Common variable immunodeficiency (CVID) is an immunodeficiency disorder with a high incidence of gastrointestinal manifestations and an increased risk of gastric carcinoma and lymphoma. This review ...discusses the latest advancements into the immunological, clinical and diagnostic aspects of gastric malignancies in patients with CVID. The exact molecular pathways underlying the relationships between CVID and gastric malignancies remain poorly understood. These include genetics, immune dysregulation and chronic infections by
. Further studies are needed to better stratify the risk for cancer in these patients, to elaborate surveillance programs aimed at preventing these complications, and to develop new and more effective therapeutic approaches.
Background & Aims
A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for ...HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option.
Methods
Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels.
Results
Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50–0.79), cabozantinib (HR = 0.76, 95% CI = 0.63–0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70–0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36–0.52), regorafenib (HR = 0.46, 95% CI = 0.37–0.56), ramucirumab (HR = 0.54, 95% CI = 0.43–0.68), brivanib (HR = 0.56, 95% CI = 0.42–0.76), S-1 (HR = 0.60, 95% CI = 0.46–0.77), axitinib (HR = 0.62, 95% CI = 0.44–0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57–0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients’ stratification.
Conclusions
The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC.
Immune checkpoint inhibitor (ICI)-related inflammatory diseases, including polymyositis (PM) and dermatomyositis (DM), in patients suffering from neoplastic disorders represent a medical challenge. ...The treatment of these conditions has taken on new urgency due to the successful and broad development of cancer-directed immunological-based therapeutic strategies. While primary and secondary PM/DM phenotypes have been pathophysiologically characterized, a rational, stepwise approach to the treatment of patients with ICI-related disease is lacking. In the absence of high-quality evidence to guide clinical judgment, the available data must be critically assessed. In this literature review, we examine partially neglected immunological and clinical findings to obtain insights into the biological profiles of ICI-related PM/DM and potential treatment options. We show that differential diagnosis is essential to stratifying patients according to prognosis and therapeutic impact. Finally, we provide a comprehensive assessment of druggable targets and suggest a stepwise patient-oriented approach for the treatment of ICI-related PM/DM.
Eukaryotic cells release vesicles of different sizes under both physiological and pathological conditions. On the basis of the respective biogenesis, extracellular vesicles are classified as ...apoptotic bodies, microvesicles, and exosomes. Among these, exosomes are considered tools for innovative therapeutic interventions, especially when engineered with effector molecules. The delivery functions of exosomes are favored by a number of typical features. These include their small size (i.e., 50-200 nm), the membrane composition tightly similar to that of producer cells, lack of toxicity, stability in serum as well as other biological fluids, and accession to virtually any organ and tissue including central nervous system. However, a number of unresolved questions still affects the possible use of exosomes in therapy. Among these are the exact identification of both in vitro and ex vivo produced vesicles, their large-scale production and purification, the uploading efficiency of therapeutic macromolecules, and the characterization of their pharmacokinetics.
Here, we discuss two key aspects to be analyzed before considering exosomes as a tool of delivery for the desired therapeutic molecule, i.e., techniques of engineering, and their in vivo biodistribution/ pharmacokinetics. In addition, an innovative approach aimed at overcoming at least part of the obstacles towards a safe and efficient use of exosomes in therapy will be discussed.
Several biologic features render exosomes an attractive tool for the delivery of therapeutic molecules. They will surely be a part of innovative therapeutic interventions as soon as few still unmet technical hindrances will be overcome.
