Immunotherapy advances最新文献

{"title":"Establishing a single-sex controlled human <i>Schistosoma mansoni</i> infection model for Uganda: protocol for safety and dose-finding trial.","authors":"Andrew Abaasa, Moses Egesa, Emmanuella Driciru, Jan Pieter R Koopman, Ronald Kiyemba, Richard E Sanya, Jacent Nassuuna, Agnes Ssali, Geofrey Kimbugwe, Anne Wajja, Govert J van Dam, Paul L A M Corstjens, Stephen Cose, Janet Seeley, Dorcas Kamuya, Emily L Webb, Maria Yazdanbakhsh, Pontiano Kaleebu, Afzal A Siddiqui, Narcis Kabatereine, Edridah Tukahebwa, Meta Roestenberg, Alison M Elliott","doi":"10.1093/immadv/ltad010","DOIUrl":"10.1093/immadv/ltad010","url":null,"abstract":"<p><p>Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A <i>Schistosoma</i> CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for <i>Schistosoma mansoni</i> in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior <i>Schistosoma</i> exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10396375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10314636","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":"Blockade of innate inflammatory cytokines TNF<b>α</b>, IL-1<b>β</b>, or IL-6 overcomes virotherapy-induced cancer equilibrium to promote tumor regression.","authors":"Michael J Walsh, Lestat R Ali, Patrick Lenehan, Courtney T Kureshi, Rakeeb Kureshi, Michael Dougan, David M Knipe, Stephanie K Dougan","doi":"10.1093/immadv/ltad011","DOIUrl":"10.1093/immadv/ltad011","url":null,"abstract":"<p><p>Cancer therapeutics can lead to immune equilibrium in which the immune response controls tumor cell expansion without fully eliminating the cancer. The factors involved in this equilibrium remain incompletely understood, especially those that would antagonize the anti-tumor immune response and lead to tumor outgrowth. We previously demonstrated that continuous treatment with a non-replicating herpes simplex virus 1 expressing interleukin (IL)-12 induces a state of cancer immune equilibrium highly dependent on interferon-γ. We profiled the IL-12 virotherapy-induced immune equilibrium in murine melanoma, identifying blockade of innate inflammatory cytokines, tumor necrosis factor alpha (TNFα), IL-1β, or IL-6 as possible synergistic interventions. Antibody depletions of each of these cytokines enhanced survival in mice treated with IL-12 virotherapy and helped to overcome equilibrium in some tumors. Single-cell RNA-sequencing demonstrated that blockade of inflammatory cytokines resulted in downregulation of overlapping inflammatory pathways in macrophages, shifting immune equilibrium towards tumor clearance, and raising the possibility that TNFα blockade could synergize with existing cancer immunotherapies.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9836301","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 systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses.","authors":"Paul R Buckley, Chloe H Lee, Agne Antanaviciute, Alison Simmons, Hashem Koohy","doi":"10.1093/immadv/ltad005","DOIUrl":"10.1093/immadv/ltad005","url":null,"abstract":"<p><p>T cell recognition of SARS-CoV-2 antigens after vaccination and/or natural infection has played a central role in resolving SARS-CoV-2 infections and generating adaptive immune memory. However, the clinical impact of SARS-CoV-2-specific T cell responses is variable and the mechanisms underlying T cell interaction with target antigens are not fully understood. This is especially true given the virus' rapid evolution, which leads to new variants with immune escape capacity. In this study, we used the Omicron variant as a model organism and took a systems approach to evaluate the impact of mutations on CD8+ T cell immunogenicity. We computed an immunogenicity potential score for each SARS-CoV-2 peptide antigen from the ancestral strain and Omicron, capturing both antigen presentation and T cell recognition probabilities. By comparing ancestral vs. Omicron immunogenicity scores, we reveal a divergent and heterogeneous landscape of impact for CD8+ T cell recognition of mutated targets in Omicron variants. While T cell recognition of Omicron peptides is broadly preserved, we observed mutated peptides with deteriorated immunogenicity that may assist breakthrough infection in some individuals. We then combined our scoring scheme with an <i>in silico</i> mutagenesis, to characterise the position- and residue-specific theoretical mutational impact on immunogenicity. While we predict many escape trajectories from the theoretical landscape of substitutions, our study suggests that Omicron mutations in T cell epitopes did not develop under cell-mediated pressure. Our study provides a generalisable platform for fostering a deeper understanding of existing and novel variant impact on antigen-specific vaccine- and/or infection-induced T cell immunity.