Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis

Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases.Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019(COVID-19)infection.COVID-19 causes pulmonary embolisms,thus new therapeutic options are required to target thrombosis,as conventional treatment options are either not effective due to the complexity of the immunethrombosis pathophysiology.In this review,we discuss regulation of immune response in respiratory diseases especially COVID-19.We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles,which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases.We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways,and thus can be recommended to treat respiratory infectious diseases.

Novel Immunotherapeutics Summit 2014

Time:January 29-31,2014Venue:San Diego,USA Website:www.ecco-org.eu/Global/Events/Other-Events/Novel-Immunotherapeutics-Summit-2014.aspx The Novel Immunotherapeutics Summit 2014 brings together experts from academia and industry to discuss cutting edge research,immuno strategies and novel therapeutics against various diseases.Topics such as cytokines,inflammation,cancer immunotherapy,immunomonitoring,biomarkers,immunosuppression,immunogenicity,immunotoxicity and innate immunity will

Novel Immunotherapeutics Summit 2014

Time:January 29-31,2014Venue:San Diego,USA Website:www.ecco-org.eu/Global/Events/Other-Events/Novel-Immunotherapeutics-Summit-2014.aspx The Novel Immunotherapeutics Summit 2014 brings together experts from academia and industry to discuss cutting edge research,immuno strategies and novel therapeutics against various diseases.Topics such as cytokines,inflammation。

Expanded Scope of Bacillus Calmette-Guerin(BCG)Vaccine Applicability in Disease Prophylaxis,Diagnostics,and Immunotherapeutics

Following the discovery of the Bacillus Calmette-Guerin(BCG)vaccine,its efficacy against Mycobacterium tuberculosis was soon established,with several countries adopting universal BCG vaccination schemes for their populations.Soon,however,studies aimed to further establish the efficacy of the vaccine in different populations discovered that the vaccine has a larger effect in reducing mortality rate than could be explained by its effect on tuberculosis alone,which sparked suggestions that the BCG vaccine could have effects on other unrelated or non-mycobacterial pathogens causing diseases in humans.These effects were termed heterologous,non-specific or off-target effects and have been shown to be due to both innate and adaptive immune system responses.Experiments carried out in a bid to further understand these effects led to many more discoveries about the applicability of the BCG vaccine for the prevention,diagnosis,and treatment of certain disease conditions.As we approach the second century since the discovery of the vaccine,we believe it is timely to review these interesting applications of the BCG vaccine,such as in the prevention of diabetes,atherosclerosis,and leukemia;the diagnosis of Kawasaki disease;and the treatment of multiple sclerosis,non-muscle invading bladder cancer,and stage III melanoma.Furthermore,complications associated with the administration of the BCG vaccine to certain groups of patients,including those with severe combined immunodeficiency and HIV,have been well described in literature,and we conclude by describing the mechanisms behind these complications and discuss their implications on vaccination strategies,especially in low-resource settings.

Comment on“Crosstalk between gut microbiota and COVID-19 impacts pancreatic cancer progression”

The coronavirus disease 2019(COVID-19)pandemic has become a global burden,further exacerbating the occurrence of risk events in cancer patients.The high risk of death from pancreatic cancer makes it one of the most lethal malignancies.Recently,it was reported in the World Journal of Gastrointestinal Oncology that COVID-19 influences pancreatic cancer progression via the lung–gut–pancreatic axis,and the authors provided insights into the intrinsic crosstalk mechanisms in which the gut microbiota is involved,the characteristics and effects of inflammatory factors,and immunotherapeutic strategies for treating both diseases.Here,we review the latest cutting-edge researches in the field of the lung-gut-pancreatic axis and discuss future perspectives to address the severe survival challenges posed by the COVID-19 pandemic in patients with pancreatic cancer.

Hepatoprotective and immunomodulatory properties of aqueous extract of Curcuma longa in carbon tetra chloride intoxicated Swiss albino mice

Objective:To evaluate the hepatoprotective and immunotherapeutic effects of aqueous extract of turmeric rhizome in CCl_4 intoxicated Swiss albino mice.Methods:first group of mice(n=5) received CCl_4 treatment at a dose of 0.5 mL/kg bw(i.p.) for 7 days.Second group was fed orally the aqueous extract of turmeric at a dose of 50 mg/kg bw for IS days.The third group was given both the turmeric extract(for 15 days,orally) and CCl_4(for last 7 days,i.p.).The fourth group was kept as a control.To study the liver function,the transaminase enzymes(SGOT and SGPT) and bilirubin level were measured in the serum of respective groups.For assaying the immunotherapeutic action of Curcuma longa(C.longa),non specific host response parameters like morphological alteration,phagocytosis,nitric oxide release,myeloperoxidase release and intracellular killing capacity of peritoneal macrophages were studied from the respective groups.Results:The result of present study suggested that CCl_4 administration increased the level of SCOT and SGPT and bilirubin level in serum.However,the aqueous extract of turmeric reduced the level of SGOT, SCFT and bilirubin in CCl_4 intoxicated mice.Apart from damaging the liver system,CCl_4 also reduced non specific host response parameters like morphological alteration,phagocytosis, nitric oxide release,myeloperoxidase release and intracellular killing capacity of peritoneal macrophages.Administration of aqueous extract of C.longa offered significant protection from these damaging actions of CCl_4 on the non specific host response in the peritoneal macrophages of CCl_4 intoxicated mice.Conclusions:In conclusion,the present study suggests that C.longa has immunotherapeutic properties along with its ability to ameliorate hepatotoxicity.