Immunotherapy is changing the Head and Neck Squamous Cell Carcinoma (HNSCC) landscape and improving outcomes for patients with recurrent or metastatic HNSCC. A deeper understanding of the tumor ...microenvironment (TME) is required in light of the limitations of patients' responses to immunotherapy. Here, we aimed to examine how Nivolumab affects infiltrating Tregs in the HNSCC TME. We used single-cell RNA sequencing data from eight tissues isolated from four HNSCC donors before and after Nivolumab treatment. Interestingly, the study found that Treg counts and suppressive activity increased following Nivolumab therapy. We also discovered that changes in the CD44-SSP1 axis, NKG2C/D-HLA-E axis, and KRAS signaling may have contributed to the increase in Treg numbers. Furthermore, our study suggests that decreasing the activity of the KRAS and Notch signaling pathways, and increasing FOXP3, CTLA-4, LAG-3, and GZMA expression, may be mechanisms that enhance the killing and suppressive capacity of Tregs. Additionally, the result of pseudo-temporal analysis of the HNSCC TME indicated that after Nivolumab therapy, the expression of certain inhibitory immune checkpoints including TIGIT, ENTPD1, and CD276 and LY9, were decreased in Tregs, while LAG-3 showed an increased expression level. The study also found that Tregs had a dense communication network with cluster two, and that certain ligand-receptor pairs, including SPP1/CD44, HLA-E/KLRC2, HLA-E/KLRK1, ANXA1/FPR3, and CXCL9/FCGR2A, had notable changes after the therapy. These changes in gene expression and cell interactions may have implications for the role of Tregs in the TME and in response to Nivolumab therapy.
Systemic lupus erythematosus (SLE) is a chronic and extremely disabling connective-tissue autoimmune disease with a tremendous impact on the quality of life (QoL). Belimumab, a ...B-lymphocyte-stimulator-specific inhibitor, is the first biologic drug approved as add-on therapy in patients with active, refractory auto-antibody-positive SLE.
The impact of belimumab on the QoL of SLE patients was evaluated using a generic questionnaire short-form health survey 36 (SF-36) and the disease-specific questionnaire SLE-specific quality of life (SLEQoL).
The Italian version of the SLEQoL and the SF-36 were administered to 46 SLE patients before and after 6 months of belimumab therapy. The control population consisted of 40 age-matched healthy individuals. The questionnaires were completed before and after belimumab treatment and the results were compared using the Wilcoxon signed-rank test. In addition, data from healthy controls and SLE patients were compared using the Mann–Whitney test. Dichotomous variables were compared using Fisher’s exact test.
For SLE patients, the addition of belimumab to their therapeutic regimen significantly improved their health-related QoL (HRQoL), according to the results of the SF-36 and SLEQoL. The comparison of the data obtained before and after belimumab treatment showed a decrease in all six SLEQoL domains and an increase in all eight SF-36 domains. Moreover, treatment led to a reduction in the median prednisone dose, to 0 mg/day (IQR 0–4.5 mg/day). Before belimumab therapy, SLE patients had a worse HRQoL than the control group, based on both questionnaires, but after belimumab treatment the outcome scores between SLE patients and controls were similar, suggesting that belimumab therapy resulted in a strong improvement in HRQoL. These findings were supported by a decrease in the SELENA-SLEDAI score, a measure of disease activity.
In addition to clinical remission and low disease activity, the goals of an innovative therapeutic strategy for SLE should include the attainment of a good HRQoL. Our study demonstrates that the combined use of the SF-36 and SLEQoL questionnaires can provide clinicians with a better understanding of the HRQoL of SLE patients.
Two mechanisms are involved in the immune escape of cancer cells: the immunoediting of tumor cells and the suppression of the immune system. Both processes have been revealed in multiple myeloma ...(MM). Complex interactions between tumor plasma cells and the bone marrow (BM) microenvironment contribute to generate an immunosuppressive milieu characterized by high concentration of immunosuppressive factors, loss of effective antigen presentation, effector cell dysfunction, and expansion of immunosuppressive cell populations, such as myeloid-derived suppressor cells, regulatory T cells and T cells expressing checkpoint molecules such as programmed cell death 1. Considering the great immunosuppressive impact of BM myeloma microenvironment, many strategies to overcome it and restore myeloma immunosurveillance have been elaborated. The most successful ones are combined approaches such as checkpoint inhibitors in combination with immunomodulatory drugs, anti-monoclonal antibodies, and proteasome inhibitors as well as chimeric antigen receptor (CAR) T cell therapy. How best to combine anti-MM therapies and what is the optimal timing to treat the patient are important questions to be addressed in future trials. Moreover, intratumor MM heterogeneity suggests the crucial importance of tailored therapies to identify patients who might benefit the most from immunotherapy, reaching deeper and more durable responses.
Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor ...microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system's role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment.
The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), ...blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.
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