ImmunoTargets and Therapy最新文献

Over the last 20 years, different therapies have been considered as the mainstay for the treatment of patients with metastatic renal cell carcinoma (mRCC). Since angiogenesis is a key mechanism in the pathogenesis of renal carcinoma, research is still focusing on the inhibition of new vessel growth through the development of novel and potent tyrosine kinase inhibitors (TKIs), such as cabozantinib. On the other hand, a new therapeutic scenario has opened up in the forefront with immunotherapy. Immune checkpoint inhibitors (ICIs), which already represent a standard treatment option in pretreated mRCC patients, are revolutionizing the frontline therapeutic armamentarium of mRCC. Upfront combination immunotherapy as well as combinations of immunotherapy with targeted agents showed to significantly improved outcomes of mRCC patients compared to single-agent TKIs. ICIs are associated with long-lasting responses. Nonetheless, several unmet needs remain, as a small proportion of patients shows primary refractoriness to immunotherapy. Multiple treatment strategies combining different mechanisms of action or targeting immune escape pathways are emerging with the aim to improve response rates and survival outcomes. This review summarizes current immunotherapeutic targets and therapies approved for mRCC, while examining mechanisms of resistance and future directions, with the aim to address novel treatment strategies and help in improving the management of this tumor.

Background: Atopic dermatitis (AD) is a common chronic, inflammatory skin condition. The pathogenesis of AD involves many cytokines that utilize the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling cascade; therefore, JAK inhibitors may be used in the treatment of AD. This review aims to evaluate the pathophysiology, efficacy, and safety of JAK inhibitors and their emerging role as a therapeutic option for patients with AD.

Methods: A PubMed search of Phase I, II, and III clinical trials was conducted for relevant literature published between January 2015 and June 2020 utilizing the key terms: JAK inhibitors, atopic dermatitis, efficacy, safety, and treatment. The search was subsequently expanded to include additional terms.

Results: In multiple Phase II and III clinical trials, JAK inhibitors were more efficacious than placebo or vehicle controls and slightly more efficacious in direct comparisons to corticosteroids. Overall, JAK inhibitors have a moderate safety profile for use in AD. Some of the more severe theoretical adverse events included thrombosis and reactivation of viral infections. While data remain limited for the long-term efficacy and safety of JAK inhibitor use in patients with AD, many ongoing clinical trials have promising preliminary results.

Discussion: Short-term data suggest that both topical and oral JAK inhibitors are efficacious and safe for use in patients with AD, although cases of thrombosis and viral disease have been reported. While the current standard treatments for AD are likely preferred, failed therapy with these agents or corticosteroid phobia may be indications for the use of JAK inhibitors in patients with AD.

Rheumatoid arthritis (RA) is an autoimmune disorder that affects joints and is characterized by synovial hyperplasia and bone erosion associated with neovascularization and infiltration of proinflammatory cells. The introduction of biological disease-modifying anti-rheumatic drugs has dramatically changed the treatment of RA over the last 20 years. However, fewer than 50% of RA patients enter remission, and 10-15% are treatment refractory. There is currently no cure for RA. Fractalkine (FKN, also known as CX3CL1) is a cell membrane-bound chemokine that can be induced on activated vascular endothelial cells. FKN has dual functions as a cell adhesion molecule and a chemoattractant. FKN binds specifically to the chemokine receptor CX3CR1, which is selectively expressed on subsets of immune cells such as patrolling monocytes and killer lymphocytes. The FKN-CX3CR1 axis is thought to play important roles in the initiation of the inflammatory cascade and can contribute to exacerbation of tissue injury in inflammatory diseases. Accordingly, studies in animal models have shown that inhibition of the FKN-CX3CR1 axis not only improves rheumatic diseases but also reduces associated complications, such as pulmonary fibrosis and cardiovascular disease. Recently, a humanized anti-FKN monoclonal antibody, E6011, showed promising efficacy with a dose-dependent clinical response and favorable safety profile in a Phase 2 clinical trial in patients with RA (NCT02960438). Taken together, the preclinical and clinical results suggest that E6011 may represent a new therapeutic approach for rheumatic diseases by suppressing a major contributor to inflammation and mitigating concomitant cardiovascular and fibrotic diseases. In this review, we describe the role of the FKN-CX3CR1 axis in rheumatic diseases and the therapeutic potential of anti-FKN monoclonal antibodies to fulfill unmet clinical needs.

The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into granulocytes and macrophages. Much preclinical data have indicated that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches indicate its potential as an important therapeutic target in several inflammatory and autoimmune disorders, for example, rheumatoid arthritis. In this review, we discuss briefly the biology of GM-CSF, raise some current issues and questions pertaining to this biology, summarize the results from preclinical models of a range of inflammatory and autoimmune disorders and list the latest clinical trials evaluating GM-CSF blockade in such disorders.