Effects of Mycobacterium vaccae vaccine in a mouse model of tuberculosis: protective action and differentially expressed genes

Background:Tuberculosis is a leading cause of death worldwide.BCG is an effective vaccine,but not widely used in many parts of the world due to a variety of issues.Mycobacterium vaccae(M.vaccae)is another vaccine used in human subjects to prevent tuberculosis.In the current study,we investigated the potential mechanisms of M.vaccae vaccination by determining differentially expressed genes in mice infected with M.tuberculosis before and after M.vaccae vaccination.Methods:Three days after exposure to M.tuberculosis H37 Rv strain(5×10~5 CFU),adult BALB/c mice randomly received either M.vaccae vaccine(22.5μg)or vehicle via intramuscular injection(n=8).Booster immunization was conducted 14 and 28 days after the primary immunization.Differentially expressed genes were identified by microarray followed by standard bioinformatics analysis.Results:M.vaccae vaccination provided protection against M.tuberculosis infection(most prominent in the lungs).We identified 2,326 upregulated and 2,221 downregulated genes in vaccinated mice.These changes could be mapped to a total of 123 signaling pathways(68 upregulated and 55 downregulated).Further analysis pinpointed to the MyD88-dependent TLR signaling pathway and PI3 K-Akt signaling pathway as most likely to be functional.Conclusions:M.vaccae vaccine provided good protection in mice against M.tuberculosis infection,via a highly complex set of molecular changes.Our findings may provide clue to guide development of more effective vaccine against tuberculosis.

Early diagnosis and therapeutic strategies for hepatocellular carcinoma:From bench to bedside

Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite being widely used,alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC.The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins,metabolites,circulating tumor deoxyribonucleic acid,and circulating non-coding ribonucleic acid.Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment,thus prolonging survival outcomes.Currently,multiple clinical trials involving locoregional,systemic therapies,and combinations of these modalities are changing therapeutic strategies for different stage HCC.Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future.This review summarizes the most recent advances in noninvasive early molecular detection,current therapy strategies,and potential immunotherapeutic innovations of HCC.

Formulation strategies in immunotherapeutic pharmaceutical products

Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health.Antibodies are the leading entity in immunotherapy,while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area.In order to enable antibody candidates or cells available as products,formulation is critical in terms of stabilize molecules or cells to achieve practical shelf life,storage and handling conditions.Here we provide a concise and contemporary review of ongoing formulation strategies and excipients used in approved antibodies and cellular therapeutic products.Excipients are categorized,and their function in formulations are discussed.

An update review on drug repurposing for COVID-19

The COVID-19 global health disaster has caused more than two million deaths globally.Although,a new therapeutic molecule has not been developed for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)as of yet.As a result,some medications that had been previously authorized for use against SARS-CoV-2 could now be given to COVID-19 patients.The use of medications to treat COVID-19 is discussed in this publication.The report also discusses the lessons learned when using combination therapy,convalescent plasma therapy,immunotherapeutic molecules,and therapeutic molecules to treat COVID-19 patients.Several beneficial outcomes were noted with anti-viral therapy and immunotherapy.The COVID-19 medicine and vaccination have undergone 9,037 clinical trials since July 2022.It may be possible to provide COVID-19 patients with a successful outcome through the short-term repurposing of an existing drug.The evaluation of potential antiviral molecules can thus lead to more clinical trials being initiated.

Immunotherapeutic effects of dendiritic cells vaccine pulsed with tumor cell lysate in mice with pancreatic carcinoma

Objective To observe the immunotherapeutic effects of dendritic cells vaccine pulsed with tumor cell lystate on mice with pancreatic carcinoma. Methods Dendritic cells (MTSC4) were pulsed with tumor cells lysate. The immune preventative and immnotherapeutic effects of DC vaccines on mice with pancreatic carcinoma were assessed. Results After vaccination of the DC vaccines,mice remained tumor-free for at least 25 days in DCs vaccines group,but in other groups the subcutaneous implantation tumorigenesis were found beginning 3 to 9 days. CTL stimulated by DC vaccines effected cytolytic activity against pancreatic carcinoma cells. The survival period was obviously prolonged in DCs vaccines group (56 ±9)d than in other groups P【0.01) and tumors (1.4 ±0.8)g in DCs vaccines group were significantly smaller than that in other groups (P 【 0. 05). Conclusion Tumor cell lysate-pulsed dendrtic cells vaccines can induce a specific and effective immune response against pancreatic carcinoma cell implanted in mice.