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9386244","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":"Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.","authors":"Natalie M Edner, Elisavet Ntavli, Lina Petersone, Chun Jing Wang, Astrid Fabri, Alexandros Kogimtzis, Vitalijs Ovcinnikovs, Ellen M Ross, Frank Heuts, Yassin Elfaki, Luke P Houghton, Toby Talbot, Amna Sheri, Alexandra Pender, David Chao, Lucy S K Walker","doi":"10.1093/immadv/ltad001","DOIUrl":"10.1093/immadv/ltad001","url":null,"abstract":"<p><p>Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10773190","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 blood persistence and expansion of transferred non-genetically modified Natural Killer cells might not be necessary for clinical activity.","authors":"Lucia Silla","doi":"10.1093/immadv/ltac024","DOIUrl":"https://doi.org/10.1093/immadv/ltac024","url":null,"abstract":"<p><p>Natural killer (NK) cells are innate lymphocytes that react without previous exposition to virus infected or malignant cells and stimulate adaptive immune response to build a long-lasting immunity against it. To that end, tissue resident NK cells are predominantly regulatory as opposed to cytotoxic. In the hematopoietic stem cell transplant (HSCT) setting, which curative potential relies on the graft versus leukemia effect, NK cells are known to play a significant role. This knowledge has paved the way to the active investigation on its anti-tumor effect outside the stem cell transplant scenario. Based on the relevant literature on the adoptive transfer of non-genetically modified NK cells for the treatment of relapsed/refractory acute leukemia and on our own experience, we discuss the role of donor cell peripheral blood persistence and expansion and its lack of correlation with anti-leukemia activity.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9320580","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":"Treg-based immunotherapy for antigen-specific immune suppression and stable tolerance induction: a perspective.","authors":"Shimon Sakaguchi,&nbsp;Ryoji Kawakami,&nbsp;Norihisa Mikami","doi":"10.1093/immadv/ltad007","DOIUrl":"https://doi.org/10.1093/immadv/ltad007","url":null,"abstract":"<p><p>FoxP3-expressing regulatory T cells (Tregs), whether naturally generated in the immune system or unnaturally induced from conventional T cells (Tconvs) in the laboratory, have much therapeutic value in treating immunological diseases and establishing transplantation tolerance. Natural Tregs (nTregs) can be selectively expanded <i>in vivo</i> by administration of low-dose IL-2 or IL-2 muteins for immune suppression. For adoptive Treg cell therapy, nTregs can be expanded <i>in vitro</i> by strong antigenic stimulation in the presence of IL-2. Synthetic receptors such as CAR can be expressed in nTregs to equip them with a particular target specificity for suppression. In addition, antigen-specific Tconvs can be converted <i>in vitro</i> to functionally stable Treg-like cells by a combination of antigenic stimulation, FoxP3 induction, and establishment of the Treg-type epigenome. This review discusses current and prospective strategies for Treg-based immune suppression and the issues to be resolved for achieving stable antigen-specific immune suppression and tolerance induction in the clinic by targeting Tregs.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0d/65/ltad007.PMC10309084.