Immunotherapy advances最新文献

{"title":"A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes.","authors":"Ashish K Marwaha,&nbsp;Samuel Chow,&nbsp;Anne M Pesenacker,&nbsp;Laura Cook,&nbsp;Annika Sun,&nbsp;S Alice Long,&nbsp;Jennie H M Yang,&nbsp;Kirsten A Ward-Hartstonge,&nbsp;Evangelia Williams,&nbsp;Clara Domingo-Vila,&nbsp;Khalif Halani,&nbsp;Kristina M Harris,&nbsp;Timothy I M Tree,&nbsp;Megan K Levings,&nbsp;Thomas Elliott,&nbsp;Rusung Tan,&nbsp;Jan P Dutz","doi":"10.1093/immadv/ltab022","DOIUrl":"https://doi.org/10.1093/immadv/ltab022","url":null,"abstract":"<p><strong>Objectives: </strong>We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia.</p><p><strong>Methods: </strong>We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses.</p><p><strong>Results: </strong>Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A.</p><p><strong>Conclusion: </strong>Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"2 1","pages":"ltab022"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9764729","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":"Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.","authors":"Stephanie Schwartz,&nbsp;Nidhi Patel,&nbsp;Tyler Longmire,&nbsp;Pushpa Jayaraman,&nbsp;Xiaomo Jiang,&nbsp;Hongbo Lu,&nbsp;Lisa Baker,&nbsp;Janelle Velez,&nbsp;Radha Ramesh,&nbsp;Anne-Sophie Wavreille,&nbsp;Melanie Verneret,&nbsp;Hong Fan,&nbsp;Tiancen Hu,&nbsp;Fangmin Xu,&nbsp;John Taraszka,&nbsp;Marc Pelletier,&nbsp;Joy Miyashiro,&nbsp;Mikael Rinne,&nbsp;Glenn Dranoff,&nbsp;Catherine Sabatos-Peyton,&nbsp;Viviana Cremasco","doi":"10.1093/immadv/ltac019","DOIUrl":"https://doi.org/10.1093/immadv/ltac019","url":null,"abstract":"<p><strong>Objectives: </strong>Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab.</p><p><strong>Methods: </strong>Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed.</p><p><strong>Results: </strong>Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9.</p><p><strong>Conclusion: </strong>Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"2 1","pages":"ltac019"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9525012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10743395","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":"Engineering CAR-NK cells: how to tune innate killer cells for cancer immunotherapy.","authors":"Dayane Schmidt,&nbsp;Sima Ebrahimabadi,&nbsp;Kauan Ribeiro de Sena Gomes,&nbsp;Graziela de Moura Aguiar,&nbsp;Mariane Cariati Tirapelle,&nbsp;Renata Nacasaki Silvestre,&nbsp;Júlia Teixeira Cottas de Azevedo,&nbsp;Dimas Tadeu Covas,&nbsp;Virginia Picanço-Castro","doi":"10.1093/immadv/ltac003","DOIUrl":"https://doi.org/10.1093/immadv/ltac003","url":null,"abstract":"<p><p>Cell therapy is an innovative approach that permits numerous possibilities in the field of cancer treatment. CAR-T cells have been successfully used in patients with hematologic relapsed/refractory. However, the need for autologous sources for T cells is still a major drawback. CAR-NK cells have emerged as a promising resource using allogeneic cells that could be established as an off-the-shelf treatment. NK cells can be obtained from various sources, such as peripheral blood (PB), bone marrow, umbilical cord blood (CB), and induced pluripotent stem cells (iPSC), as well as cell lines. Genetic engineering of NK cells to express different CAR constructs for hematological cancers and solid tumors has shown promising preclinical results and they are currently being explored in multiple clinical trials. Several strategies have been employed to improve CAR-NK-cell expansion and cytotoxicity efficiency. In this article, we review the latest achievements and progress made in the field of CAR-NK-cell therapy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"2 1","pages":"ltac003"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10309720","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":"Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: an early window of opportunity?","authors":"Tamiko R Katsumoto,&nbsp;Kalin L Wilson,&nbsp;Vinay K Giri,&nbsp;Han Zhu,&nbsp;Shuchi Anand,&nbsp;Kavitha J Ramchandran,&nbsp;Beth A Martin,&nbsp;Muharrem Yunce,&nbsp;Srikanth Muppidi","doi":"10.1093/immadv/ltac012","DOIUrl":"https://doi.org/10.1093/immadv/ltac012","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several advanced malignancies leading to durable remission in a subset of patients. Their rapidly expanding use has led to an increased frequency of immune-related adverse events (irAEs). The pathogenesis of irAEs is poorly understood but may involve aberrant activation of T cells leading to inflammatory cytokine release or production of pathogenic antibodies leading to organ damage. Severe irAEs can be extremely debilitating and, in some cases, life threatening. IrAEs may not always be corticosteroid responsive or may require excessively high, often toxic, corticosteroid doses. Therapeutic plasma exchange (PLEX) is a treatment modality that has shown promising results for the management of certain severe irAEs, including irAEs that are not mentioned in current treatment guidelines. PLEX may attenuate ongoing irAEs and prevent delayed irAEs by accelerating clearance of the ICI, or by acutely removing pathogenic antibodies, cytokines, and chemokines. Here, we summarize examples from the literature in which PLEX was successfully used for the treatment of irAEs. We posit that timing may be a critical factor and that earlier utilization of PLEX for life-threatening irAEs may result in more favorable outcomes. In individuals at high risk for irAEs, the availability of PLEX as a potential therapeutic mitigation strategy may encourage life-saving ICI use or rechallenge. Future research will be critical to better define which indications are most amenable to PLEX, particularly to establish the optimal place in the sequence of irAE therapies and to assess the ramifications of ICI removal on cancer outcomes.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"2 1","pages":"ltac012"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/b8/ltac012.PMC9257781.