Immunotherapy advances最新文献

{"title":"Pharmacokinetics of hyaluronidase-facilitated subcutaneous immunoglobulin 10% in pediatric patients with primary immunodeficiency disease.","authors":"Zhaoyang Li, Yang Teng, Sharon Russo-Schwarzbaum, Barbara McCoy","doi":"10.1093/immadv/ltag003","DOIUrl":"https://doi.org/10.1093/immadv/ltag003","url":null,"abstract":"<p><strong>Introduction: </strong>Hyaluronidase-facilitated subcutaneous immunoglobulin 10% (fSCIG 10%) is a unique and effective treatment for primary immunodeficiency disease (PID), allowing for less frequent administration than conventional subcutaneous immunoglobulin therapies.</p><p><strong>Methods: </strong>The pharmacokinetics (PK) of fSCIG 10% in pediatric patients (aged 2 to <16 years at screening) with PID was assessed in a prospective, phase 3, open-label, multicenter, clinical trial conducted in the USA. Patients previously treated with intravenous or conventional subcutaneous immunoglobulin therapy (consistent dose for ≥3 months) received fSCIG 10% via a dose ramp-up schedule for ≤6 weeks (Epoch 1), then at full target dose every 3-4 weeks for ≤3 years (Epoch 2). Serum total immunoglobulin G (IgG) trough levels were reported throughout Epoch 2 across pediatric age groups (2 to <6, 6 to <12, and 12 to ≤16 years); serial PK were characterized at the Month 6 infusion. In total, 44 patients (mean age: 9.0 years; 59% male and 91% White) were eligible for the study.</p><p><strong>Results: </strong>Mean total IgG trough levels during Epoch 2 were similar across age groups. Geometric mean area under the IgG concentration-time curve per week ranged from 63.4 to 76.8 g·day/L, and body weight-adjusted apparent clearance ranged from 1.5 to 1.9 ml/day/kg.</p><p><strong>Conclusion: </strong>This study showed that serum total IgG trough levels were effectively maintained in pediatric patients with PID treated with fSCIG 10%, regardless of age. The dosing strategy for pediatric patients should be informed by assessing individual IgG levels and clinical status as for adults.</p><p><strong>Clinical trials registration: </strong>The study is registered with the ClinicalTrials.gov registry at https://clinicaltrials.gov/ct2/study/NCT03277313 (ClinicalTrials.gov Identifier: NCT03277313).</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag003"},"PeriodicalIF":4.9,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13049483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625079","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":"Chimeric CD3ζ chains containing CD28 signalling motifs enhance antigen-specific IL-2 production and expansion of human TCR-engineered T cells <i>in vitro</i>.","authors":"Samuel J Burgess, Hans J Stauss, Emma C Morris","doi":"10.1093/immadv/ltaf038","DOIUrl":"https://doi.org/10.1093/immadv/ltaf038","url":null,"abstract":"<p><p>Gene-engineered T-cell products have been developed for immunotherapy to treat cancers, with great success observed in haematological malignancies but limited efficacy in treating solid cancers. TCR-engineered T cells utilize transferred TCRs targeting tumour-associated and cancer-specific peptides presented by MHC molecules. The CD3ζ chains are part of the TCR-CD3 complex expressed by T cells and mediate signal transduction when the TCR binds to MHC-presented peptides. In this study, we explored whether co-stimulation domains, that were effective in improving the function of T cells engineered with chimeric antigen receptors (CARs), can be exploited to improve the functionality of TCR-engineered T cells. We inserted the signalling domains of CD28 or 4-1BB at the membrane proximal or the membrane distal position of the intracellular tail of CD3ζ and engineered human T cells to express a specific TCR in combination with either modified CD3ζ or unmodified control. Antigen-specific <i>in vitro</i> stimulation assays revealed that T cells expressing CD3ζ constructs with CD28 signal domains displayed enhanced peptide-specific IL-2 production and, following repeated antigen stimulation, expanded to substantially greater numbers than T cells expressing unmodified CD3ζ. Importantly, greater expansion seen with the CD28-containing ζ did not result in any reduction of effector function as assessed by peptide-specific cytotoxicity and cytokine production. The data indicate that modification of the CD3ζ chain with a CD28 signal motif provides an opportunity to improve antigen-specific expansion and effector function of TCR-engineered T cells by combining signal 1 and co-stimulatory signal 2 in one molecular TCR-CD3 complex.