Immune-modulating Agents Research Articles

Recent Advances in Metabolomics and Lipidomics Studies in Human and Animal Models of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease of the central nervous system (CNS) that leads to a loss of myelin. There are three main types of MS: relapsing-remitting MS (RRMS) and primary and secondary progressive disease (PPMS, SPMS). The differentiation in the pathogenesis of these two latter courses is still unclear. The underlying mechanisms of MS are yet to be elucidated, and the treatment relies on immune-modifying agents. Recently, lipidomics and metabolomics studies using human biofluids, mainly plasma and cerebrospinal fluid (CSF), have suggested an important role of lipids and metabolites in the pathophysiology of MS. In this review, the results from studies on metabolomics and lipidomics analyses performed on biological samples of MS patients and MS-like animal models are presented and analyzed. Based on the collected findings, the biochemical pathways in human and animal cohorts involved were investigated and biological mechanisms and the potential role they have in MS are discussed. Limitations and challenges of metabolomics and lipidomics approaches are presented while concluding that metabolomics and lipidomics may provide a more holistic approach and provide biomarkers for early diagnosis of MS disease.

Optimized Fabrication of Dendritic Mesoporous Silica Nanoparticles as Efficient Delivery System for Cancer Immunotherapy.

In the past decade, cancer immunotherapy has revolutionized the field of oncology. Major immunotherapy approaches such as immune checkpoint inhibitors, cancer vaccines, adoptive cell therapy, cytokines, and immunomodulators have shown great promise in preclinical and clinical settings. Among them, immunomodulatory agents including cancer vaccines are particularly appealing; however, they face limitations, notably the absence of efficient and precise targeted delivery of immune-modulatory agents to specific immune cells and the potential for off-target toxicity. Nanomaterials can play a pivotal role in addressing targeting and other challenges in cancer immunotherapy. Dendritic mesoporous silica nanoparticles (DMSNs) can enhance the efficacy of cancer vaccines by enhancing the effective loading of immune modulatory agents owing to their tunable pore sizes. In this work, an emulsion-based method is optimized to customize the pore size of DMSNs and loaded DMSNs with ovalbumin (OVA) and cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (CpG-OVA-DMSNs). The immunotherapeutic effect of DMSNs is achieved through controlled chemical release of OVA and CpG in antigen-presenting cells (APCs). The results demonstrated that CpG-OVA-DMSNs efficiently activated the immune response in APCs and reduced tumor growth in the murine B16-OVA tumor model.

Pancreatic cancer is feeling the heat.

Pancreatic adenocarcinoma (PDAC) is considered an immunologically 'cold' tumor that fails to attract or support effector T cells. Most PDACs are resistant to immune checkpoint blockade due to the complex signaling pathways that exist within its tumor microenvironment. Recent advances in genomic and proteomic technology advances are finally uncovering the complex inflammatory cellular and intercellular signals that require modulation and reprogramming. The goal is to 'turn up the heat' on PDACs with combination immunotherapies that incorporate T cell activating agents and immune modulatory agents, and successfully eradicate tumors. Here, we discuss progress and promising new research that is moving the field toward this goal.

Autologous Serum Therapy in Recalcitrant Chronic Spontaneous Urticaria: Experience from Three Dermatology Clinics in Malaysia

Abstract Autohemotherapy is a commonly used treatment for recalcitrant chronic urticaria in some countries. Herein we report our experience using autologous serum therapy in eight patients with recalcitrant chronic spontaneous urticaria. Autologous serum therapy was initiated weekly for nine weeks followed by every fortnightly. Urticaria Activity Score (UAS) 7, Dermatology Life Quality Index (DLQI), and reduction of antihistamine usage were used to assess the treatment response. Eight patients (age range: 25–76 years old; four females and four males) had one to ten years of duration of recalcitrant chronic spontaneous urticaria. All failed to respond to high doses of second-generation antihistamines and five to immune-modulating agents. Three did not respond to omalizumab. At week nine, the reduction of UAS7 ranged from 76.2% to 100%. There was more than an 80% improvement in DLQI in all patients. The number of wheals seemed to be reduced first followed by pruritus. Three patients had stopped antihistamines by week eight of treatment. No adverse events were reported in all eight patients. Autologous serum therapy may serve as an alternative treatment for recalcitrant chronic spontaneous urticaria. Apart from the practicality, which requires frequent clinic visits, venipuncture, and centrifugation, it is cheap and effective with minimal adverse events.

