function but also inhibits T cell exhaustion. Conclusions: In summary, targeting CD96 serves as a valuable checkpoint against dormant tumor cells, presenting a therapeutically actionable strategy for preventing disease relapse.

Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeutics

Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain. We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb). Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively. Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration. This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.

Casirivimab-imdevimab monoclonal antibody treatment for an immunocompromised patient with persistent SARS-CoV-2 infection: a case report

BackgroundPersistent acute SARS-CoV- 2 infection is characterised by the persistence of symptoms of a COVID-19 illness and a persistently positive SARS-CoV-2 RT PCR result. It is often seen in immunocompromised individuals. Currently, there are no approved treatment regimens or guidelines for management.MethodsOur patient is a middle-aged male who had received chemotherapy prior to the onset of his SARS- CoV-2 infection and subsequently was diagnosed with a persistent and acute SARS- CoV-2 infection after presenting to us with a pyrexia of unknown origin. He was treated on an off-label basis following informed consent with casirivimab-imdevimab monoclonal antibody therapy, comprising two IgG1 neutralising human monoclonal antibodies at a dose of 600 mg each.ResultsOur patient had significant clinical improvement on treatment with the monoclonal antibody therapy and it was well tolerated without any adverse effects. He is currently doing well during follow up.ConclusionsCasirivimab-imdevimab monoclonal antibody therapy could be beneficial for people with persistent acute SARS-CoV-2 infection. Therapy is warranted on a case-to-case basis. This highlights the need to identify immunocompromised individuals who are at risk of developing persistent acute SARS-CoV-2 infection to enable their prompt treatment.

Chemotherapy plus EGFR antibody as conversion treatment in RAS wild type, right-sided metastatic colon cancer: A systematic review and meta-analysis.

e15568 Background: The optimal conversion strategy for right-sided RAS wild type (WT) metastatic colorectal cancer (mCRC) remains a contentious issue, especially regarding the role of EGFR antibodies. EGFR antibody treatment might be an attractive option in patients with contraindications to bevacizumab or in hyperselected patients with microsatellite stable subtypes and without RAS/BRAF/HER2 alterations, potentially allowing a shorter time to conversion surgery. Methods: We performed a systematic search of PubMed/MEDLINE and EMBASE for randomized trials reporting the overall response rate (ORR) and resection rate following chemotherapy (CT) plus anti-EGFR agents (cetuximab or panitumumab) for right-sided mCRC. Studies were selected regardless of whether the resection rate was a study endpoint or not. We used a random-effects model with generic inverse variance to compute pooled ORR and resection rates and to compare CT regimens combined with anti-EGFR or anti-VEGF agents. Results: Ten randomized trials with a total of 4465 mCRC patients were included; seven trials reported the resection rate as a secondary endpoint. 828/4465 (18.5%) patients were right-sided, of whom 419/828 (50.6%) patients received CT doublet or triplet plus anti-EGFR, 263/828 (31.8%) treated with CT plus bevacizumab, and 146/828 (17.6%) patients with CT alone. The ORR was significantly higher in the anti-EGFR group compared to CT alone (50.89% vs 31.03%, OR: 2.23 [95% CI: 1.50-3.32], p &lt; 0.01). No significant difference in ORR was observed between the CT plus anti-EGFR and CT plus bevacizumab groups (50.89% vs 53.32%, OR: 0.89 [95% CI: 0.65-1.21], p = 0.44). Resection rates were 8.08% for CT plus anti-EGFR, 4.79% for CT plus bevacizumab, and 12.24% for CT alone, with no significant differences among the three arms (χ2= 2.15, p = 0.34). Subgroup analysis of RAS/BRAF WT patients with right-sided tumors from the PARADIGM and PEAK trials showed no difference in progression-free survival (PFS) between the CT plus anti-EGFR or bevacizumab groups (11.01m vs 11.60m, HR = 1.04 [95% CI: 0.58-1.50]), but there was a trend toward improved overall survival (OS) with anti-EGFR treatment (30.66m vs 28.67m, HR = 0.81 [95% CI: 0.45-1.17]). Conclusions: The data indicate that augmenting chemotherapy with anti-EGFR could be a viable conversion therapy for patients with RAS/BRAF WT right-sided mCRC, underscoring its potential utility in this subset of patients.

