Immunotherapy advances最新文献

{"title":"CSF1R defines the mononuclear phagocyte system lineage in human blood in health and COVID-19.","authors":"Theo W Combes, Federica Orsenigo, Alexander Stewart, A S Jeewaka R Mendis, Deborah Dunn-Walters, Siamon Gordon, Fernando O Martinez","doi":"10.1093/immadv/ltab003","DOIUrl":"10.1093/immadv/ltab003","url":null,"abstract":"<p><p>Mononuclear phagocytes defend tissues, present antigens, and mediate recovery and healing. To date, we lack a marker to unify mononuclear phagocytes in humans or that informs us about their origin. Here, we reassess mononuclear phagocyte ontogeny in human blood through the lineage receptor CSF1R, in the steady state and in COVID-19. We define CSF1R as the first sensitive and reproducible pan-phagocyte lineage marker, to identify and enumerate all conventional monocytes, and the myeloid dendritic cells. In the steady state, CSF1R is sufficient for sorting and immuno-magnetic isolation. In pathology, changes in CSF1R are more sensitive than CD14 and CD16. In COVID-19, a significant drop in membrane CSF1R is useful for stratifying patients, beyond the power of cell categories published thus far, which fail to capture COVID-19 specific events. Importantly, CSF1R defines cells which are neither conventional monocytes nor DCs, which are missed in published analysis. CSF1R decrease can be linked <i>ex vivo</i> to high CSF1 levels. Blood assessment of CSF1R+ cells opens a developmental window to the Mononuclear Phagocyte System in transit from bone marrow to tissues, supports isolation and phenotypic characterisation, identifies novel cell types, and singles out CSF1R inhibition as therapeutic target in COVID-19 and other diseases.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab003"},"PeriodicalIF":4.1,"publicationDate":"2021-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40664157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrin-directed antibody-based immunotherapy: focus on VLA-4.","authors":"Wilson Savino,&nbsp;Beatriz Chaves,&nbsp;Adriana Cesar Bonomo,&nbsp;Vinicius Cotta-de-Almeida","doi":"10.1093/immadv/ltab002","DOIUrl":"https://doi.org/10.1093/immadv/ltab002","url":null,"abstract":"<p><p>One major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the α4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing <i>in vitro</i> transendothial and fibronectin-driven migration of CD4⁺ and CD8⁺ T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab002"},"PeriodicalIF":0.0,"publicationDate":"2021-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltab002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40578948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upcoming immunotherapeutic combinations for B-cell lymphoma.","authors":"Patrick Greve,&nbsp;Friederike A G Meyer-Wentrup,&nbsp;Victor Peperzak,&nbsp;Marianne Boes","doi":"10.1093/immadv/ltab001","DOIUrl":"https://doi.org/10.1093/immadv/ltab001","url":null,"abstract":"<p><p>After initial introduction for B-cell lymphomas as adjuvant therapies to established cancer treatments, immune checkpoint inhibitors and other immunotherapies are now integrated in mainstream regimens, both in adult and pediatric patients. We here provide an overview of the current status of combination therapies for B-cell lymphoma, by in-depth analysis of combination therapy trials registered between 2015-2020. Our analysis provides new insight into the rapid evolution in lymphoma treatment, as propelled by new additions to the treatment arsenal. We conclude with prospects on upcoming clinical trials which will likely use systematic testing approaches of more combinations of established chemotherapy regimens with new agents, as well as new combinations of immunotherapy and targeted therapy. Future trials will be set up as basket or umbrella-type trials to facilitate the evaluation of new drugs targeting specific genetic changes in the tumor or associated immune microenvironment. As such, lymphoma patients will benefit by receiving more tailored treatment that is based on synergistic effects of chemotherapy combined with new agents targeting specific aspects of tumor biology and the immune system.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab001"},"PeriodicalIF":0.0,"publicationDate":"2021-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltab001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40578947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Special Review: The future of Immunotherapy.","authors":"Cornelis J M Melief","doi":"10.1093/immadv/ltaa005","DOIUrl":"https://doi.org/10.1093/immadv/ltaa005","url":null,"abstract":"<p><p>During the last two decades, two main schools of modern immunotherapy have come to the forefront. The chimeric anti-CD20 antibody rituximab that was introduced for the treatment of refractory follicular lymphoma in 1998 was one of the first examples of the school of passive immunotherapy. Subsequently major and ever more costly efforts were spent on the development of blockbuster monotherapies including other monoclonal but also bispecific antibodies of highly defined specificity and subclass, antibody-drug conjugates (ADCs), as well as <i>ex vivo</i> expanded tumor-infiltrating lymphocytes, chimeric antigen receptor (CAR)-transduced T cells, and TCR-transduced T cells. On the other hand, there is the school that works toward active induction of patient B- or T-cell immunity against antigens of choice, or active tolerance against pathogenic allergens, auto-antigens or allo-antigens. Stradled in between these two approaches is treatment with blockers of T cell checkpoint control, which releases the brakes of T cells that have already responded to antigen. Extensive and detailed insight into the cellular and molecular interactions that regulate specific immune responses is indispensable in order to be able to optimize efficacy and rule out treatment related toxicity. This applies to all types of immunotherapy. Our knowledge of the checks and balances in the immune system is still increasing at an unprecedented pace, fostering ever more effective and specific (combination) immunotherapies and offering a rich harvest of innovative immunotherapies in the years ahead.