Nanomaterial-based drug delivery of immunomodulatory factors for bone and cartilage tissue engineering.

As life expectancy continues to increase, so do disorders related to the musculoskeletal system. Orthopedics-related impairments remain a challenge, with nearly 325 thousand and 120 thousand deaths recorded in 2019. Musculoskeletal system, including bone and cartilage tissue, is a living system in which cells constantly interact with the immune system, which plays a key role in the tissue repair process. An alternative to bridge the gap between these two systems is exploiting nanomaterials, as they have proven to serve as delivery agents of an array of molecules, including immunomodulatory agents (anti-inflammatory drugs, cytokines), as well as having the ability to mimic tissue by their nanoscopic structure and promote tissue repair per se. Therefore, this review outlooks nanomaterials and immunomodulatory factors widely employed in the area of bone and cartilage tissue engineering. Emerging developments in nanomaterials for delivery of immunomodulatory agents for bone and cartilage tissue engineering applications have also been discussed. It can be concluded that latest progress in nanotechnology have enabled to design intricate systems with the ability to deliver biologically active agents, promoting tissue repair and regeneration; thus, nanomaterials studied herein have shown great potential to serve as immunomodulatory agents in the area of tissue engineering.

The role and participation of immune cells in the endometrial tumor microenvironment.

The tumor microenvironment is surrounded by blood vessels and consists of malignant, non-malignant, and immune cells, as well as signalling molecules, which primarily affect the therapeutic response and curative effects of drugs in clinical studies. Tumor-infiltrating immune cells participate in tumor progression, impact anticancer therapy, and eventually lead to the development of immune tolerance. Immunotherapy is evolving as a promising therapeutic intervention to stimulate and activate the immune system to suppress cancer cell growth. Endometrial cancer (EC) is an immunogenic disease, and in recent years, immunotherapy has shown benefit in the treatment of recurrent and advanced EC. This review discusses the key molecular pathways associated with the intra-tumoral immune response and the involvement of circulatory signalling molecules. Specific immunologic signatures in EC which offer targets for immunomodulating agents, are also discussed. We have summarized the available literature in support of using immunotherapy in EC. Lastly, we have also discussed ongoing clinical trials that may offer additional promising immunotherapy options in the future. The manuscript also explored innovative approaches for screening and identifying effective drugs, and to reduce the financial burdens for the development of personalized treatment strategies. Collectively, we aim to provide a comprehensive review of the role of immune cells and the tumor microenvironment in the development, progression, and treatment of EC.

A Meta-Analysis of the Efficacy of Pomalidomide-Based Regimens for the Treatment of Relapsed/Refractory Multiple Myeloma After Lenalidomide Exposure.

INTRODUCTION: The objective was to assess the benefit of pomalidomide-based combination regimens in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide. A pooled estimate was obtained for efficacy outcomes including overall response rate (ORR), complete response (CR) rate, and progression-free survival (PFS) based on multiple trials conducted in this patient population. PATIENTS AND METHODS: A literature search was conducted on March 22, 2022 for relevant trials published between January 1, 2016 and the search date. The search identified 12 eligible trials with publications dated between 2016 and 2021. The meta-analyses were conducted among the intention-to-treat (ITT) population (patients treated in all lines of therapy) and 2 subpopulations: 2L (only patients treated in the second line [2L]) and ≥2L (patients treated in the 2L and beyond). RESULTS: From the meta-analyses, ORR was 69.9% for ITT, 74.4% for ≥2L, and 87.2% for 2L. CR rate was 12.1% for ITT, 17.6% for ≥2L, and 29.7% for 2L. One-year PFS rates were 55.1% for ITT, 59.1% for ≥2L, and 74.0% for 2L. Two-year PFS rates were 29.3% for ITT, 36.0% for ≥2L, and 41.9% for 2L. CONCLUSION: Pomalidomide-based combination regimens were effective in patients with RRMM previously treated with lenalidomide and tended to be associated with better outcomes when used earlier in the treatment pathway. A drug class switch may not always be necessary when making treatment decisions for patients with RRMM for whom the benefits of lenalidomide have been exhausted, although this must be supported by comparative studies.

