Frontiers in immunology
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Frontiers in immunology · Jan 2018
ReviewTargeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy.
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. ⋯ Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.
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Frontiers in immunology · Jan 2018
ReviewTherapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis.
Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. ⋯ Modulation of the microbiota consists of either resupplying the pool of beneficial microbes by administration of probiotics, improving the intestinal microenvironment to enhance the growth of beneficial species by dietary interventions and prebiotics, or by totally recolonizing the gut with a fecal microbiota transplantation (FMT). We propose that there are three potential opportunities to utilize these treatment modalities over the course of sepsis: to decrease sepsis incidence, to improve sepsis outcome, and to decrease late mortality after sepsis. Exploring these three avenues will provide insight into how disturbances of the microbiota can predispose to, or even perpetuate the dysregulated immune response associated with this syndrome, which in turn could be associated with improved sepsis management.
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Frontiers in immunology · Jan 2018
ReviewThe Role of Monocytes and Macrophages in Acute and Acute-on-Chronic Liver Failure.
Acute and acute-on-chronic liver failure (ALF and ACLF), though distinct clinical entities, are considered syndromes of innate immune dysfunction. Patients with ALF and ACLF display evidence of a pro-inflammatory state with local liver inflammation, features of systemic inflammatory response syndrome (SIRS) and vascular endothelial dysfunction that drive progression to multi-organ failure. In an apparent paradox, these patients are concurrently immunosuppressed, exhibiting acquired immune defects that render them highly susceptible to infections. ⋯ Hence, peripheral monocytes show numerous acquired defects in acute liver failure syndromes that impair their anti-microbial programmes and contribute to enhanced susceptibility to sepsis. This review will highlight the cellular and molecular mechanisms by which monocytes and macrophages contribute to the pathophysiology of ALF and ACLF, considering both hepatic inflammation and systemic immunosuppression. We identify areas for further research and potential targets for immune-based therapies to treat these devastating conditions.
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Frontiers in immunology · Jan 2018
ReviewImmune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells.
T cells equipped with chimeric antigen receptors (CAR T cells) have recently provided promising advances as a novel immunotherapeutic approach for cancer treatment. CAR T cell therapy has shown stunning results especially in B-cell malignancies; however, it has shown less success against solid tumors, which is more supposed to be related to the specific characteristics of the tumor microenvironment. ⋯ Specific hurdles and problems that limit the optimal function of CAR T cells, especially on solid tumors, and possible solutions according to new modifications and generations of CAR T cells have been introduced here. We also provide information of the future directions on how to enhance engineering the next smarter generations of CAR T cells in order to decrease the adverse effects and increase the potency and efficacy of CAR T cells against cancer.
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Frontiers in immunology · Jan 2018
ReviewThe Evolving Landscape of Immunotherapy-Based Combinations for Frontline Treatment of Advanced Renal Cell Carcinoma.
Insights into the biology of advanced renal cell carcinoma (aRCC) and the development of agents targeting the vascular endothelial growth factor (VEGF) pathway have positively impacted the outcomes for patients with aRCC. With the recent approval of the dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, by the U. ⋯ The frontline treatment options for renal cell carcinoma are evolving rapidly and will lead to the approval of other combination immunotherapies-especially those with VEGF inhibitors. Here we review the clinical data for dual immune checkpoint inhibition with nivolumab plus ipilimumab as well as the emerging data for ICI plus VEGF inhibitor combinations and discuss the challenges these will pose for the clinical practitioner.