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltaa005"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltaa005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10681634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancement of antigen-specific immunotherapy: knowledge transfer between allergy and autoimmunity.","authors":"Naomi Richardson,&nbsp;David Cameron Wraith","doi":"10.1093/immadv/ltab009","DOIUrl":"https://doi.org/10.1093/immadv/ltab009","url":null,"abstract":"<p><p>Targeted restoration of immunological tolerance to self-antigens or innocuous environmental allergens represents the ultimate aim of treatment options in autoimmune and allergic disease. Antigen-specific immunotherapy (ASI) is the only intervention that has proven disease-modifying efficacy as evidenced by induction of long-term remission in a number of allergic conditions. Mounting evidence is now indicating that specific targeting of pathogenic T cells in autoinflammatory and autoimmune settings enables effective restoration of immune homeostasis between effector and regulatory cells and alters the immunological course of disease. Here, we discuss the key lessons learned during the development of antigen-specific immunotherapies and how these can be applied to inform future interventions. Armed with this knowledge and current high-throughput technology to track immune cell phenotype and function, it may no longer be a matter of 'if' but 'when' this ultimate aim of targeted tolerance restoration is realised.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltab009"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fd/7b/ltab009.PMC9327121.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9944584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Ipilimumab: a review of immunotherapeutic approaches in clinical trials in melanoma","authors":"G. Middleton","doi":"10.1093/immadv/ltaa010","DOIUrl":"https://doi.org/10.1093/immadv/ltaa010","url":null,"abstract":"Summary In this first in a series of ‘Trials Watch’ articles, we briefly review a highly selected set of clinical trials that are currently recruiting or about to open to recruitment in melanoma, the disease first transformed by the introduction of immune checkpoint blockade inhibitors (ICI). We place equal emphasis on phase I/II studies investigating the activity of biologically compelling novel immunotherapeutics, and on randomised trials of ICI with and without novel agents, as these latter studies optimise the standard-of-care use of ICI, and determine whether novel agents become part of the approved therapeutic armamentarium. We do not consider here combination therapy with other checkpoint antagonists or agonists besides combination of anti-PD-1/PD-L1 monoclonal antibodies (mAbs) with anti-CTLA4 mAbs, as these will be reviewed in a subsequent article in this series. A glossary of agents to be discussed is found at the end of this article.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltaa010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43716089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulating innovation in the early development of cell therapies","authors":"A. Exley, J. McBlane","doi":"10.1093/immadv/ltaa011","DOIUrl":"https://doi.org/10.1093/immadv/ltaa011","url":null,"abstract":"\u0000 Clinical need for paradigm shifts in efficacy and safety is driving the rapid and wide-ranging innovation in cell therapies for cancer beyond existing regulatory frameworks. Critical issues emerging during clinical trials frequently reflect unresolved elements of the regulation of innovation conundrum from earlier stages of development. We address this challenge using a global regulators’ perspective on the preclinical development of cell therapies, as a navigational aid to intended commercial use which maximises the clinical relevance of developmental data. We examine the implications of tumour targeting based on B cell, natural killer cell, conventional and unconventional T cell receptor domains; multiplex approaches; genetic manipulation strategies; and autologous versus allogeneic cell sources. We propose that detailed characterisation of both the cell source and final product is critical to optimising manufacture of individualised autologous or off the shelf allogeneic cell therapies, enabling product consistency to underpin extrapolation of clinical trial data to the expected commercial use. We highlight preclinical approaches to characterising target antigens including the Human Cell Atlas initiative, multi-dimensional cell culture, and safety testing against activated, proliferating or stressed control cells. Practical solutions are provided for preclinical toxicity studies when cell therapies target uniquely human tumour antigens, including illustrative mitigation measures for potential toxicity likely to support timely approval of first-in-human clinical trials. We recommend addressing the regulation of innovation conundrum through serial engagement between innovators and regulators early in the development of cell therapies for cancer, accelerating patient access while safeguarding against unacceptable toxicities.