29 Pilot study of an implantable microdevice forin vivo evaluation of drug response in renal cell carcinoma (NCT05700461)

Abstract Background There are multiple therapies for renal cell carcinoma (RCC), yet no personalized biomarkers exist that can guide optimal treatment for individual patients. We developed implantable microdevices (IMD) that can be placed within a target tumor using a standard small-gauge interventional needle under imaging guidance. The IMDs deliver spatially segregated microdoses of up to 20 different drugs and/or combinations over multiple days, and then are retrieved surgically with surrounding tissue. This allows for the assessment of tumor response to multiple drugs in vivo within the native tumor microenvironment, without exposing the patient to systemic drug toxicity. We are conducting a trial to evaluate the safety and feasibility of IMD implantation in RCC tumors and subsequent collection of drug response data on targeted, cytotoxic, and immune-modulatory agents. Methods Eligible patients have suspected or confirmed RCC and are planned for standard surgical resection of either their primary tumor or metastasis. Three days prior to surgery, one or more IMDs are implanted percutaneously into the tumor under CT guidance. Following nephrectomy or excision of a metastasis, the microdevices with surrounding tumor are removed en bloc; subsequently, the tissue is fixed, embedded and sectioned. The tumor/IMD cross-sections are analyzed for drug effect for each of the spatially separate treatment effects using a wide range of techniques, including immunohistochemistry for proliferation and pathway markers, spatial immune profiling using a panel of 25 tumor microenvironment markers, and spatial transcriptomics. Patients receive subsequent standard of care systemic treatment as per their oncologist’s discretion. Five patients have been enrolled and a total of 16 IMDs have been implanted to date. Enrollment is ongoing for a planned total of 20 patients. Success is defined as meeting both safety and feasibility endpoints. Safety is defined as two or fewer safety failures out of 20 enrolled patients. Feasibility is defined as 16 or more patients with successful microdevice implantation and retrieval of interpretable data. IMDs will be analyzed to explore spatially segregated drug effects on the tumor microenvironment including tumor cell death and immune cell activation, as well as evidence of differential tumor drug sensitivity across treatments and patients. Conclusions Implantation of microdevices in RCC tumors may be a useful approach to improve treatment selection and accelerate drug development. Trial enrollment is ongoing.

Prolonged exposure to the synthetic glucocorticoid dexamethasone induces brain damage via oxidative stress and apoptotic response in adult Daniorerio

Due to its extensive use as a painkiller, anti-inflammatory, and immune modulatory agent, as well as its effectiveness in treating severe COVID-19, dexamethasone, a synthetic glucocorticoid, has gained attention not only for its impact on public health but also for its environmental implications. Various studies have reported its presence in aquatic environments, including urban waters, surface samples, sediments, drinking water, and wastewater effluents. However, limited information is available regarding its toxic effects on nontarget aquatic organisms. Therefore, this study aimed to investigate the mechanism of toxicity underlying dexamethasone-induced brain damage in the bioindicator Danio rerio following long-term exposure. Adult zebrafish were treated with environmentally relevant concentrations of dexamethasone (20, 40, and 60 ng L-1) for 28 days. To elucidate the possible mechanisms involved in the toxicity of the pharmaceutical compound, we conducted a behavioral test battery (Novel Tank and Light and Dark tests), oxidative stress biomarkers, acetylcholinesterase enzyme activity quantification, histopathological analysis, and gene expression analysis using qRT-PCR (p53, bcl-2, bax, caspase-3, nrf1, and nrf2).The results revealed that the pharmaceutical compound could produce anxiety-like symptoms, increase the oxidative-induced stress response, decrease the activity of acetylcholinesterase enzyme, and cause histopathological alterations, including perineuronal vacuolization, granular and molecular layers deterioration, cell swallowing and intracellular spaces. The expression of genes involved in the apoptotic process (p53, bax, and casp-3) and antioxidant defense (nrf1 and nrf2) was upregulated in response to oxidative damage, while the expression of the anti-apoptotic gene bcl-2 was down-regulated indicating that the environmental presence of dexamethasone may pose a threat to wildlife and human health.