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltaf038"},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13042253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610861","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":"Overall survival by baseline and on-treatment systemic immune-inflammation index in patients with advanced cancer receiving immune checkpoint inhibitors: a large single-centre cohort study.","authors":"Oliver John Kennedy, Rebecca Lee, Fiona Blackhall, Ananya Choudhury, Robert Metcalf, Tom Waddell, Paul Lorigan","doi":"10.1093/immadv/ltaf031","DOIUrl":"https://doi.org/10.1093/immadv/ltaf031","url":null,"abstract":"<p><p>The Systemic Immune-Inflammation Index (SIII; neutrophils/lymphocytes × platelets) is a low-cost biomarker proposed to predict outcomes with immune checkpoint inhibitors (ICIs). This study evaluated associations of baseline and early on-treatment changes in SIII with overall survival (OS) for common ICI regimens. Patients with advanced cancer treated with ICIs at a UK centre were categorized by baseline SIII (above vs. below the median) and by changes at 3-6 weeks (increase/decrease). OS was analysed using Kaplan-Meier estimates. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable Cox regression. Among 2578 patients included, 1514 deaths occurred over a median follow-up of 2.6 years. Common regimens included pembrolizumab or atezolizumab with (15.9%) or without chemotherapy (13.9%) for NSCLC, and nivolumab plus ipilimumab for melanoma (12.6%). Lower baseline SIII was associated with improved OS (28.1 vs. 11.1 months; aHR 0.56, 0.50-0.62), with a weaker association observed in those receiving ICI-targeted therapy combinations. An on-treatment increase in SIII was linked to reduced OS (16.8 vs. 21.5 months; aHR 1.33, 1.18-1.49). Patients with low baseline SIII and an on-treatment decline had the longest OS (33.2 months), whereas those with high baseline SIII and an on-treatment increase had the shortest (8.2 months; aHR 2.88, 2.41-3.44; interaction between baseline and on-treatment SIII <i>P</i> < 0.001). SIII is a low-cost, readily available biomarker. Both baseline SIII levels and on-treatment changes in SIII are significantly associated with OS. SIII may help identify patients who could benefit from closer monitoring or treatment adjustments.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltaf031"},"PeriodicalIF":4.9,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13023032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576826","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":"PD-1 inhibitor-induced rheumatic, endocrine, and sarcoidosis-like immune-related adverse events in metastatic melanoma are associated with improved survival and lower corticosteroid exposure.","authors":"Maria Lindén, Hifaa Al Remawi, Anna Fager, Levent M Akyürek, Anna Rudin, Lars Ny, Sara Bjursten, Ankur Pandita, Max Levin","doi":"10.1093/immadv/ltag004","DOIUrl":"10.1093/immadv/ltag004","url":null,"abstract":"<p><strong>Introduction: </strong>Programmed cell death protein 1 (PD-1) inhibitors improve survival in advanced melanoma but can induce immune-related adverse events (irAEs). IrAEs have been linked to better outcomes. However, it remains unclear whether specific irAE types drive this effect and how corticosteroid treatment of irAEs influences survival.</p><p><strong>Materials and methods: </strong>A seven-year retrospective cohort study of 301 patients with advanced cutaneous melanoma treated with single-agent PD-1 inhibition at Sahlgrenska University Hospital. irAEs were identified using CTCAE v4.0/v5.0, and irAEs requiring systemic corticosteroids or endocrine replacement therapy were included. Corticosteroid therapy was categorized as low dose (≤0.5 mg/kg prednisolone equivalent) or high dose (>0.5 mg/kg). Overall survival (OS) was assessed using Kaplan-Meier and Cox models, including time-dependent analyses to address immortal time bias.</p><p><strong>Results: </strong>Patients with irAE (109 of 301 patients) had longer OS than those without irAEs. Of the eight most common irAEs, four were associated with superior survival, one was borderline significant, and three were non-significant. Rheumatic irAEs and late-onset thyroid irAEs remained associated with improved OS after adjustment for negative prognostic factors and immoral time bias. Colitis irAE were borderline significant in univariate analysis. Sarcoidosis-like and hypophysitis irAEs were rare but conferred excellent outcomes. Hepatitis, nephritis, and pneumonitis were not associated with better survival. Most survival-associated irAEs were treated with a lower start dose of corticosteroids but duration and time to onset were similar to non-survival-associated irAEs.</p><p><strong>Conclusion: </strong>Rheumatic, endocrine, and sarcoidosis-like irAEs are markers of superior survival and suggest that lower initial corticosteroid doses may preserve PD-1 inhibitor efficacy.