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10123148","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":"Lytic efficiency of immunosuppressive drug-resistant armoured T cells against circulating HBV-related HCC in whole blood.","authors":"Meiyin Lin,&nbsp;Sebastian Chakrit Bhakdi,&nbsp;Damien Tan,&nbsp;Joycelyn Jie Xin Lee,&nbsp;David Wai Meng Tai,&nbsp;Andrea Pavesi,&nbsp;Lu-En Wai,&nbsp;Tina Wang,&nbsp;Antonio Bertoletti,&nbsp;Anthony Tanoto Tan","doi":"10.1093/immadv/ltad015","DOIUrl":"https://doi.org/10.1093/immadv/ltad015","url":null,"abstract":"<p><p>Recurrence of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) after liver transplant (LT) is mediated by circulating tumour cells (CTCs) and exacerbated by the immunosuppressants required to prevent graft rejection. To circumvent the effects of immunosuppressants, we developed immunosuppressive drug-resistant armoured HBV-specific T-cell receptor-redirected T cells (IDRA HBV-TCR). However, their ability to eliminate HBV-HCC circulating in the whole blood has never been tested, and whether their lytic efficacy is compatible with the number of adoptively transferred T cells <i>in vivo</i> has never been measured. Hence, we developed a microscopy-based assay to quantify CTCs in whole blood. The assay was then used to quantify the efficacy of IDRA HBV-TCRs to lyse free-floating HBV-HCC cells in the presence of Tacrolimus and Mycophenolate Mofetil (MMF). We demonstrated that a panel of antibodies (AFP, GPC3, Vimentin, pan-Cytokeratin, and CD45) specific for HCC tumour antigens and immune cells can effectively differentiate HCC-CTCs in whole blood. Through dose-titration experiments, we observed that in the presence of immunosuppressive drugs, a minimum of 20 000 IDRA HBV-TCR T cells/ml of whole blood is necessary to lyse ~63.5% of free-floating HBV-HCC cells within 16 hours. In conclusion, IDRA HBV-TCR T cells can lyse free-floating HBV-HCC cells in whole blood in the presence of Tacrolimus and MMF. The quantity of IDRA-HBV TCR T cells required can be achieved by the adoptive transfer of 5 × 10⁶ IDRA-HBV TCR-T cells/kg, supporting the utilisation of IDRA HBV-TCR T cells to eliminate CTCs as prophylaxis against recurrence after LT.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/19/10/ltad015.PMC10460197.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10109074","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":"Correction to: Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor.","authors":"","doi":"10.1093/immadv/ltad002","DOIUrl":"https://doi.org/10.1093/immadv/ltad002","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1093/immadv/ltac019.].</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9938635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10826769","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":"TIGIT-based immunotherapeutics in lung cancer.","authors":"Akshay J Patel,&nbsp;Gary W Middleton","doi":"10.1093/immadv/ltad009","DOIUrl":"https://doi.org/10.1093/immadv/ltad009","url":null,"abstract":"<p><p>In this review, we explore the biology of the TIGIT checkpoint and its potential as a therapeutic target in lung cancer. We briefly review a highly selected set of clinical trials that have reported or are currently recruiting in non-small cell and small cell lung cancer, a disease transformed by the advent of PD-1/PD-L1 checkpoint blockade immunotherapy. We explore the murine data underlying TIGIT blockade and further explore the reliance of effective anti-TIGIT therapy on DNAM-1(CD226)-positive activated effector CD8+ T cells. The synergism with anti-PD-1 therapy is also explored. Future directions in the realm of overcoming resistance to checkpoint blockade and extending the repertoire of other checkpoints are also briefly explored.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9648653","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":"Correction to: Advancement of antigen-specific immunotherapy: knowledge transfer between allergy and autoimmunity.","authors":"","doi":"10.1093/immadv/ltad004","DOIUrl":"https://doi.org/10.1093/immadv/ltad004","url":null,"abstract":"[This corrects the article DOI: 10.1093/immadv/ltab009.].","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/40/15/ltad004.PMC10374272.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10255637","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}