Immunotherapy advances最新文献

{"title":"A summary of current NKG2D-based CAR clinical trials.","authors":"Sophie Curio,&nbsp;Gustav Jonsson,&nbsp;Sonja Marinović","doi":"10.1093/immadv/ltab018","DOIUrl":"https://doi.org/10.1093/immadv/ltab018","url":null,"abstract":"<p><p>Cancer immunotherapies have significantly improved patient survival and treatment options in recent years. Nonetheless, the success of immunotherapy is limited to certain cancer types and specific subgroups of patients, making the development of new therapeutic approaches a topic of ongoing research. Chimeric antigen receptor (CAR) cells are engineered immune cells that are programmed to specifically eliminate cancer cells. Ideally, a CAR recognizes antigens that are restricted to tumor cells to avoid off-target effects. NKG2D is an activating immunoreceptor and an important player in anti-tumor immunity due to its ability to recognize tumor cells and initiate an anti-tumor immune response. Ligands for NKG2D are expressed on malignant or stressed cells and typically absent from healthy tissue, making it a promising CAR candidate. Here, we provide a summary of past and ongoing NKG2D-based CAR clinical trials and comment on potential pitfalls.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39484613","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":"Enhancing co-stimulation of CAR T cells to improve treatment outcomes in solid cancers.","authors":"Aaron J Harrison,&nbsp;Xin Du,&nbsp;Bianca von Scheidt,&nbsp;Michael H Kershaw,&nbsp;Clare Y Slaney","doi":"10.1093/immadv/ltab016","DOIUrl":"https://doi.org/10.1093/immadv/ltab016","url":null,"abstract":"<p><p>Co-stimulation is a fundamental component of T cell biology and plays a key role in determining the quality of T cell proliferation, differentiation, and memory formation. T cell-based immunotherapies, such as chimeric antigen receptor (CAR) T cell immunotherapy, are no exception. Solid tumours have largely been refractory to CAR T cell therapy owing to an immunosuppressive microenvironment which limits CAR T cell persistence and effector function. In order to eradicate solid cancers, increasingly sophisticated strategies are being developed to deliver these vital co-stimulatory signals to CAR T cells, often specifically within the tumour microenvironment. These include designing novel co-stimulatory domains within the CAR or other synthetic receptors, arming CAR T cells with cytokines or using CAR T cells in combination with agonist antibodies. This review discusses the evolving role of co-stimulation in CAR T cell therapies and the strategies employed to target co-stimulatory pathways in CAR T cells, with a view to improve responses in solid tumours.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4d/d4/ltab016.PMC9327106.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596069","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":"Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact.","authors":"Sifan Zhang,&nbsp;Becca Asquith,&nbsp;Richard Szydlo,&nbsp;John S Tregoning,&nbsp;Katrina M Pollock","doi":"10.1093/immadv/ltab015","DOIUrl":"https://doi.org/10.1093/immadv/ltab015","url":null,"abstract":"<p><p>Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, a review of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease. Autopsy data demonstrated infiltration of T cells into organs, particularly the lung. Seventy-four clinical trials are on-going that could target T cell-related pathogenesis, particularly IL-6 pathways. SARS-CoV-2 infection interrupts T cell circulation in patients with severe COVID-19. This could be due to redistribution of T cells into infected organs, activation induced exhaustion, apoptosis, or pyroptosis. Measuring T cell dynamics during COVID-19 will inform clinical risk-stratification of hospitalised patients and could identify those who would benefit most from treatments that target T cells.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9364037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40696407","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":null,"pages":null},"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":"Association between incidental statin use and skeletal myopathies in patients treated with immune checkpoint inhibitors.","authors":"Zsofia D Drobni,&nbsp;Sean P Murphy,&nbsp;Raza M Alvi,&nbsp;Charlotte Lee,&nbsp;Jingyi Gong,&nbsp;Ramya C Mosarla,&nbsp;Paula K Rambarat,&nbsp;Sarah B Hartmann,&nbsp;Hannah K Gilman,&nbsp;Leyre Zubiri,&nbsp;Vineet K Raghu,&nbsp;Ryan J Sullivan,&nbsp;Amna Zafar,&nbsp;Daniel A Zlotoff,&nbsp;Meghan E Sise,&nbsp;Amanda C Guidon,&nbsp;Kerry L Reynolds,&nbsp;Michael Dougan,&nbsp;Tomas G Neilan","doi":"10.1093/immadv/ltab014","DOIUrl":"https://doi.org/10.1093/immadv/ltab014","url":null,"abstract":"<p><strong>Objectives: </strong>Skeletal myopathies are highly morbid, and in rare cases even fatal, immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI). Skeletal myopathies are also a recognized statin-associated side effect. It is unknown whether concurrent use of statins and ICIs increases the risk of skeletal myopathies.