Alpha-Synuclein Targeting Monoclonal Antibody Therapy Treatment for Parkinson’s Disease

An investigation was done on plausible antibody treatments for alpha-synuclein, which is an instigator for the dopamine-lacking neurodegenerative disease Parkinson’s to occur in patients due to its aggregation. Trials working towards slowing the pathogenesis of Parkinson’s Disease through monoclonal antibodies for alpha-synuclein were analyzed. Previously, similar therapies were done in other neurodegenerative diseases like Alzheimer’s, allowing for a hopeful hypothesis in Parkinson’s. Active and Passive antibody treatments were compared and discussed: Pranizeumab, Cipanemab, PD01A, and UB-312. Trials often found success in animal models and not the same outcome in humans within the passive studies. In active studies, however, more hopeful results were presented, showing built immunity towards alpha-synuclein and enhancement of motor symptoms. Though some studies led to a dead end, studies use information to complete future phases. Monoclonal antibody treatment for Parkinson’s Disease is a real future in the fight for reducing the pathogenesis of Parkinson’s Disease.

ICAM-1 may promote the loss of dopaminergic neurons by regulating inflammation in MPTP-induced Parkinson’s disease mouse models

Parkinson’s disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.

Predictive value of circulating immune cell changes in response to PD-1 blockade and TKI therapy in patients with hepatocellular carcinoma

Purpose: This study investigated the dynamic changes in circulating immune cells following immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs), and interventional therapy in hepatocellular carcinoma (HCC).Methods: HCC patients undergoing transarterial chemoembolization (TACE), TKI, and ICI treatment were included in the treatment group. Peripheral blood samples were collected from these patients before each cycle of PD-1 blockade treatment. Flow cytometry analysis was conducted to assess the composition of peripheral immune cells and identify PD-1-expressing T cells.Results: The treatment group showed a median time-to-tumor progression (TTP) of 8 months and an overall survival (OS) of 19 months. In comparison, the control group had 6 months and 15 months respectively. These differences were statistically significant (P = 0.029 for TTP and P = 0.020 for OS). In HCC patients receiving Lenvatinib, more circulating natural killer (NK) cells were noted. After 1–2 cycles of PD-1 antibody treatment, a general decline in the proportion of circulating PD-1+T cells was found, indicating individual variations in response.Conclusion: Circulating immune cells have the potential to serve as indicators of the response to immunotherapy, providing a means to monitor dynamic changes and optimize treatment for HCC.

CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.

Targeting Gαi2 in neutrophils protects from myocardial ischemia reperfusion injury.

Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gαi proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gαi2 proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gαi2 in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2-/- → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gαi2 in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2-/- vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gαi2 for mIRI. Here, we show that infarct size was substantially reduced when Gαi2 signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2fl/fl LysM-Cre+/tg vs 42.0% Gnai2fl/fl; p < 0.01) or selectively blocked with specific antibodies directed against Gαi2 (AAR: 19.0% (anti-Gαi2) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2fl/fl; LysM-Cre+/tg) vs 31 (Gnai2fl/fl); p < 0.001) and in anti-Gαi2 antibody-treated (PNCs: 9 (anti-Gαi2) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gαi2 antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gαi2 antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gαi2) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gαi2 inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.

Antiviral therapies for the management of persistent coronavirus disease 2019 in immunocompromised hosts: A narrative review.