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltaa011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42039856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNAM1 and TIGIT balance the T cell response, with low T cell TIGIT expression corresponding to inflammation in psoriatic disease","authors":"M. Jacobs, J. Pouw, M. O. Olde Nordkamp, T. Radstake, E. Leijten, M. Boes","doi":"10.1093/immadv/ltaa004","DOIUrl":"https://doi.org/10.1093/immadv/ltaa004","url":null,"abstract":"Summary Objectives Signals at the contact site of antigen-presenting cells (APCs) and T cells help orchestrate the adaptive immune response. CD155 on APCs can interact with the stimulatory receptor DNAM1 or inhibitory receptor TIGIT on T cells. The CD155/DNAM1/TIGIT axis is under extensive investigation as immunotherapy target in inflammatory diseases including cancer, chronic infection and autoimmune diseases. We investigated a possible role for CD155/DNAM1/TIGIT signaling in psoriatic disease. Methods By flow cytometry, we analyzed peripheral blood mononuclear cells of patients with psoriasis (n = 20) or psoriatic arthritis (n = 21), and healthy individuals (n = 7). We measured CD155, TIGIT, and DNAM1 expression on leukocyte subsets and compared activation-induced cytokine production between CD155-positive and CD155-negative APCs. We assessed the effects of TIGIT and DNAM1 blockade on T cell activation, and related the expression of CD155/DNAM1/TIGIT axis molecules to measures of disease activity. Results High CD155 expression associates with tumor necrosis factor (TNF) production in myeloid and plasmacytoid dendritic cells (DC). In CD1c+ myeloid DC, activation-induced CD155 expression associates with increased HLA-DR expression. CD8 T cells – but not CD4 T cells – express high levels of TIGIT. DNAM1 blockade decreases T cell pro-inflammatory cytokine production, while TIGIT blockade increased T cell proliferation. Finally, T cell TIGIT expression shows an inverse correlation with inflammation biomarkers in psoriatic disease. Conclusion CD155 is increased on pro-inflammatory APCs, while the receptors DNAM1 and TIGIT expressed on T cells balance the inflammatory response by T cells. In psoriatic disease, low TIGIT expression on T cells is associated with systemic inflammation.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltaa004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44775105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D₃ replacement enhances antigen-specific immunity in older adults.","authors":"Emma S Chambers, Milica Vukmanovic-Stejic, Carolin T Turner, Barbara B Shih, Hugh Trahair, Gabriele Pollara, Evdokia Tsaliki, Malcolm Rustin, Tom C Freeman, Neil A Mabbott, Mahdad Noursadeghi, Adrian R Martineau, Arne N Akbar","doi":"10.1093/immadv/ltaa008","DOIUrl":"10.1093/immadv/ltaa008","url":null,"abstract":"<p><strong>Introduction: </strong>Ageing is associated with increased number of infections, decreased vaccine efficacy and increased systemic inflammation termed inflammageing. These changes are reflected by reduced recall responses to varicella zoster virus (VZV) challenge in the skin of older adults. Vitamin D deficiency is more common in the old and has been associated with frailty and increased inflammation. In addition, vitamin D increases immunoregulatory mechanisms and therefore has the potential to inhibit inflammageing.</p><p><strong>Objectives: </strong>We investigated the use of vitamin D₃ replacement to enhance cutaneous antigen-specific immunity in older adults (≥65 years).</p><p><strong>Methods: </strong>Vitamin D insufficient older adults (<i>n</i> = 18) were administered 6400IU of vitamin D₃/day orally for 14 weeks. Antigen-specific immunity to VZV was assessed by clinical score assessment of the injection site and transcriptional analysis of skin biopsies collected from challenged injection sites pre- and post-vitamin D₃ replacement.</p><p><strong>Results: </strong>We showed that older adults had reduced VZV-specific cutaneous immune response and increased non-specific inflammation as compared to young. Increased non-specific inflammation observed in the skin of older adults negatively correlated with vitamin D sufficiency. We showed that vitamin D₃ supplementation significantly increased the response to cutaneous VZV antigen challenge in older adults. This enhancement was associated with a reduction in inflammatory monocyte infiltration with a concomitant enhancement of T cell recruitment to the site of antigen challenge in the skin.</p><p><strong>Conclusion: </strong>Vitamin D₃ replacement can boost antigen-specific immunity in older adults with sub-optimal vitamin D status.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltaa008"},"PeriodicalIF":4.1,"publicationDate":"2020-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9585673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9264401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting clinical response to costimulation blockade in autoimmunity.","authors":"Natalie M Edner, Chun Jing Wang, Lina Petersone, Lucy S K Walker","doi":"10.1093/immadv/ltaa003","DOIUrl":"10.1093/immadv/ltaa003","url":null,"abstract":"<p><p>Curbing unwanted T cell responses by costimulation blockade has been a recognised immunosuppressive strategy for the last 15 years. However, our understanding of how best to deploy this intervention is still evolving. A key challenge has been the heterogeneity in the clinical response to costimulation blockade, and an inability to predict which individuals are likely to benefit most. Here, we discuss our recent findings based on the use of costimulation blockade in people with type 1 diabetes (T1D) and place them in the context of the current literature. We discuss how profiling follicular helper T cells (Tfh) in pre-treatment blood samples may have value in predicting which individuals are likely to benefit from costimulation blockade drugs such as abatacept.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltaa003"},"PeriodicalIF":4.1,"publicationDate":"2020-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33438193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}