</p><p><strong>Methods: </strong>This was a retrospective cohort study of all patients who were treated with an ICI at a single academic institution (Massachusetts General Hospital, Boston, MA, USA). The primary outcome of interest was the development of a skeletal myopathy. The secondary outcome of interest was an elevated creatine kinase level (above the upper limit of normal).</p><p><strong>Results: </strong>Among 2757 patients, 861 (31.2%) were treated with a statin at the time of ICI start. Statin users were older, more likely to be male and had a higher prevalence of cardiovascular and non-cardiovascular co-morbidities. During a median follow-up of 194 days (inter quartile range 65-410), a skeletal myopathy occurred in 33 patients (1.2%) and was more common among statin users (2.7 vs. 0.9%, <i>P</i> < 0.001). Creatine kinase (CK) elevation was present in 16.3% (114/699) and was higher among statin users (20.0 vs. 14.3%, <i>P</i> = 0.067). In a multivariable Cox model, statin therapy was associated with a >2-fold higher risk for skeletal myopathy (HR, 2.19; 95% confidence interval, 1.07-4.50; <i>P</i> = 0.033).</p><p><strong>Conclusion: </strong>In this large cohort of ICI-treated patients, a higher risk was observed for skeletal myopathies and elevation in CK levels in patients undergoing concurrent statin therapy. Prospective observational studies are warranted to further elucidate the potential association between statin use and ICI-associated myopathies.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ee/b6/ltab014.PMC8444991.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39453027","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":"α2-3 Sialic acid binding and uptake by human monocyte-derived dendritic cells alters metabolism and cytokine release and initiates tolerizing T cell programming.","authors":"Joyce Lübbers,&nbsp;Rui-Jún Eveline Li,&nbsp;Friederike S Gorki,&nbsp;Sven C M Bruijns,&nbsp;Ashley Gallagher,&nbsp;Hakan Kalay,&nbsp;Martino Ambrosini,&nbsp;Douwe Molenaar,&nbsp;Jan Van den Bossche,&nbsp;Sandra J van Vliet,&nbsp;Yvette van Kooyk","doi":"10.1093/immadv/ltab012","DOIUrl":"https://doi.org/10.1093/immadv/ltab012","url":null,"abstract":"<p><p>Dendritic cells (DCs) are key in the initiation of the adaptive T cell responses to tailor adequate immunity that corresponds to the type of pathogen encountered. Oppositely, DCs control the resolution phase of inflammation and are able to induce tolerance after receiving anti-inflammatory cytokines or upon encounter of self-associated molecular patterns, such as α2-3 linked sialic acid (α2-3sia).</p><p><strong>Objective: </strong>We here investigated whether α2-3sia, that bind immune inhibitory Siglec receptors, would alter signaling and reprogramming of LPS-stimulated human monocyte-derived DCs (moDCs).</p><p><strong>Methods and results: </strong>Transcriptomic analysis of moDCs stimulated with α2-3sia-conjugated dendrimers revealed differentially expressed genes related to metabolic pathways, cytokines, and T cell differentiation. An increase in genes involved in ATPase regulator activity, oxidoreductase activity, and glycogen metabolic processes was detected. Metabolic extracellular flux analysis confirmed a more energetic moDC phenotype upon α2-3sia binding as evidenced by an increase in both glycolysis and mitochondrial oxidative phosphorylation. T_H1 differentiation promoting genes <i>IFNL</i> and <i>IL27</i>, were significantly downregulated in the presence of α2-3sia. Functional assays confirmed that α2-3sia binding to moDCs induced phosphorylation of Siglec-9, reduced production of inflammatory cytokines IL-12 and IL-6, and increased IL-10. Surprisingly, α2-3sia-differentiated moDCs promoted FoxP3⁺CD25^+/-CD127^- regulatory T cell differentiation and decreased FoxP3^-CD25^-CD127^- effector T cell proliferation.</p><p><strong>Conclusions: </strong>In conclusion, we demonstrate that α2-3sia binding to moDCs, phosphorylates Siglec-9, alters metabolic pathways, cytokine signaling, and T cell differentiation processes in moDCs and promotes regulatory T cells. The sialic acid-Siglec axis on DCs is therefore, a novel target to induce tolerance and to explore for immunotherapeutic interventions aimed to restore inflammatory processes.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596071","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":"Targeting immunometabolism to treat COVID-19.","authors":"Shane M O'Carroll, Luke A J O'Neill","doi":"10.1093/immadv/ltab013","DOIUrl":"10.1093/immadv/ltab013","url":null,"abstract":"<p><p>The COVID-19 crisis has emphasised the need for antiviral therapies to combat current and future viral zoonoses. Recent studies have shown that immune cells such as macrophages are the main contributors to the inflammatory response seen in the later inflammatory phase of COVID-19. Immune cells in the context of a viral infection such as SARS-CoV-2 undergo metabolic reprogramming to elicit these pro-inflammatory effector functions. The evidence of metabolic reprogramming in COVID-19 offers opportunities for metabolites with immunomodulatory properties to be investigated as potential therapies to combat this hyper-inflammatory response. Recent research indicates that the metabolite itaconate, previously known to be broadly antibacterial, may have both antiviral and immunomodulatory potential. Furthermore, low itaconate levels have shown to correlate with COVID-19 disease severity, potentially implicating its importance in the disease. The antiviral potential of itaconate has encouraged researchers to synthesise itaconate derivatives for antiviral screening, with some encouraging results. This review summarises the antiviral and immunomodulatory potential of immunometabolic modulators including metformin, peroxisome proliferator-activated receptor agonists and TEPP-46 as well as itaconate, and its derivatives and their potential use as broad spectrum anti-viral agents.