Risk of thromboembolic events associated with different multiple myeloma regimens in Taiwan: a nested case-control study.

Although novel agents for multiple myeloma (MM) have a better response rate and survival in both newly diagnosed and relapsed/refractory MM patients, concerns regarding the association between MM treatments and thromboembolic events have been raised. The aim of this population-based study was to examine the association between different combinations of MM treatments and the risk of thromboembolic events. We conducted a nested case-control study using the Taiwan Cancer Registry (TCR) and National Health Insurance Research Database (NHIRD). Adult patients newly diagnosed with MM and treated with at least one of the immunomodulatory agents between 2008 and 2016 were identified. Among them, we further identified patients who developed thromboembolic events as cases and selected controls matched by age, sex and duration of MM diagnosis at a ratio of 1:5. The index date was defined as the day one year before the diagnosis date of thromboembolic events in the case group and the corresponding date in the control group. Conditional logistic regression was used to examine the association between different MM treatment regimens and the risk of thromboembolic events. A total of 4,180 newly diagnosed MM patients treated with at least one of the immunomodulatory agents were identified (mean age: 67.2 years; male: 55.7%). In this MM cohort, we further identified 388 cases and 1,940 matched controls (mean age: 71 years; male: 64.2%). The use of a thalidomide/bortezomib/steroid combination (odds ratio (OR) 2.95 [95% confidence interval (CI) 1.47-5.95]), thalidomide monotherapy (OR 3.33; 95% CI, 1.59-6.94), and a thalidomide/steroid combination (OR 4.24; 95% CI, 2.00-8.98) were associated with an increased risk of thromboembolic events. Other risk factors, particularly a history of thromboembolic events, including ischemic heart disease and pulmonary embolism, were significantly associated with increased risk of thromboembolic events. We found that the use of thalidomide alone and in specific combinations was associated with an increased risk of thromboembolic events.

Status and Future Directions of Therapeutics and Prognosis of Cardiac Amyloidosis.

Accumulation of aberrant proteins in the heart causes cardiac amyloidosis, an uncommon and complicated illness. It can be classified into two main types: light chain (AL) and transthyretin (ATTR). The diagnosis of cardiac amyloidosis is challenging due to its non-specific clinical presentation and lack of definitive diagnostic tests. Diagnostic accuracy has increased with the advent of modern imaging methods, including cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Depending on the severity of cardiac amyloidosis, a number of treatments may be attempted and specified according to the subtype of amyloidosis and the presence of complications. However, there are still significant challenges in treating this condition due to its complexity and lack of effective treatments. The prognosis for patients with cardiac amyloidosis is poor. Despite recent advances in diagnosis and treatment, there is still a need for more effective treatments to improve outcomes for patients with this condition. Therefore, we aim to review the current and future therapeutics reported in the literature and among ongoing clinical trials recruiting patients with CA.

Biological treatment for bullous pemphigoid.

Background: Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous disease. Topical or systemic corticosteroids are often used as the first-line treatment. However, long-term corticosteroid use may lead to significant side effects. Therefore, various adjuvant immunosuppressant therapies are used as steroid-sparing agents, with accumulating reports of biological treatments for severely recalcitrant BP. Objective: To describe the clinical and immunological features of a series of patients with recalcitrant BP treated with immunobiological therapies. To assess the efficacy and safety of their therapies. Methods: Patients receiving biological treatment for BP from two centers were assessed. Here, we described the clinical, immunopathological, and immunofluorescence findings of adult patients with BP and analyzed the clinical response and adverse events associated with various biological therapies. Results: We identified nine eligible patients treated with rituximab (seven), omalizumab (three), or dupilumab (one). The mean age at diagnosis was 60.4 years, the average BP duration before biologic initiation was 1.9 years, and the average previous treatment failure was 2.11 therapies. The mean follow-up period from the first biological treatment to the last visit was 29.3 months. Satisfactory response, defined as clinical improvement, was achieved in 78% (7) of the patients, and total BP clearance was achieved in 55% (5) of the patients at the last follow-up visit. Additional rituximab courses improved the disease outcomes. No adverse events were reported. Conclusions: Efficient and safe novel therapies can be considered in recalcitrant steroid-dependent BP non-responsive to conventional immunosuppressant therapies.