Innovative hydrogel-based delivery systems for immunotherapy:A review of pre-clinical progress

Immunotherapy has markedly reinvented how we treat cancer,as shown by numerous Food and Drug Administration(FDA)drug approvals that have made significant clinical impact and ongoing clinical trials.However,undesirable side effects,such as autoimmunity and inflammation,and inconsistent clinical outcomes remain a major challenge.Improving response rates across various immunotherapeutic reagents is imperative to enhance overall effectiveness and reduce adverse side effects.To address this challenge,interdisciplinary approaches have been explored by incorporating immunotherapies into hydrogels,enabling finecontrolled delivery to target tissues.This review focuses on recent progress in the utilization of hydrogel-based delivery systems for cancer immunotherapy and their potential to further enhance treatment response rates.Specifically,recent preclinical advances in hydrogels implemented with immune checkpoint inhibitors,combination therapies,and vaccines,along with selfassembled peptide hydrogels,are reviewed.We also discuss technological advances and drawbacks in this area and provide insights to ultimately realize the clinical application of hydrogels in cancer immunotherapy.

Multifunctional nanocomposites modulating the tumor microenvironment for enhanced cancer immunotherapy

Cancer immunotherapy has gained momentum for treating malignant tumors over the past decade.Checkpoint blockade and chimeric antigen receptor cell therapy(CAR-T)have shown considerable potency against liquid and solid cancers.However,the tumor microenvironment(TME)is highly immunosuppressive and hampers the effect of currently available cancer immunotherapies on overall treatment outcomes.Advancements in the design and engineering of nanomaterials have opened new avenues to modulate the TME.Progress in the current nanocomposite technology can overcome immunosuppression and trigger robust immunotherapeutic responses by integrating synergistic functions of different molecules.We will review recent advancements in nanomedical applications and discuss specifically designed nanocomposites modulating the TME for cancer immunotherapy.In addition,we provide information on the current landscape of clinical-stage nanocomposites for cancer immunotherapy.

Immune landscape and response to oncolytic virus-based immunotherapy

Oncolytic virus(OV)-based immunotherapy has emerged as a promising strategy for cancer treatment,offering a unique potential to selectively target malignant cells while sparing normal tissues.However,the immunosuppressive nature of tumor microenvironment(TME)poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents,as it restricts the activation and recruitment of immune cells.This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses.We examine the role of OVs in targeting specific immune cell populations,including dendritic cells,T cells,natural killer cells,and macrophages,and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis.Additionally,we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy.In conclusion,this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy,underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

Immunotherapy for triple-negative breast cancer:A molecular insight into the microenvironment,treatment,and resistance

Clinicians have very limited options to treat triple-negative breast cancer(TNBC)due to the lack of effective targeted drugs.Recently,the findings of the mechanism underlying tumor-intrinsic immune escape have fueled a wave of studies into immunotherapy in breast cancer(BC).Compared with other BC subtypes,TNBC shows a better response to immunotherapy due to the higher level of tumor mutation burden and lymphocyte infiltration.Thereinto,immune checkpoint inhibitors(ICIs)achieved the first success of immunotherapy for TNBC and are widely utilized with conventional treatments in the neoadjuvant/adjuvant and advanced stages.However,a large number of TNBC patients fail to demonstrate a good response to ICIs,and the acquired resistance to ICI-based therapies is clinically emerging,which is a major challenge for immunotherapy in TNBC.Here we review the latest advances in TNBC immune microenvironment,immunotherapy,and immunotherapeutic resistance and discuss the challenges and potential approaches to improve the clinical benefit of immunotherapy against TNBC.

Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer

Despite therapeutic advancements,the prognosis of locally advanced non-small cell lung cancer(LANSCLC),which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes,remains poor.The emergence of immunotherapy with immune checkpoint blockade(ICB)is transforming cancer treatment.However,only a fraction of lung cancer patients benefit from ICB.Significant clinical evidence suggests that the proinflammatory tumor microenvironment(TME)and programmed death-ligand 1(PD-L1)expression correlate positively with response to the PD-1/PD-L1 blockade.We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized(AeroNP-CDN)for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon(IFN)genes in macrophages and dendritic cells(DCs).Using a mouse model that recapitulates the clinical LANSCLC,we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype,activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+T cells for adaptive anticancer immunity.Intriguingly,activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors,which,however,set a stage for response to anti-PD-L1 treatment.Indeed,anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice.Importantly,AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity.In conclusion,this study demonstrates a potential nano-immunotherapy strategy for LANSCLC,and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.

Therapeutics to harness the immune microenvironment in multiple myeloma

Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion.Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents.Recently,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses.While current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease progression.The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies.The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies.Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance.Here,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance.Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

The immunology of human cytomegalovirus latency： could latent infection be cleared by novel immunotherapeutic strategies？

While the host immune response following primary human cytomegalovirus （HCMV） infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lyric infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latenUy infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.