Immunotherapy advances最新文献

{"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":"The MARVEL trial: a phase 2b randomised placebo-controlled trial of oral MitoQ in moderate ulcerative colitis","authors":"Emily Gwyer Findlay, G. Sutton, G. Ho","doi":"10.1093/immadv/ltaa002","DOIUrl":"https://doi.org/10.1093/immadv/ltaa002","url":null,"abstract":"Summary Ulcerative colitis (UC) is an inflammatory disease of the large bowel which is characterised by dysregulated immunity and death to epithelial cells in the bowel, leading to prolonged inflammation. This can ultimately lead to surgery to remove the large bowel, with a risk of cancer developing if inflammation persists. Current therapies – which target the incoming immune cells or the cytokines they produce – are improving significantly but they are expensive and are immunosuppressive, leading to risk of infection. Here, we discuss a new trial which targets an early inducer of inflammation – the production of reactive oxygen species (ROS) by mitochondria. Previous work has shown that excessive mitochondrial ROS induces inflammatory signalling through the cGAS-STING pathway, leading to dysregulated immunity and death of epithelial cells. In this MARVEL trial (Mitochondrial Anti-oxidant therapy to Resolve Inflammation in Ulcerative Colitis) individuals with an active UC flare-up will be given a mitochondrial anti-oxidant (MitoQ) or placebo tablet in addition to standard medical treatment, in order to suppress inflammation as it develops. This phase 2b trial will repurpose MitoQ, which has been previously tested in other large trials in different disease settings, and will measure clinical response and markers of inflammation over 24 weeks. It is hoped that this trial will develop a new target for UC through re-purposing a relatively cheap, non-toxic and well-characterised drug.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47880806","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}