Antiviral agents with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a critical role in disease management; however, little is known regarding the efficacy of these medications in the treatment of SARS-CoV-2 infection in immunocompromised patients, particularly in the management of persistent SARS-CoV-2 positivity. This narrative review discusses the management of persistent coronavirus disease 2019 in immunocompromised hosts, with a focus on antiviral therapies. We identified 84 cases from the literature describing a variety of approaches, including prolonged antiviral therapy (n = 11), combination antivirals (n = 13), and mixed therapy with antiviral and antibody treatments (n = 60). A high proportion had an underlying haematologic malignancy (n = 67, 80%), and were in receipt of anti-CD20 agents (n = 51, 60%). Success was reported in 70 cases (83%) which varied according to the therapy type. Combination therapies with antivirals may be an effective approach for individuals with persistent SARS-CoV-2 positivity, particularly those that incorporate treatments aimed at increasing neutralizing antibody levels. Any novel approaches taken to this difficult management dilemma should be mindful of the emergence of antiviral resistance.

Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator.

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

Stress Affects Mast Cell Proteases in Murine Skin in a Model of Atopic Dermatitis-like Allergic Inflammation.

Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.

#3105 Tocilizumab for treatment of antibody mediated rejection in kidney transplant patients

Abstract Background and Aims Chronic active antibody-mediated rejection (caABMR) causes 40% of long-term graft failure after kidney transplantation (KT). Early treatment is of great importance, however, hard clinical evidence is still lacking. Currently the combination of plasmapheresis (PF), rituximab and intravenous immunoglobulin is used as standard treatment. Tocilizumab (TCZ) is a monoclonal antibody, IL-6 receptor antagonist, and it inhibits the production of donor-specific antibodies (DSA). We hypothesized that tocilizumab administration has an additional effect on graft survival and non-inferior to standard therapy in KT patients with ABMR. Method Retrospective single-center noninferiority case-control study was performed by involving 73 KT patients (43.5 ± 14.3 years, females 31, eGFR 19.5 ± 13.4) with biopsy proven ABMR diagnosed between June 2017 and May 2022. 19 patients received 8 mg/kg intravenous TCZ therapy for 6 months (12 aABMR, 7 caABMR, 38.6 ± 12.8 years, females 6). In the control group (C, n=54, 10 aABMR, 44 caABMR, 45.2 ± 14.5 years, females 25), 20 patients received plasmapheresis treatment, the rest stayed on optimized maintenance therapy (tacrolimus, mycophenolic acid, prednisolone). Baseline demographic data, standard laboratory data, proteinuria and DSA level were also monitored and analyzed. Results Graft loss occurred in 13 cases (6 aABMR, 7 caABMR) in KT on TCZ therapy and 43 (6 aABMR, 37 caABMR) in C group, meaning significantly lower risk of graft loss in the TCZ group (RR 0.69, p=0.036) during the median follow-up of 11.3 (IQR 2.5-23.1) months. In TCZ group, all caABMR patients lost their graft during the observation. In TCZ group, 1 year after the TCZ treatment, DSA (pooled) was lower (7028 (575-17782) versus 1605 (551-16903), p&amp;lt;0.05). Conclusion Early administration of TCZ seems to be noninferior to standard therapy and effective to prevent early graft loss as part of standard therapy in aABMR. Further clinical studies are needed to clarify clinical indications of TCZ and its long-term effects on the course of chronic active ABMR.

Implementing a closed system drug transfer device to enable nurses to prepare monoclonal antibody treatment.

Efforts to increase capacity for oncology treatment in the author's Chemotherapy Day Unit, while allowing staff to treat more patients and offer more flexibility to patients, increased strain on the Aseptic Pharmacy at the author's Trust. Therefore, the possibility of nurse-led drug preparation was explored. Nurse-led monoclonal antibody (MAb) preparation was piloted to investigate whether a reduction in reliance on Aseptic Pharmacy could co-exist with maintaining optimal treatment capacity. The effectiveness of a closed system transfer device (CSTD) to protect nurses against drug exposure was also explored. A risk assessment for MAbs considered for nurse-led preparation was created, alongside a procedure for the safe handling of systemic anti-cancer therapy (SACT) with the use of a CSTD. The pilot resulted in an 89% reduction in the time patients had to wait for MAbs to be prepared. Seven oncology drugs were included in the new procedure without increasing the risk of exposure for nurses. The pilot successfully reduced demand on Aseptic Pharmacy while enabling efficient capacity use on the Chemotherapy Day Unit. The use of the CSTD minimised the risk of nurse exposure to SACT.

Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Anti-chitinase-3-like 1 antibody attenuated atopic dermatitis-like skin inflammation through inhibition of STAT3-dependent CXCL8 expression.

Chitinase-3-like 1 (CHI3L1) causes skin inflammation in the progression of atopic dermatitis. We investigated if anti-CHI3L1 antibody could prevent the development of atopic dermatitis and its mechanisms of action. The effect of CHI3L1 antibody on phthalic anhydride-induced atopic dermatitis animal model and in vitro reconstructed human skin (RHS) model were investigated. Expression and release of atopic dermatitis-related cytokines were determined using an enzyme-linked immunosorbent assay, and RT-qPCR, STAT3 and CXCL8 signalling were measured by western blotting. Anti-CHI3L1 antibody suppressed phthalic anhydride-induced epidermal thickening, clinical score, IgE level and infiltration of inflammatory cells, and reduced phthalic anhydride-induced inflammatory cytokines concentration. In addition, CHI3L1 antibody treatment inhibited the expression of STAT3 activity in phthalic anhydride-treated skin. It was also confirmed that CHI3L1 antibody treatment alleviated atopic dermatitis-related inflammation in the RHS model. The inhibitory effects of CHI3L1 antibody was similar or more effective compared with that of the IL-4 antibody. We further found that CHI3L1 is associated with CXCL8 by protein-association network analysis. siRNA of CHI3L1 blocked the mRNA levels of CHI3L1, IL-1β, IL-4, CXCL8, TSLP, and the expression of CHI3L1 and p-STAT, and the level of CXCL8, whereas recombinant level of CXCL8 was elevated. Moreover, siRNA of STAT3 reduced the mRNA level of these cytokines. CHI3L1 and p-STAT3 expression correlated with the reduced CXCL8 level in the RHS in vitro model. Our data demonstrated that CHI3L1 antibody could be a promising effective therapeutic drug for atopic dermatitis.

Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.

Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade. The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control. PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade.

Metabolic changes enhance necroptosis of type 2 diabetes mellitus mice infected with Mycobacterium tuberculosis.

Previously, we found that Mycobacterium tuberculosis (Mtb) infection in type 2 diabetes mellitus (T2DM) mice enhances inflammatory cytokine production which drives pathological immune responses and mortality. In the current study, using a T2DM Mtb infection mice model, we determined the mechanisms that make T2DM mice alveolar macrophages (AMs) more inflammatory upon Mtb infection. Among various cell death pathways, necroptosis is a major pathway involved in inflammatory cytokine production by T2DM mice AMs. Anti-TNFR1 antibody treatment of Mtb-infected AMs from T2DM mice significantly reduced expression of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) (necroptosis markers) and IL-6 production. Metabolic profile comparison of Mtb-infected AMs from T2DM mice and Mtb-infected AMs of nondiabetic control mice indicated that 2-ketohexanoic acid and deoxyadenosine monophosphate were significantly abundant, and acetylcholine and pyridoxine (Vitamin B6) were significantly less abundant in T2DM mice AMs infected with Mtb. 2-Ketohexanoic acid enhanced expression of TNFR1, RIPK3, MLKL and inflammatory cytokine production in the lungs of Mtb-infected nondiabetic mice. In contrast, pyridoxine inhibited RIPK3, MLKL and enhanced expression of Caspase 3 (apoptosis marker) in the lungs of Mtb-infected T2DM mice. Our findings demonstrate that metabolic changes in Mtb-infected T2DM mice enhance TNFR1-mediated necroptosis of AMs, which leads to excess inflammation and lung pathology.