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9780090","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":"Seven mysteries of LAG-3: a multi-faceted immune receptor of increasing complexity.","authors":"Stephanie E A Burnell, Lorenzo Capitani, Bruce J MacLachlan, Georgina H Mason, Awen M Gallimore, Andrew Godkin","doi":"10.1093/immadv/ltab025","DOIUrl":"10.1093/immadv/ltab025","url":null,"abstract":"<p><p>Despite three decades of research to its name and increasing interest in immunotherapies that target it, LAG-3 remains an elusive co-inhibitory receptor in comparison to the well-established PD-1 and CTLA-4. As such, LAG-3 targeting therapies have yet to achieve the clinical success of therapies targeting other checkpoints. This could, in part, be attributed to the many unanswered questions that remain regarding LAG-3 biology. Of these, we address: (i) the function of the many LAG-3-ligand interactions, (ii) the hurdles that remain to acquire a high-resolution structure of LAG-3, (iii) the under-studied LAG-3 signal transduction mechanism, (iv) the elusive soluble form of LAG-3, (v) the implications of the lack of (significant) phenotype of LAG-3 knockout mice, (vi) the reports of LAG-3 expression on the epithelium, and (vii) the conflicting reports of LAG-3 expression (and potential contributions to pathology) in the brain. These mysteries which surround LAG-3 highlight how the ever-evolving study of its biology continues to reveal ever-increasing complexity in its role as an immune receptor. Importantly, answering the questions which shroud LAG-3 in mystery will allow the maximum therapeutic benefit of LAG-3 targeting immunotherapies in cancer, autoimmunity and beyond.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"2 1","pages":"ltab025"},"PeriodicalIF":0.0,"publicationDate":"2021-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48745506","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 clinical correlates of vaccine-induced immune thrombotic thrombocytopenia after immunisation with adenovirus vector-based SARS-CoV-2 vaccines.","authors":"Eleanor R Gaunt, Neil A Mabbott","doi":"10.1093/immadv/ltab019","DOIUrl":"10.1093/immadv/ltab019","url":null,"abstract":"<p><p>We are at a critical stage in the COVID-19 pandemic where vaccinations are being rolled out globally, in a race against time to get ahead of the SARS-CoV-2 coronavirus and the emergence of more highly transmissible variants. A range of vaccines have been created and received either emergency approval or full licensure. To attain the upper hand, maximum vaccine synthesis, deployment, and uptake as rapidly as possible is essential. However, vaccine uptake, particularly in younger adults is dropping, at least in part fuelled by reports of rare complications associated with specific vaccines. This review considers how vaccination with adenovirus vector-based vaccines against the SARS-CoV-2 coronavirus might cause rare cases of thrombosis and thrombocytopenia in some recipients. A thorough understanding of the underlying cellular and molecular mechanisms that mediate this syndrome may help to identify methods to prevent these very rare, but serious side effects. This will also help facilitate the identification of those at highest risk from these outcomes, so that we can work towards a stratified approach to vaccine deployment to mitigate these risks.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltab019"},"PeriodicalIF":0.0,"publicationDate":"2021-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10732190","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":"Adaptive immunity and vaccination - iron in the spotlight.","authors":"Alexandra E Preston,&nbsp;Hal Drakesmith,&nbsp;Joe N Frost","doi":"10.1093/immadv/ltab007","DOIUrl":"10.1093/immadv/ltab007","url":null,"abstract":"<p><p>Vaccination programmes are critically important to suppress the burden of infectious diseases, saving countless lives globally, as emphasised by the current COVID-19 pandemic. Effective adaptive immune responses are complex processes subject to multiple influences. Recent genetic, pre-clinical, and clinical studies have converged to show that availability of iron is a key factor regulating the development of T and B cell responses to infection and immunisation. Lymphocytes obtain iron from circulating transferrin. The amount of iron bound to transferrin is dependent on dietary iron availability and is decreased during inflammation via upregulation of the iron-regulatory hormone, hepcidin. As iron deficiency and chronic inflammatory states are both globally prevalent health problems, the potential impact of low iron availability on immune responses is significant. We describe the evidence supporting the importance of iron in immunity, highlight important unknowns, and discuss how therapeutic interventions to modulate iron availability might be implementable in the context of vaccination and infectious disease.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltab007"},"PeriodicalIF":0.0,"publicationDate":"2021-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9149796","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":"Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.","authors":"Matthias Eberl,&nbsp;Eric Oldfield,&nbsp;Thomas Herrmann","doi":"10.1093/immadv/ltab005","DOIUrl":"https://doi.org/10.1093/immadv/ltab005","url":null,"abstract":"<p><p>Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like (<i>E</i>)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), the penultimate metabolite in the MEP isoprenoid biosynthesis pathway, and intermediates of the riboflavin biosynthesis pathway and their metabolites allows the immune system to rapidly sense pathogen-associated molecular patterns that are shared by a wide range of micro-organisms. Given the essential nature of these metabolic pathways for microbial viability, they have emerged as promising targets for the development of novel antibiotics. Here, we review recent findings that link enzymatic inhibition of microbial metabolism with alterations in the levels of unconventional T cell ligands produced by treated micro-organisms that have given rise to the concept of 'immuno-antibiotics': combining direct antimicrobial activity with an immunotherapeutic effect via modulation of unconventional T cell responses.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"1 1","pages":"ltab005"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/immadv/ltab005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10334639","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}