Treatment refractory arthritis and stroke - A case of infective endocarditis caused by Tropheryma whipplei.

Whipple´s disease is a rare multisystem condition affecting < 1/1.000.000 per year. The condition often presents with polyarthritis, diarrhea, and intestinal malabsorption. Endocarditis is seen in a minority of these patients, and is typically culture negative, as the causative agent Tropheryma whipplei does not grow in ordinary culture media. We present the case of a 78-year-old man with a history of seronegative polyarthritis that was refractory to treatment with several biological agents for a duration of 5 years prior to presentation to the emergency department with stroke. Echocardiography revealed aortic valve endocarditis with a 3.6 cm vegetation and multiple smaller vegetations. The patient underwent surgery with aortic valve replacement followed by prolonged antibiotic treatment. 16 S rDNA PCR analysis of the resected valve revealed T. whipplei as the causative agent. Two years after surgery and treatment with antibiotics, the patient's previously longstanding arthritis had totally disappeared and all rheumatological treatment had been discontinued.

Coronavirus disease 2019 (COVID-19) in pediatric patients with autoimmune disorders.

Coronavirus disease 2019 (COVID-19) infection in pediatric patients with autoimmune disorders is an area of particular concern since autoimmune diseases can increase the risk of complications from the virus. However, as the infection rates were significantly higher in adults compared to children, this at-risk group of children was relatively underrepresented in COVID-19 research. The underlying inflammatory basis of autoimmune diseases and medications that affect the immune system, such as corticosteroids, could increase the risk of severe infection in this group of patients. COVID-19 could reportedly lead to a variety of alterations in the immune system. These alterations are plausibly dependent on the underlying immune-mediated diseases or prior use of immunomodulatory drugs. Patients administrating immunomodulatory agents, especially those with severe immune system dysregulation, can experience severe symptoms of COVID-19. Nonetheless, receiving immunosuppressive medications can benefit patients by preventing cytokine storm syndromes and lung tissue damage, threatening outcomes of COVID-19. CONCLUSION: In this review, we sought to evaluate the currently available literature on the impact of autoimmune disease and its related therapeutic approaches on the COVID-19 infection course of disease in children and reflect on the gaps in the evidence and the need for further research in this field. WHAT IS KNOWN: • The majority of children infected with COVID-19 demonstrate mild to moderate clinical manifestations compared to adults, whereas those children with pre-existing autoimmune conditions are at a greater risk for severe symptoms. •There is currently limited understanding of the pathophysiology and clinical outcomes of COVID-19 in pediatric patients with autoimmune disorders due to scattered reports and inadequate evidence. WHAT IS NEW: • Generally, children with autoimmune disorders have more unfavorable outcomes than healthy children; yet, the severity is not extreme, and is highly dependent on their autoimmune disease type and severity, as well as the medication they are taking.

Optimal timing and drug combination of selinexor in multiple myeloma: a systematic review and meta-analysis.