“Cyclophosphamide and analogues; a matter of dose and schedule for dual anticancer activities”

Cyclophosphamide and ifosfamide are major alkylating agents but their therapeutics uses are limiting by the toxicity due to several toxicities. Indeed conventional chemotherapies are generally used with the maximum tolerated dose. In contrast, metronomic schedule aims to get a minimum dose for efficacy with a good safety. Depending on the dose, their mechanisms of action are different and offer a dual activity: at high dose, cyclophosphamide is mainly used in graft conditioning for its immunosuppressive properties, while at metronomic dose it is used as an immunoactive agent. Currently, at metronomic dose, cyclophosphamide is studied in clinic against various types of cancer, alone or in combination with others anticancer drugs (anti-angiogenic, immune-modulating agents, immune checkpoints blockers, vaccines, radiotherapy, others conventional anticancer agents), as a nth-line or first-line treatment. More than three quarters of clinical studies show promising results, mostly in breast, ovarian and prostate cancers. Taking advantage of the immune system, use dual antitumor action's chemotherapy is clearly a therapeutic strategy that deserves to be confirmed in order to improve the efficacy/toxicity balance of anticancer treatments, and to use CPM or analogues as a standard of care.

Current cell therapies for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which multiple organs are damaged by the immune system. Although standard treatment options such as hydroxychloroquine (HCQ), glucocorticoids (GCs), and other immunosuppressive or immune-modulating agents can help to manage symptoms, they do not offer a cure. Hence, there is an urgent need for the development of novel drugs and therapies. In recent decades, cell therapies have been used for the treatment of SLE with encouraging results. Hematopoietic stem cell transplantation, mesenchymal stem cells, regulatory T (Treg) cell, natural killer cells, and chimeric antigen receptor T (CAR T) cells are advanced cell therapies which have been developed and evaluated in clinical trials in humans. In clinical application, each of these approaches has shown advantages and disadvantages. In addition, further studies are necessary to conclusively establish the safety and efficacy of these therapies. This review provides a summary of recent clinical trials investigating cell therapies for SLE treatment, along with a discussion on the potential of other cell-based therapies. The factors influencing the selection of common cell therapies for individual patients are also highlighted.

Mesoporous Silica Nanoparticles as an Ideal Platform for Cancer Immunotherapy: Recent Advances and Future Directions.

Cancer immunotherapy recently transforms the traditional approaches against various cancer malignancies. Immunotherapy includes systemic and local treatments to enhance immune responses against cancer and involves strategies such as immune checkpoints, cancer vaccines, immune modulatory agents, mimetic antigen-presenting cells, and adoptive cell therapy. Despite promising results, these approaches still suffer from several limitations including lack of precise delivery of immune-modulatory agents to the target cells and off-target toxicity, among others, that can be overcome using nanotechnology. Mesoporous silica nanoparticles (MSNs) are investigated to improve various aspects of cancer immunotherapy attributed to the advantageous structural features of this nanomaterial. MSNs can be engineered to alter their properties such as size, shape, porosity, surface functionality, and adjuvanticity. This review explores the immunological properties of MSNs and the use of MSNs as delivery vehicles for immune-adjuvants, vaccines, and mimetic antigen-presenting cells (APCs). The review also details the current strategies to remodel the tumor microenvironment to positively reciprocate toward the anti-tumor immune cells and the use of MSNs for immunotherapy in combination with other anti-tumor therapies including photodynamic/thermal therapies to enhance the therapeutic effect against cancer. Last, the present demands and future scenarios for the use of MSNs for cancer immunotherapy are discussed.

The double life of a chemotherapy drug: Immunomodulatory functions of gemcitabine in cancer.