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2021-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39166840","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":"Type 2 immunity is maintained during cancer-associated adipose tissue wasting.","authors":"Patrick J Lenehan, Assunta Cirella, Amiko M Uchida, Stephanie J Crowley, Tatyana Sharova, Genevieve Boland, Michael Dougan, Stephanie K Dougan, Max Heckler","doi":"10.1093/immadv/ltab011","DOIUrl":"10.1093/immadv/ltab011","url":null,"abstract":"<p><strong>Objectives: </strong>Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the development of other adipose tissue (AT) pathologies such as obesity have been well described, the immune microenvironment has not been studied in the context of cachexia.</p><p><strong>Methods: </strong>We performed bulk RNA-sequencing, cytokine arrays, and flow cytometry to characterize the immune landscape of visceral AT (VAT) in the setting of pancreatic and colorectal cancers.</p><p><strong>Results: </strong>The cachexia inducing factor IL-6 is strongly elevated in the wasting VAT of cancer bearing mice, but the regulatory type 2 immune landscape which characterizes healthy VAT is maintained. Pathologic skewing toward Th1 and Th17 inflammation is absent. Similarly, the VAT of patients with colorectal cancer is characterized by a Th2 signature with abundant IL-33 and eotaxin-2, albeit also with high levels of IL-6.</p><p><strong>Conclusions: </strong>Wasting AT during the development of cachexia may not undergo drastic changes in immune composition like those seen in obese AT. Our approach provides a framework for future immunologic analyses of cancer associated cachexia.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2021-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/47/1e/ltab011.PMC8286632.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39207952","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":"A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy.","authors":"Laura J Pallett, Sarah Dimeloe, Linda V Sinclair, Adam J Byrne, Anna Schurich","doi":"10.1093/immadv/ltab010","DOIUrl":"10.1093/immadv/ltab010","url":null,"abstract":"<p><p>Within the tumour microenvironment (TME), there is a cellular 'tug-of-war' for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39453026","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":"Behind the scenes with basophils: an emerging therapeutic target.","authors":"Hemali Shah,&nbsp;Stephanie Eisenbarth,&nbsp;Christopher A Tormey,&nbsp;Alexa J Siddon","doi":"10.1093/immadv/ltab008","DOIUrl":"https://doi.org/10.1093/immadv/ltab008","url":null,"abstract":"<p><p>Though basophils were originally viewed as redundant blood 'mast cells', the implementation of flow cytometry has established basophils as unique leukocytes with critical immunomodulatory functions. Basophils play an active role in allergic inflammation, autoimmunity, and hematological malignancies. They are distinguishable from other leukocytes by their characteristic metachromatic deep-purple cytoplasmic, round granules. Mature basophils are phenotypically characterized by surface expression of IL-3Rα (CD123); IL-3 drives basophil differentiation, degranulation, and synthesis of inflammatory mediators including type 2 cytokines. Basophil degranulation is the predominant source of histamine in peripheral blood, promoting allergic responses. Basophils serve as a bridge between innate and adaptive immunity by secreting IL-4 which supports eosinophil migration, monocyte differentiation into macrophages, B-cell activation, and CD4 T-cell differentiation into Th2 cells. Further, basophilia is a key phenomenon in myeloid neoplasms, especially chronic myeloid leukemia (CML) for which it is a diagnostic criterion. Increased circulating basophils, often with aberrant immunophenotype, have been detected in patients with CML and other myeloproliferative neoplasms (MPNs). The significance of basophils' immunoregulatory functions in malignant and non-malignant diseases is an active area of research. Ongoing and future research can inform the development of immunotherapies that target basophils to impact allergic, autoimmune, and malignant disease states. This review article aims to provide an overview of basophil biology, identification strategies, and roles and dysregulation in diseases.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/09/6d/ltab008.PMC9327101.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40596070","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}