OBJECTIVES: Multiple myeloma (MM) remains an incurable disease despite advances in treatment options. Recently, selinexor has shown promising efficacy for relapsed/refractory multiple myeloma (RRMM), whereas its optimal timing and drug combination remain unclear. In order to assess the various regimens that incorporate selinexor, a systematic review and meta-analysis was conducted. METHODS: Clinical trials and real-world studies involving MM patients treated with selinexor were included. Pooled risk ratio (RR) was calculated to compare the rates, along with a 95% confidence interval (CI) and concurrent p-value assessment. A random-effects model was employed to provide a more conservative evaluation. RESULTS: A total of 16 studies enrolling 817 patients were reviewed. The usage of selinexor as the fifth-line or prior therapy achieved a higher objective response rate (ORR) (65.9% versus 23.4%, p < 0.01) and longer pooled progression-free survival (PFS) (median: 12.5 months versus 2.9 months, p < 0.01) than those after the fifth-line usage. In addition, early usage also resulted in a consistent trend of pooled overall survival (median: 22.7 months versus 8.9 months, p = 0.26), compared with post-fifth-line usage. Selinexor and dexamethasone (Xd) plus either protease inhibitors (PIs) or immunomodulatory drugs (IMiDs) achieved better ORRs than the Xd-only regimen for RRMM, with ORRs of 56.1%, 52.5% and 24.6%, respectively (p < 0.01). CONCLUSION: In conclusion, using selinexor as the fifth-line or prior therapy had a beneficial impact on RRMM. The regimen of Xd plus PIs or IMiDs was recommended.

Immunomodulatory nanosystems: An emerging strategy to combat viral infections.

The viral infection spreads with the assistance of a host. Traditional antiviral therapies cannot provide long-term immunity against emerging and drug-resistant viral infections. Immunotherapy has evolved as an efficient approach for disease prevention and treatment, which include cancer, infections, inflammatory, and immune disorders. Immunomodulatory nanosystems can dramatically enhance therapeutic outcomes by combating many therapeutic challenges, such as poor immune stimulation and off-target adverse effects. Recently, immunomodulatory nanosystems have emerged as a potent antiviral strategy to intercept viral infections effectively. This review introduces major viral infections with their primary symptoms, route of transmission & targeted organ, and different stages of the viral life cycle with respective traditional blockers. The IMNs have an exceptional capacity for precisely modulating the immune system for therapeutic applications. The nano sized immunomodulatory systems permit the immune cells to interact with infectious agents enhancing lymphatic drainage and endocytosis by the over-reactive immune cells in the infected areas. Immune cells that can be modulated upon viral infection via various immunomodulatory nanosystems have been discussed. Advancement in theranostics can yield an accurate diagnosis, adequate treatment, and real-time screening of viral infections. Nanosystem-based drug delivery can continue to thrive in diagnosing, treating, and preventing viral infections. The curative medicine for remerging and drug-resistant viruses remains challenging, though certain systems have expanded our perception and initiated a new research domain in antiviral treatments.

Relapsed/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse.

Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).

The Risk of Sarcoidosis Misdiagnosis and the Harmful Effect of Corticosteroids When the Disease Picture Is Incomplete.

Sarcoidosis is a complex granulomatous disease of unknown etiology. Due to the heterogeneity of the disease, the diagnosis remains challenging in many cases, often at the physician's discretion, requiring a thorough and complex investigation. Many other granulomatous diseases have the potential to mimic sarcoidosis, whether infectious, occupational, or autoimmune diseases and starting an unnecessary corticosteroid treatment can worsen the patient's prognosis, leading to side effects that can be harder to treat than the actual disease.

Exploring the perspective of patients with immune-mediated inflammatory diseases and care providers on the use of immunomodulatory drugs in infections: an interview study.