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag004"},"PeriodicalIF":4.9,"publicationDate":"2026-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12965203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379852","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":"Neuraminidase A controls pneumococcal recognition and fate: deficiency enhances immune sensing and intracellular survival, while treatment promotes phagocytic clearance.","authors":"Kristine Farmen, Georgia Yfanti, Fabienne Geers, Johanna Hollenbeck, Miguel Tofiño Vian, Thomas P Kohler, Sven Hammerschmidt, Federico Iovino","doi":"10.1093/immadv/ltag002","DOIUrl":"https://doi.org/10.1093/immadv/ltag002","url":null,"abstract":"<p><p><i>Streptococcus pneumoniae</i> (pneumococcus) is a leading cause of bacterial meningitis worldwide and is associated with cerebrovascular complications and long-term neurological sequelae. These outcomes are largely driven by an excessive yet ineffective neuroinflammatory response. Although pneumococci express multiple virulence factors that enable immune evasion, how these factors modulate phagocytic responses in the central nervous system remains unclear. Here, we identify neuraminidase A (NanA) as a critical regulator of phagocytic activation in microglia and macrophages. Using murine and human microglia and RAW 264.7 macrophages, we show that NanA deficiency increases bacterial adhesion, indicating enhanced immune recognition, but paradoxically promotes intracellular bacterial survival. Despite elevated expression of the phagocytic marker CD68, microglia infected with NanA-deficient pneumococci fail to efficiently eliminate intracellular bacteria, as evidenced by unchanged levels of the lysosomal enzyme cathepsin 3 compared with NanA-expressing strains. Treatment with recombinant NanA restored phagocytic activation and significantly enhanced clearance of NanA-deficient bacteria. This effect was dependent on NanA sialidase activity, as enzymatically inactive NanA failed to restore immune sensing. Notably, this immunomodulatory function was specific to the secreted form of NanA produced by the invasive TIGR4 strain and was not observed with membrane-anchored NanA from D39-derived mutants. Together, these findings reveal an unexpected role for NanA in promoting effective innate immune activation and bacterial clearance, highlighting its potential as a therapeutic target for pneumococcal meningitis and invasive pneumococcal disease.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag002"},"PeriodicalIF":4.9,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13001807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147500857","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":"Comprehensive spatial and immune profiling of metastatic mismatch repair-deficient colorectal cancer reveals response to immunotherapy.","authors":"Ilkyu Park, Hari Kang, Se-Hee Kim, YunJae Jung, Won-Suk Lee","doi":"10.1093/immadv/ltag001","DOIUrl":"10.1093/immadv/ltag001","url":null,"abstract":"<p><strong>Introduction: </strong>Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit variable clinical responses to immune checkpoint inhibitors (ICIs) despite their high immunogenicity.</p><p><strong>Methods: </strong>To investigate the molecular and spatial determinants of this heterogeneity, we analyzed five metastatic sites (colon, liver, peritoneum, left ovary, and right ovary) from a dMMR CRC patient treated with pembrolizumab using bulk and single-cell RNA sequencing combined with multiplex immunohistochemistry.</p><p><strong>Results: </strong>Responsive lesions were characterized by enriched cytotoxic and interferon-γ signatures, greater CD8⁺ T-cell infiltration, and close spatial proximity between programmed death-ligand 1(PD-L1)⁺ tumor cells and M1-like macrophages. In contrast, resistant lesions demonstrated reduced effector cell presence and were enriched in immunosuppressive programs, including SPP1⁺ and CD163⁺ macrophages, noncanonical WNT5A/B signaling, and TGF-β-mediated matrix remodeling.</p><p><strong>Conclusion: </strong>Collectively, these findings highlight the importance of spatial immune architecture and macrophage polarization in shaping ICI responses in dMMR CRC and underscore the need for spatial profiling to guide immunotherapy strategies in metastatic disease.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltag001"},"PeriodicalIF":4.