Regulating the regulatory T cells as cell therapies in autoimmunity and cancer.

Regulatory T cells (Tregs), possess a pivotal function in the maintenance of immune homeostasis. The dysregulated activity of Tregs has been associated with the onset of autoimmune diseases and cancer. Hence, Tregs are promising targets for interventions aimed at steering the immune response toward the desired path, either by augmenting the immune system to eliminate infected and cancerous cells or by dampening it to curtail the damage to self-tissues in autoimmune disorders. The activation of Tregs has been observed to have a potent immunosuppressive effect against T cells that respond to self-antigens, thus safeguarding our body against autoimmunity. Therefore, promoting Treg cell stability presents a promising strategy for preventing or managing chronic inflammation that results from various autoimmune diseases. On the other hand, Tregs have been found to be overactivated in several forms of cancer, and their role as immune response regulators with immunosuppressive properties poses a significant impediment to the successful implementation of cancer immunotherapy. However, the targeting of Tregs in a systemic manner may lead to the onset of severe inflammation and autoimmune toxicity. It is imperative to develop more selective methods for targeting the function of Tregs in tumors. In this review, our objective is to elucidate the function of Tregs in tumors and autoimmunity while also delving into numerous therapeutic strategies for reprogramming their function. Our focus is on reprogramming Tregs in a highly activated phenotype driven by the activation of key surface receptors and metabolic reprogramming. Furthermore, we examine Treg-based therapies in autoimmunity, with a specific emphasis on Chimeric Antigen Receptor (CAR)-Treg therapy and T-cell receptor (TCR)-Treg therapy. Finally, we discuss key challenges and the future steps in reprogramming Tregs that could lead to the development of novel and effective cancer immunotherapies.

Nivolumab plus ipilimumab combination therapy in cancer: Current evidence to date.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy, yielding significant antitumor responses across multiple cancer types. Combination ICI therapy with anti-CTLA-4 and anti-PD-1 antibodies outperforms either antibody alone in terms of clinical efficacy. As a consequence, the U.S. Food and Drug Administration (FDA) approved ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) as the first-ever approved therapies for combined ICI in patients with metastatic melanoma. Despite the success of ICIs, treatment with checkpoint inhibitor combinations poses significant clinical challenges, such as increased rates of immune-related adverse events (irAEs) and drug resistance. Thus, identifying optimal prognostic biomarkers could help to monitor the safety and efficacy of ICIs and identify patients who may benefit the most from these treatments. In this review, we will first go over the fundamentals of the CTLA-4 and PD-1 pathways, as well as the mechanisms of ICI resistance. The results of clinical findings that evaluated the combination of ipilimumab and nivolumab are then summarized to support future research in the field of combination therapy. Finally, the irAEs associated with combined ICI therapy, as well as the underlying biomarkers involved in their management, are discussed.

Reflux definitions in esophageal multi-channel intraluminal impedance.

Aim: In this study, we aim to propose consensus-based interpretations to enhance both automatic, and manual analysis and then present our recommendations about reflux-related variables to enhance Multichannel Intraluminal (MII) measurements. Background: Multichannel Intraluminal Impedance-pH (MII-pH) monitoring is the most sensible option to evaluate Gastroesophageal Reflux Disease (GERD), specifically for the patients with normal endoscopy findings, and persistent symptoms without response to Proton Pomp Inhibitor therapy. There were only a few studies on the interpretation of reflux events in MII tracings. Methods: Several 200 episodes of reflux events were reviewed during several meetings in five steps, to discuss and categorize unresolved issues within existing interpretations, and propose technical principles for accurate characterization of reflux events. Results: In this study, we show that baseline impedance is determined using a moving average procedure to the impedance data of each channel with a time window of 60 seconds based on this finding; a liquid reflux event is defined as a retrograde 50% drop in baseline impedance, gas reflux event is defined as a rapid increase in impedance greater than 5 kΩ, Mixed liquid-gas reflux is defined as gas reflux occurring immediately before or during liquid reflux. Conclusion: The reliability of final diagnosis is significantly dependent on the accurate detection of reflux events, which is currently confronting technical limitations. A pathological reflux event propagates to at least three of the impedance sites, according to the literature. We think that taking three impedance locations into account might be too strict.