Objectives: Immunomodulatory agents are safe and effective as treatment for various immune-mediated inflammatory diseases (IMIDs), but are associated with a slightly increased infection risk. It is uncertain whether, in the event of an infection, continuation or temporary interruption of immunomodulatory agents leads to better outcomes. Owing to this uncertainty, it is of importance to explore the perspectives of health-care providers (HCPs) and patients on this topic. In this study, we set out to identify and provide an overview of reasons for both treatment strategies. Methods: Semi-structured interviews were conducted with HCPs involved in the pharmacological treatment of IMIDs and with IMID patients using one or more immunomodulatory agent. Purposive sampling was used to enrich data variation. Interviews were conducted until data saturation was reached and subsequently analysed using qualitative content analysis. Results: In total, 13 HCPs and 19 IMID patients were interviewed. A wide range of reasons for both treatment strategies were identified, categorized into 10 overarching themes, including IMID characteristics, infection characteristics and the patient-HCP relationship. Conclusion: In this interview study, we identified various reasons for continuation or temporary interruption of immunomodulatory agents during infections for both IMID patients and HCPs. We found overlapping themes, such as IMID characteristics; however, the content and interpretation of these themes might differ between HCPs and patients. Both HCPs and patients mentioned that the decision for a treatment strategy is often about weighing benefits against risks (e.g. infection severity vs disease flare).

Efficacy and safety of selinexor-based regimens for relapsed/refractory multiple myeloma: a systematic review of literature.

With the incorporation of novel agents in earlier lines of therapy, an increasing number of multiple myeloma patients are refractory to traditional classes of drugs. Selinexor in combination with dexamethasone has emerged as a viable option for heavily pretreated triple-class relapsed and refractory multiple myeloma (RRMM). In this systematic review, we analyzed available literature on the role of selinexor in RRMM. The Boston trial demonstrated that selinexor when combined with dexamethasone and bortezomib is associated with a better depth and duration of response without excessive toxicity, compared with bortezomib and dexamethasone alone. Similarly, selinexor in combination with carfilzomib and dexamethasone was found to have a durable response and tolerable safety profile in both carfilzomib-naive and carfilzomib refractory RRMM patients. Selinexor in combination with IMiDs (lenalidomide and pomalidomide) as well as CD38 monoclonal antibodies (daratumumab) also have promising results. Selinexor combination therapy is both safe and effective for patients with pretreated RRMM.

Clinical Management of Triple-Class Refractory Multiple Myeloma: A Review of Current Strategies and Emerging Therapies.

Major progress has been made in the upfront treatment of multiple myeloma, but the disease ultimately relapses and leads to death in the vast majority of those afflicted. New treatment strategies and modalities are necessary to treat myeloma in relapse, particularly in cases of triple-refractory status defined by disease progression during or shortly after treatment with immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibody therapy. In this manuscript, we review recent promising developments in the treatment of triple-class refractory myeloma including bispecific antibodies and T cell engagers, chimeric antigen receptor cellular therapies, as well as chemotherapeutics with novel mechanisms of action.

Pomalidomide- and dexamethasone-based regimens in the treatment of refractory/relapsed multiple myeloma.

Pomalidomide is a potent immunomodulatory agent that is currently a standard of care backbone for the treatment of multiple myeloma (MM) patients in the relapsed/refractory setting after exposure to lenalidomide and a proteasome inhibitor. The present review addresses current knowledge regarding the clinical use of pomalidomide in relapsed myeloma patients. Pomalidomide has direct myeloma cell tumoricidal effects by activating proteasomal degradation of Ikaros and Aiolos transcription factors and also indirect effects by modulation of immune responses, interaction with bone marrow stromal cells, and inhibition of angiogenesis. It is approved by regulatory authorities as doublet combination with dexamethasone but four more triplets are also approved for this setting. Many ongoing trials are evaluating the pomalidomide-dexamethasone backbone with newer anti-myeloma class agents or in quadruplet combinations. Pomalidomide-dexamethasone is currently one of the powerful tools available for use in the relapsed/refractory MM setting. Insights into the synergistic immunomodulatory effects of pomalidomide and other anti-myeloma agents and the mechanisms that overcome clonal resistance will potentially allow targeted use of triplet combinations at each relapse.

Managing patients with myelofibrosis and thrombocytopenia.