Chronic spontaneous urticaria (CSU) is considered to be an autoimmune disorder (type I and type II) in 50% of all cases. However, autoreactive T cells and their proximity with activated mast cells in the skin of CSU patients are believed to be the primary event in mast cell degranulation. The finding of anti-FcɛRIα on mast cells or IgE autoantibodies against thyroid antigens should be considered to be a consequence of the auto-reactive T cells' recognition of the above-mentioned antigens. Our recent finding of increased Th17 and IL-17 expression in both CD4+ T cells and mast cells in the skin of severe CSU patients is supportive for the major role that T cells perform in the pathogenesis of CSU. Supporting this are numerous previous reports in which increased serum IL-17 was found to be in association with CSU disease severity. The beneficial effect of anti-IL-17A (secukinumab) in CSU patients in whom high dose anti-histamines, recurrent course of steroids and omalizumab fail to achieve a reasonable response should be investigated as a new therapeutic strategy in future studies with a large cohort of patients.

The multiple myeloma (MM) therapeutic landscape has evolved significantly with the approval of numerous novel agents, including next generation proteasome inhibitors (PIs), immunomodulatory agents (IMIDs), and monoclonal antibodies (MoABs) targeting CD38 and SLAMF7. While these discoveries have led to an unprecedented improval in patient outcomes, the disease still remains incurable. Immunotherapeutic approaches have shown substantial promise in recent studies of chimeric antigen receptor T-cell (CAR T-cell) therapy, bispecific antibodies, and antibody drug conjugates targeting B-cell maturation antigen (BCMA). This review will highlight these novel and targeted therapies in MM, with particular focus on PIs, IMIDs, MoAb and BCMA-directed immunotherapy.

Human papillomavirus (HPV)-related malignancies are responsible for almost all cases of cervical cancer in women, and over 50% of all cases of head and neck carcinoma. Worldwide, HPV-positive malignancies account for 4.5% of the global cancer burden, or over 600,000 cases per year. HPV infection is a pressing public health issue, as more than 80% of all individuals have been exposed to HPV by age 50, representing an important target for vaccine development to reduce the incidence of cancer and the economic cost of HPV-related health issues. The approval of Gardasil^® as a prophylactic vaccine for high-risk HPV 16 and 18 and low-risk HPV6 and 11 for people aged 11-26 in 2006, and of Cervarix^® in 2009, revolutionized the field and has since reduced HPV infection in young populations. Unfortunately, prophylactic vaccination does not induce immunity in those with established HPV infections or HPV-induced neoplasms, and there are currently no therapeutic HPV vaccines approved by the US Food and Drug Administration. This comprehensive review will detail the progress made in the development of therapeutic vaccines against high-risk HPV types, and potential combinations with other immunotherapeutic agents for more efficient and rational designs of combination treatments for HPV-associated malignancies.

Sepsis refers to a systemic inflammatory response syndrome resulting from microbial infections, and is partly attributable to dysregulated inflammation and associated immunosuppression. A ubiquitous nuclear protein, HMGB1, is secreted by activated leukocytes to orchestrate inflammatory responses during early stages of sepsis. When it is released by injured somatic cells at overwhelmingly higher quantities, HMGB1 may induce macrophage pyroptosis and immunosuppression, thereby impairing the host's ability to eradicate microbial infections. A number of endogenous proteins have been shown to bind HMGB1 to modulate its extracellular functions. Here, we discuss an emerging possibility to develop therapeutic antibodies against harmless proteins that collude with pathogenic mediators for the clinical management of human sepsis and other inflammatory diseases.

The global threat of COVID-19 is continued with no commercially available vaccine or drug yet. While the application of convalescent therapy is usually beneficial, for critically ill patients, the detrimental effect associated with some antibodies is also reported. The immunoglobulin G (IgG) antibody in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is described, albeit the lack of defining whether the difference in subclasses has a beneficial or detrimental role. IgG2 has limited ability to activate innate immune cells and complement-mediated inflammation, which have been inversely described in SARS-CoV-2 pathogenesis. The expansion of IgG2 is promoted by interferon γ (IFN-γ); however, there is a low level of IFN-γ in COVID-19 patients. Therefore, this review describes the importance of targeting IgG2, with IFN-γ in minimizing the SARS-CoV-2 associated inflammation, and may provide insight into the design of vaccine or antibody-based therapies to COVID-19 disease.

Atopic dermatitis (AD) is an immune-mediated inflammatory skin disease characterized by a predominant type 2 immune response. Type 2 immunity is driven by multiple cytokines, including interleukin (IL)‑4 and IL-13 that are considered central to AD pathogenesis and key therapeutic targets. The dual inhibition of these two cytokines or the selective inhibition of IL-13 proved elevated efficacy in treating AD, whereas the selective inhibition of IL-4 has been poorly investigated as IL-4 inhibiting agents did not show any advance in clinical development programs. This review describes the pathogenic role of IL-4 in AD and briefly resumes the main features of compounds selectively blocking IL-4.