Immunotherapy advances最新文献

{"title":"Combination of genetically engineered T cells and immune checkpoint blockade for the treatment of cancer.","authors":"Rafaela Rossetti,&nbsp;Heloísa Brand,&nbsp;Sarah Caroline Gomes Lima,&nbsp;Izadora Peter Furtado,&nbsp;Roberta Maraninchi Silveira,&nbsp;Daianne Maciely Carvalho Fantacini,&nbsp;Dimas Tadeu Covas,&nbsp;Lucas Eduardo Botelho de Souza","doi":"10.1093/immadv/ltac005","DOIUrl":"https://doi.org/10.1093/immadv/ltac005","url":null,"abstract":"<p><p>Immune checkpoint (IC) blockade using monoclonal antibodies is currently one of the most successful immunotherapeutic interventions to treat cancer. By reinvigorating antitumor exhausted T cells, this approach can lead to durable clinical responses. However, the majority of patients either do not respond or present a short-lived response to IC blockade, in part due to a scarcity of tumor-specific T cells within the tumor microenvironment. Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) or engineered T-cell receptors (TCRs) provide the necessary tumor-specific immune cell population to target cancer cells. However, this therapy has been considerably ineffective against solid tumors in part due to IC-mediated immunosuppressive effects within the tumor microenvironment. These limitations could be overcome by associating adoptive cell transfer of genetically engineered T cells and IC blockade. In this comprehensive review, we highlight the strategies and outcomes of preclinical and clinical attempts to disrupt IC signaling in adoptive T-cell transfer against cancer. These strategies include combined administration of genetically engineered T cells and IC inhibitors, engineered T cells with intrinsic modifications to disrupt IC signaling, and the design of CARs against IC molecules. The current landscape indicates that the synergy of the fast-paced refinements of gene-editing technologies and synthetic biology and the increased comprehension of IC signaling will certainly translate into a novel and more effective immunotherapeutic approaches to treat patients with cancer.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltac005"},"PeriodicalIF":0.0,"publicationDate":"2022-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1e/14/ltac005.PMC9327125.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40666623","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":"HBV-HCC treatment with mRNA electroporated HBV-TCR T cells.","authors":"Anthony T Tan,&nbsp;Antonio Bertoletti","doi":"10.1093/immadv/ltab026","DOIUrl":"https://doi.org/10.1093/immadv/ltab026","url":null,"abstract":"<p><p>Hepatocellular carcinoma is a significant global health challenge with steadily increasing incidence in the East Asia region. While both Hepatitis C and B virus infections account for the majority of HCC cases, the advent of potent antivirals against HCV infection has biased the aetiology towards chronic HBV infection that at the moment remains without an effective cure. For this reason, HBV-HCC remains a persistent global problem. Treatment options for intermediate to advanced stages of HBV-HCC remain limited, hence novel therapeutic strategies are required to fulfil this medical need. Following the considerable success of adoptive T-cell immunotherapy against B-cell malignancies, it is conceivable to envision whether the same could be achieved against HBV-HCC. In this review, we describe the development of T-cell therapy strategies for HBV-HCC and discuss the safety and the efficacy of the strategies in terms of the direct killing of tumour cells and the other alterations possibly induced by the action of the T cells.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab026"},"PeriodicalIF":0.0,"publicationDate":"2021-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40666624","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":4.1,"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":"Editor's Note: Relates to: 'Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells'.","authors":"Matthias Eberl,&nbsp;Eric Oldfield,&nbsp;Thomas Herrmann","doi":"10.1093/immadv/ltab023","DOIUrl":"https://doi.org/10.1093/immadv/ltab023","url":null,"abstract":"We would like to alert readers to the recent retraction of one of the papers (Singh et al . [ref. 22]) cited in this review, which advocated the use of IspH inhibitors as ‘immuno-antibiotics’. The authors of the review discuss some of the findings by Singh et al . in the text and make reference to the work in Table 1 and Figure 2. Despite the retraction of this paper from the literature, the Editors at Immunotherapy Advances agree with Eberl et al . that there is a large body of complementary evidence in the literature demonstrating that the MEP pathway is an attractive target for the devel-opment of novel antibiotics and that manipulation of the MEP pathway has a direct effect on anti-microbial γδ T cell responses. As such we are confident that this retraction does not affect the validity of their article.","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab023"},"PeriodicalIF":0.0,"publicationDate":"2021-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40578944","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 phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes.","authors":"Ashish K Marwaha, Samuel Chow, Anne M Pesenacker, Laura Cook, Annika Sun, S Alice Long, Jennie H M Yang, Kirsten A Ward-Hartstonge, Evangelia Williams, Clara Domingo-Vila, Khalif Halani, Kristina M Harris, Timothy I M Tree, Megan K Levings, Thomas Elliott, Rusung Tan, Jan P Dutz","doi":"10.1093/immadv/ltab022","DOIUrl":"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":4.1,"publicationDate":"2021-11-13","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":"Oral tolerance as antigen-specific immunotherapy.","authors":"Natália Pinheiro-Rosa,&nbsp;Lícia Torres,&nbsp;Mariana de Almeida Oliveira,&nbsp;Marcos Felipe Andrade-Oliveira,&nbsp;Mauro Andrade de Freitas Guimarães,&nbsp;Monique Macedo Coelho,&nbsp;Juliana de Lima Alves,&nbsp;Tatiani Uceli Maioli,&nbsp;Ana M Caetano Faria","doi":"10.1093/immadv/ltab017","DOIUrl":"https://doi.org/10.1093/immadv/ltab017","url":null,"abstract":"<p><p>Oral tolerance is a physiological phenomenon described more than a century ago as a suppressive immune response to antigens that gain access to the body by the oral route. It is a robust and long-lasting event with local and systemic effects in which the generation of mucosally induced regulatory T cells (iTreg) plays an essential role. The idea of using oral tolerance to inhibit autoimmune and allergic diseases by oral administration of target antigens was an important development that was successfully tested in 1980s. Since then, several studies have shown that feeding specific antigens can be used to prevent and control chronic inflammatory diseases in both animal models and clinically. Therefore, oral tolerance can be classified as an antigen-specific form of oral immunotherapy (OIT). In the light of novel findings on mechanisms, sites of induction and factors affecting oral tolerance, this review will focus on specific characteristics of oral tolerance induction and how they impact in its therapeutic application.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":" ","pages":"ltab017"},"PeriodicalIF":0.0,"publicationDate":"2021-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40578945","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":4.1,"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}