INTRODUCTION: Given the progressive nature of myelofibrosis, the incidence of thrombocytopenia increases over time. Furthermore, approved drugs ruxolitinib and fedratinib, induce thrombocytopenia. Hence, treatment of myelofibrosis patients with low platelet counts is an unmet need. AREAS COVERED: This review summarizes the current and emerging treatment options available for patients with myelofibrosis and thrombocytopenia. In the first section of this review, we summarized the use of JAK inhibitors in patients with thrombocytopenia, and in the second part, we focused on use of therapies other than JAK Inhibitors such as steroids, immunomodulatory agents, androgens and other novel agents. EXPERT OPINION: Up to 25% of patients with myelofibrosis have platelet counts below 100,000 at presentation. Patients with thrombocytopenia are more likely to be anemic and PRBC transfusion-dependent, as well as have high-risk disease characteristics and a poor overall survival rate. Among all JAK inhibitors studied in phase 3 clinical trials, pacritinib seems not to induce significant thrombocytopenia while maintaining a good spleen response. Severe thrombocytopenia is a major impediment to myelofibrosis therapy, and more research, particularly on novel therapeutic agents aimed at cytopenic patient populations, is needed.

Update on the Contemporary Treatment of Light Chain Amyloidosis Including Stem Cell Transplantation.

The management of immunoglobulin light chain (AL) amyloidosis is complex. Emerging data have shown promising results for several novel agents. We review the management of AL amyloidosis, including factors that determine transplant eligibility, treatment options for transplant-ineligible patients, and treatment options for relapsed/refractory AL amyloidosis. For carefully selected patients, high-dose melphalan and stem cell transplantation is recommended. Transplant eligibility criteria generally include biopsy-proven amyloidosis, evidence of a plasma cell dyscrasia, involvement of at least one major organ, and adequate performance status. For transplant-ineligible patients, bortezomib-based regimens are recommended, including: 1) bortezomib, oral melphalan, and dexamethasone (BMDex); 2) bortezomib, cyclophosphamide, and dexamethasone (CyBorD or VCd); and 3) subcutaneous daratumumab (DARA SC) and VCd. The latter option is based on a landmark trial that led to the first US Food and Drug Administration-approved therapy for AL amyloidosis. For relapsed/refractory disease, novel therapeutics including proteosome inhibitors, immunomodulatory agents, and monoclonal antibodies have shown promising results. In this review, we summarize data for various therapeutics in different clinical scenarios of AL amyloidosis.

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma.

Multiple Myeloma (MM) is an incurable malignancy with current treatment choices primarily comprising combination regimens implemented with a risk-adapted approach. Cereblon (CRBN)-targeting immunomodulatory agents (IMiDs®) lenalidomide (LEN) and pomalidomide (POM) play a central role in combination regimens due to their pleiotropic antitumor/immunomodulatory mechanisms that synergize with many anti-myeloma approved or developmental agents. Currently, more potent next generation cereblon E3 ligase modulators (CELMoDs®) - iberdomide (IBER) and CC-92480 are in clinical development. With an expanding number of active agents/therapeutic modalities and a myriad of combinatorial possibilities, physicians and drug developers share an opportunity and challenge to combine and sequence therapies to maximize long-term patient benefit. Understanding drug mechanisms and their application in combination settings as well as the unique disease biology considerations from newly diagnosed (NDMM), relapsed/refractory (RRMM), and maintenance settings will be vital to guide the development of future MM therapies centered on a backbone of IMiD or CELMoD agents. Key aspects of drug activity are critical to consider while evaluating potential combinations: direct antitumor effects, indirect antitumor cytotoxicity, immune surveillance, and adverse side effects. In addition, the treatment journey from NDMM to early and late MM relapses are connected to genomic and immune changes associated with disease progression and acquisition of resistance mechanisms. Based on the types of combinations used and the goals of therapy, insights into mechanisms of drug activity and resistance may inform treatment decisions for patients with MM. Here we focus on the evolving understanding of the molecular mechanisms of CRBN-binding drugs and how they can be differentiated and suggest a strategic framework to optimize efficacy and safety of combinations using these agents.