Although the development of immunotherapies has been revolutionary in the treatment of several cancers, many cancer types remain unresponsive to immune-based treatment and are largely managed by chemotherapy drugs. However, chemotherapeutics are not infallible and are frequently rendered ineffective as resistance develops from prolonged exposure. Recent investigations have indicated that some chemotherapy drugs have additional functions beyond their normative cytotoxic capacity and are in fact immune-modifying agents. Of the pharmaceuticals with identified immune-editing properties, gemcitabine is well-studied and of interest to clinicians and scientists alike. Gemcitabine is a chemotherapy drug approved for the treatment of multiple cancers, including breast, lung, pancreatic, and ovarian. Because of its broad applications, relatively low toxicity profile, and history as a favorable combinatory partner, there is promise in the recharacterization of gemcitabine in the context of the immune system. Such efforts may allow the identification of suitable immunotherapeutic combinations, wherein gemcitabine can be used as a priming agent to improve immunotherapy efficacy in traditionally insensitive cancers. This review looks to highlight documented immunomodulatory abilities of one of the most well-known chemotherapy agents, gemcitabine, relating to its influence on cells and proteins of the immune system.

Immunomodulatory Effects of a Herbo-Mineral Ayurvedic Formulation in Experimental Models.

Ayurveda, an ancient Indian system of medicine, encapsulates comprehensive principles and formulations for disease prevention and treatment. A herbo-mineral Ayurvedic formulation, IMMBO, comprising Mandoor Bhasma and 18 herbs has shown promising results in treating allergic rhinitis in clinical studies. This discussed series of experimental studies were conducted to explore the immuno-modulatory potential of IMMBO. A series of experimental studies were carried out in immunosuppressed rats to explore the immune-modulatory effects of IMMBO. IMMBO was effective in reinstating neutrophil activation, stimulating cellular and humoral immunity, and counteracting immunosuppression at the molecular level. The modulation of key signalling molecules, including tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-1 beta (IL-1β), extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), and nuclear factor-kappa B (NF-κb), showcased the formulation's multifaceted impact. Additionally, its ability to block histamine release suggests potential in controlling allergic states, positioning it as a promising therapeutic candidate for immune-related disorders. However, the precise mode of action remains elusive, warranting further in-depth pharmacological studies. This research substantiates the ancient Ayurvedic wisdom using modern scientific parameters, endorsing IMMBO's potential as an immune-modulatory agent.

Nanocurcumin modulates Th17 cell responses in moderate and severe COPD patients

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory process in the airways that results in airflow obstruction. It is mainly linked to cigarette smoke exposure. Th17 cells have a role in the pathogenesis of COPD by secreting pro-inflammatory cytokines, which cause hyperinflammation and progression of the disease.This study aimed to assess the potential therapeutic effects of nanocurcumin on the Th17 cell frequency and its responses in moderate and severe COPD patients. This study included 20 patients with severe COPD hospitalized in an intensive care unit (ICU) and 20 patients with moderate COPD. Th17 cell frequency, Th17-related factors gene expression (RAR-related orphan receptor t (RORγt), IL-17, IL-21, IL-23, and granulocyte-macrophage colony-stimulating factor), and serum levels of Th17-related cytokines were assessed before and after treatment in both placebo and nanocurcumin-treated groups using flow cytometry, real-time PCR, and ELISA, respectively.According to our findings, in moderate and severe nanocurcumin-treated COPD patients, there was a substantial reduction in the frequency of Th17 cells, mRNA expression, and cytokines secretion level of Th17-related factors compared to the placebo group. Furthermore, after treatment, the metrics mentioned above were considerably lower in the nanocurcumin-treated group compared to before treatment.Nanocurcumin has been shown to decrease the number of Th17 cells and their related inflammatory cytokines in moderate and severe COPD patients. As a result, it might be used as an immune-modulatory agent to alleviate the patient's inflammatory state.

