A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in a diverse clinical manifestation of the COVID-19 disease. While adaptive immune responses are essential for SARS-CoV-2 virus clearance, the innate immune cells, such as macrophages, may contribute, in some cases, to the disease progression. Macrophages have shown a significant production of IL-6, suggesting they may contribute to the excessive inflammation in COVID-19 disease. Macrophage Activation Syndrome may further explain the high serum levels of CRP, which are normally lacking in viral infections. In adaptive immune responses, it has been revealed that cytotoxic CD8+ T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3. Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules and, therefore, inhibits the T cell-mediated immune responses, humoral immune responses also play a substantial role. Specific IgA response appears to be stronger and more persistent than the IgM response. Moreover, IgM and IgG antibodies show similar dynamics in COVID-19 disease.

TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL–based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.