Immunological reviews
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Immunological reviews · Jan 2021
ReviewHuman antiviral B cell responses: Emerging lessons from hepatitis B and COVID-19.
Humoral immunity is a critical component of the coordinated response required to resolve viral infections and mediate protection following pathogen clearance or vaccination. A better understanding of factors shaping the memory B cell response will allow tailored development of efficient preventative vaccines against emerging acute viral infections, therapeutic vaccines, and immunotherapies for chronic viral infections. ⋯ Hepatitis B provides a paradigm where successful B cell responses in resolved or vaccinated individuals can be contrasted to the failed response in chronic infection, while also exemplifying the degree to which B cell responses within infected individuals can differ to two antigens from the same virus. Drawing on studies in other human and murine infections, including emerging data from COVID-19, we consider the influence of antigen quantity and structure on the quality of the B cell response, the role of differential CD4 help, the importance of germinal center vs extrafollicular responses and the emerging concept that responses residing in non-lymphoid organs can participate in B cell memory.
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Immunological reviews · Jul 2020
ReviewThe role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity.
This article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus-mediated disease. The initial sections focus on seasonal coronaviruses, SARS-CoV, and MERS-CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS-CoV-2 and COVID-19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS-CoV-2.
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Immunological reviews · Jul 2019
ReviewT cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance.
Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)-modified T cells can induce durable remissions in patients with refractory B-lymphoid cancers. By contrast, results applying CAR-modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. ⋯ Herein, we summarize recent clinical data demonstrating that TCR-based immunotherapies can mediate regression of solid malignancies, including immune-checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR-based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non-viral genome integration techniques.
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By increasing disease-free survival and offering the potential for long-term cure, chimeric antigen receptor (CAR) T-cell therapy has dramatically expanded therapeutic options among those with high-risk B-cell malignancies. As CAR T-cell utilization evolves however, novel challenges are generated. These include determining how to optimally integrate CAR T cells into standard of care and overcoming mechanisms of resistance to CAR T-cell therapy, such as evolutionary stress induced on cancer cells leading to immunophenotypic changes that allow leukemia to evade this targeted therapy. ⋯ Additionally, as understanding of CAR behavior in humans has developed, strategies have appropriately evolved to proactively mitigate toxicities. These challenges offer complimentary insights and guide next steps to enhance the efficacy of this novel therapeutic modality. With a focus on B-cell malignancies as the paradigm for effective CAR T-cell therapy, this review describes advances in the field as well as current challenges and future directions.
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The advent of chimeric antigen receptor T (CAR-T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized "living therapy" is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR-T. The overwhelming release of cytokines and chemokines by activated CAR-T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. ⋯ Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR-T-related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR-T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR-T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.