Abstract 7274: Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model

Abstract Cysteine-binding targeted drugs AMG-510 and MRTX-849 provide a new therapeutic approach for advanced KRASG12C mutant cancers. However, clinical response has been limited. Responders eventually develop adaptive resistance by gaining additional MAPK pathway mutations, resulting in limited therapeutic benefit. High-dose pulsatile treatment with MAPK pathway inhibitors has been proposed as an alternative strategy to alleviate adaptive resistance while maintaining tumor control. The sensitivity of tumor cells to pan-inhibitors of the MAPK pathway, crucial for proliferation, creates a therapeutic opportunity window for immune cells to restore their function during an intermittent regimen. Congruently, we have previously shown that intermittent pan-MAPK pathway inhibitor treatment delays drug resistance, supports T cell activation, and enhances tumor delay when combined with immunotherapy. In this study, we investigated the effects of continuous and pulsatile KRASG12C inhibition on tumor and immune cells in order to design combinatorial strategies with immune-modulating agents that overcome drug resistance. Our data suggest that a weekly single high-dose regimen of AMG-510 is less effective at achieving tumor control in preclinical mouse models of KRAS mutant lung cancer compared to daily treatments. However, supplementing this pulsatile regimen with lower maintenance doses markedly slows the growth of LLC KRASG12C lung cancer. Flow cytometry analysis revealed that high-dose pulse regimen enhances T cell activation, evidenced by increased expression of TCF-1, Ki67, PD-1, and GITR, along with lower expression of co-inhibitory molecules Lag-3 and Tim-3, 3 days after treatment. In vitro, AMG-510 also improves the antigen presentation of OVA-expressing LLC-KML lung cancer cells via MHC class I and, to a lesser extent, MHC class II. Furthermore, we found that while combinatorial therapy with PD-1 blockade alone does not significantly impact tumor control, the combination with CTLA-4 blockade shows efficacy across pulsatile and continuous AMG-510 dosing cohorts. Overall, our findings suggest that the utilization of intermittent dosing regimens for selective KRASG12C inhibitors is a promising approach for improving clinical responses in lung cancers with KRAS mutations. Future experiments will aim to delineate MAPK pathway behavior in vivo and in vitro under pulsatile and continuous treatment, assess immunogenicity, and further characterize immune changes in the different treatment regimens, with the goal of designing more efficient cancer therapies utilizing selective KRAS inhibitors. Citation Format: Valeria Estrada Navarro, Vincent Panneton, Lauren Dong, Hyejin Choi, Divya Venkatesh, Rachana Maniyar, Isabell Schulze, Jedd D. Wolchok, Taha Merghoub. Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7274.

Abstract 6426: Identification of potential immune biomarkers for GSK-3 inhibitor elraglusib (9-ING-41) in patients with relapsed/refractory metastatic cancer

Abstract Cytokines mediate strong immunomodulatory effects in cancer. Elraglusib (9-ING-41), an inhibitor of GSK-3, is a potent antitumor and immune-modulatory agent in phase 2 clinical trials for the treatment of various cancers. Here, we examined the immune environment of elraglusib-treated cancer patients by measuring peripheral blood protein levels to explore whether the expression level of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) is correlated with clinical outcome. Using a customized Luminex platform, the expression of forty CCSG hypothesized to be linked to GSK-3 activity was assessed in pre-dose plasma samples obtained from 45 cancer patients with relapsed/refractory metastatic disease (NCT03678883; the 1801 trial). All patients in the 1801 trial were treated with elraglusib (dose range: 1-15 mg/kg) either as a single agent (Part 1; n=21) or in combination with chemotherapy (Part 2; n=24). Pre-dose peripheral blood protein levels were examined as binary predictors of clinical outcome using optimal cutoff points determined by maximally selected rank statistics. In the aggregate Part 1 and 2 populations (n=45), we identified 13 CCSG that significantly stratified the cohort by overall survival (OS). High pre-dose levels of CD95 and TNFRSF10C were associated with better OS. CD95 was a better prognostic of OS than TNFRSF10C (HR: 2.27, 95% CI: 1.10-4.67, p-value: 0.023). Low pre-dose levels of 11 CCSG were also significantly associated with favorable OS, with IL-8 being the most predictive (HR: 0.137, 95% CI: 0.0545-0.346, p-value: <0.0001). Part 1 and 2 predose samples were also analyzed separately, and many of the biomarkers identified in the aggregate analysis retained significance in the separated analysis. In Part 1, CXCL5, IFN-alpha, and IL-18 emerged as unique markers, and in Part 2, CCL22 was the single unique marker.The results of our exploratory study identified several putative biomarkers of elraglusib clinical benefit and demonstrated potential immunomodulatory mechanisms of elraglusib that will be used to inform the further clinical development of elraglusib for the treatment of metastatic cancer. Citation Format: Taylor Weiskittel, Kelsey Huntington, Leiqing Zhang, Austin Koukol, Benedito A. Carneiro, Hu Li, Andrey Ugolkov, Wafik El-Deiry, Andrew Mazar. Identification of potential immune biomarkers for GSK-3 inhibitor elraglusib (9-ING-41) in patients with relapsed/refractory metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6426.

MRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell...

Immunogenomic Exploration of Cutaneous Manifestations and Therapeutic Targets in Systemic SclerosisVivian Li DO,*

This analysis of current literature explores specific immunogenomic signatures underlying cutaneous manifestations in systemic sclerosis (SSc), a complex autoimmune disorder characterized by fibrosis, vasculopathy, and immune dysregulation. By employing integrated transcriptomic and epigenomic analyses of skin biopsies obtained from SSc patients presenting varying degrees of cutaneous involvement, researchers aim to discern dysregulated immune pathways, gene expression signatures, and epigenetic modifications correlated with disease progression and severity. Additionally, investigating the therapeutic potential of immune-modulating agents, including JAK inhibitors and immune checkpoint inhibitors, in mitigating skin fibrosis and inflammation in SSc may unlock novel avenues for personalized treatment strategies tailored to the immunogenomic profile of individual patients. Future research should focus on validating identified biomarkers, exploring the mechanistic basis of immunogenomic alterations, and translating these findings into clinical practice to optimize therapeutic outcomes and enhance the management of cutaneous manifestations in SSc.

A Review for Vaccination Guidelines in Patients with Central Nervous System Demyelinating Diseases including COVID-19 Vaccination

Since coronavirus disease 2019 (COVID-19) pandemic by severe acute respiratory syndrome coronavirus-2, several vaccines for COVID-19 have been approved for use and vaccination is encouraged worldwide. Despite these circumstances, it remains still controversial to vaccinate patients with central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorders using immunosuppressive agents. We reviewed recent studies about vaccination, including COVID-19 vaccination in patients with CNS demyelinating diseases. Also, we summarized updated guidelines about vaccinations for patients with MS. According to recent guidelines, regular vaccinations are recommended for patients with CNS demyelinating diseases and most immunosuppressants or immune-modulating agents did not affect the efficacy of vaccinations. However, several treatments such as rituximab should be adjusted treatment schedules before vaccination. Through this review, clinicians will be given useful information to choose the best vaccination strategy according to current evidence and expert knowledge.

A Review for Vaccination Guidelines in Patients with Central Nervous System Demyelinating Diseases including COVID-19 Vaccination

Since coronavirus disease 2019 (COVID-19) pandemic by severe acute respiratory syndrome coronavirus-2, several vaccines for COVID-19 have been approved for use and vaccination is encouraged worldwide. Despite these circumstances, it remains still controversial to vaccinate patients with central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorders using immunosuppressive agents. We reviewed recent studies about vaccination, including COVID-19 vaccination in patients with CNS demyelinating diseases. Also, we summarized updated guidelines about vaccinations for patients with MS. According to recent guidelines, regular vaccinations are recommended for patients with CNS demyelinating diseases and most immunosuppressants or immune-modulating agents did not affect the efficacy of vaccinations. However, several treatments such as rituximab should be adjusted treatment schedules before vaccination. Through this review, clinicians will be given useful information to choose the best vaccination strategy according to current evidence and expert knowledge.

Advancements in the treatment of geographic atrophy: focus on pegcetacoplan in age-related macular degeneration

Geographic atrophy (GA) is a progressive form of age-related macular degeneration characterized by the degeneration of retinal pigment epithelial cells and photoreceptor death. The dysregulation of the complement cascade has been implicated in GA progression. This review provides a comprehensive overview of the pathophysiology of age-related macular degeneration and GA, discusses current therapeutic options, and focuses on the recent breakthrough drug, pegcetacoplan (SYFOVRE). Pegcetacoplan is a complement inhibitor that selectively targets the C3 complement protein, effectively modulating complement activation. Clinical trials, including the OAKS and DERBY studies, have demonstrated the efficacy of SYFOVRE in reducing the growth of GA lesions compared to placebo. The FDA approval of SYFOVRE as the first and only definitive therapy for GA marks a significant milestone in the management of this debilitating condition. The review also explores potential future treatment strategies, including immune-modulating agents and ocular gene therapy. While SYFOVRE offers new hope for GA patients, further research is needed to evaluate its long-term benefits, safety profile, and optimal treatment regimens.

Preclinical Studies Demonstrating Efficacy of Tasquinimod in Models of Advanced Myeloproliferative Neoplasm (MPN) in Blastic Phase

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. Also called calprotectins, A8 and A9 can form homodimers or heterodimers and bind Ca++. A8 and A9 are secreted into the extracellular space and plasma, where they interact with TLR4 (Toll like receptor 4), RAGE (Receptor for Advanced Glycation End products) and CD33. Intracellularly, they act as Ca++ biosensors and activate NADPH oxidase, stimulating ROS production, which activates NLRP3 inflammasome. A8 and A9 also amplify the inflammatory response through TLR4, and induce inflammatory cytokines, including TNFα and IL-6, through activation of NFkB and MAP kinase pathways. A8 and A9 are highly expressed in AML, especially myelomonocytic and monocytic AML, and are associated with poor prognosis. Through scRNA-Seq analysis, A8/A9 heterocomplex was shown to be highly expressed in myeloid and stromal cells and marked progression of bone marrow fibrosis in PMF (Primary Myelofibrosis). In the murine JAK2-V617F-driven PMF model, Tasquinimod (TM, Active Biotech), an orally active, quinoline-3-carboxamide linomide analogue immune-modulatory agent was shown to bind A9, inhibiting its interaction with TLR and RAGE receptors. Notably, TM treatment reduced myeloproliferation, splenomegaly and MF in JAK2-V617F mice. Therefore, based on these findings, in present studies, we determined in vitro and in vivo efficacy of TM against cellular models of advanced MPN cell lines and patient-derived (PD) CD34+ blastic phase (BP, > 5% blasts in PB) MPN cells. Treatment with TM (10 to 30 µM for 96 hours) induced loss of viability in the MPN-AML SET2, HEL92.1.7 cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. RNA-Seq analysis showed that exposure to TM (20 µM for 16 hours) led to negative enrichment of the gene-sets of MYC and E2F targets, of mTORC1 and IL6-JAK-STAT3 signaling, and of inflammatory response in PD MPN-AML cells. This was associated with log2 fold-decline in MYC, BCL2, CDK6, MPL, CCND1 and myeloperoxidase (MPO), but upregulation of mRNA of GFI1 and p21. CyTOF analysis revealed that TM treatment significantly reduced expressions of A8, A9, p-ERK, MPO, CXCR4, Cyclin D1, PU.1 and Ki67, but increased protein levels of GFI1, p21 and cleaved PARP in phenotypically defined PD, CD34+ MPN-BP cells expressing high levels of CLEC12A, CD99, CD123 but low expression of CD11b. Additionally, our findings showed that co-treatment with TM (5 to 30 µM) and ruxolitinib (250 to 1000 nM), BET inhibitor OTX015 (50 to 250 nM) or pelabresib (CPI-0610) (100 to 500 nM), or BCL2/Bcl-xL inhibitor navitoclax induced synergistic lethality in advanced MPN-BP cells exhibiting delta synergy scores of >1.0 (by the ZIP method). Notably, our findings also demonstrated that treatment with TM (10 or 30 mg/kg/day, by oral gavage) for 8-weeks, significantly improved survival without inducing any toxicity in immune-depleted NSG mice engrafted with PDX cells of MPN-AML with mutations in CALR and TERT. In a separate experiment on the same PDX model, treatment with TM (30 mg/kg/day) also induced significantly greater survival advantage than treatment with ruxolitinib (30 mg/kg/day) or OTX015 (30 mg/kg/day) by oral gavage. These findings clearly demonstrate preclinical efficacy of TM in advanced MPN-BP cellular models and create the rationale to further interrogate the efficacy of TM alone and in combinations with current, front-line therapies for advanced MPN with excess blasts.