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12898929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146203547","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":"Turning the tide: harnessing vaccines and viruses to fight cancer.","authors":"Callum Blee, Munitta Muthana, Greg Wells, Sarah Danson","doi":"10.1093/immadv/ltaf033","DOIUrl":"10.1093/immadv/ltaf033","url":null,"abstract":"<p><p>Cancer vaccines and oncolytic viruses (OVs) represent promising immunotherapeutic strategies, harnessing adaptive and innate immune responses for targeted tumour eradication. Cancer vaccines aim to induce tumour-specific cytotoxic T lymphocytes (CTLs) through antigen presentation, while OVs mediate direct tumour lysis and stimulate immunogenic cell death, enhancing anti-tumour immunity. Despite keen interest, with over 350 clinical trials initiated since 2020, challenges persist in carrying the success seen in a pre-clinical setting to a clinical one. Advancements in preclinical modelling are essential for bridging the gap between <i>in vitro</i> findings and clinical efficacy. Traditional two-dimensional (2D) cultures, although cost-effective and reproducible, fail to recapitulate the complexity of the tumour microenvironment (TME). Three-dimensional (3D) models including spheroids, organoids, tumour-on-a-chip, and bioprinting offer improved architectural and physiological relevance, allowing for the assessment of immune cell infiltration and viral spread. <i>In silico</i> models further complement these systems by enabling high-throughput neoantigen prediction and therapy simulation. <i>In vivo</i> models such as patient-derived xenografts (PDXs), genetically engineered mouse models (GEMMs), and syngeneic models provide critical insights into tumour-immune dynamics and therapeutic efficacy in a systemic context at a whole organism level. Integrating 2D, 3D, <i>in silico</i>, and <i>in vivo</i> platforms provides a versatile basis for the preclinical evaluation of cancer vaccines and OVs. This multidisciplinary approach is vital to advancing personalized immunotherapies, improving biomarker development, and accelerating the translation of novel treatments.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltaf033"},"PeriodicalIF":4.9,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145829188","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 intratumoral regulatory T cells by CD137 aptamer-shRNA chimeras.","authors":"Kang Yi Lee, Yu Mei, Haiyan Liu, Herbert Schwarz","doi":"10.1093/immadv/ltaf037","DOIUrl":"10.1093/immadv/ltaf037","url":null,"abstract":"<p><strong>Introduction: </strong>The cytokine CD137 (TNFRSF9, 4-1BB) is best known as a T cell costimulatory molecule. However, CD137 is also part of a negative feedback mechanism that limits T cell activation, and that is employed by regulatory T cells (Tregs) to prevent an overstimulation of T cells and subsequent autoimmune damage. CD137 has been identified as the gene that most significantly distinguishes intra- from extratumoral Tregs. CD137⁺ Tregs are more immunosuppressive than CD137^- ones, and CD137 levels on intratumoral Tregs correlate with a poor prognosis for cancer patients. In addition, CD137 is also ectopically expressed on several types of malignant cells that usurp this physiological feedback mechanism to evade immune surveillance. This suggests CD137 as a target for eliminating or changing intratumoral Tregs. Here we demonstrate that a murine CD137-specific aptamer can bind to CD137 on malignant cells and T cells and be internalized.</p><p><strong>Methods and results: </strong>We fused the aptamer to short hairpin (sh) RNAs that are specific for Enhancer of zeste homolog 2 (EzH2) or neuropilin-1 (Nrp1), and demonstrated their uptake into CD137⁺ malignant cells and Tregs, and the subsequent downregulation or EzH2 and Nrp1.</p><p><strong>Conclusion: </strong>This study confirms CD137 as a target for tumor immunotherapy and introduces CD137 aptamer-shRNA chimeras as novel tools to be evaluated for their usefulness in cancer treatment.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltaf037"},"PeriodicalIF":4.9,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12822494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146031906","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":"Preclinical assessment of MAGE-A4-specific TCR-NK cells against solid tumors.","authors":"Margherita Boieri, Justyna Kmiecik, Maja Sandve, Zara Hannoun, Martha Eimstad Haugstøyl, Inês Cardoso, Sarah Vollmers, Anja Ruppelt Oldenburg, Luz Maria Mora-Velandia, Camilla Sletten, Giulia Malachin, Artur Cieslar-Pobuda, Liliane Christ, Pimthanya Wanichawan, Dennis Clement, Michelle Lu Saetersmoen, Frida Loe Haugen, Amanda Malene Ruud, Julia Mayumi Ino, Pranav Oberoi, Anders Holm, Emilie Gauthy, Namir Jafar Hassan, Sylvie Pollmann, Luise Ullrike Weigand","doi":"10.1093/immadv/ltaf036","DOIUrl":"10.1093/immadv/ltaf036","url":null,"abstract":"<p><p>T cell (Tc) receptor (TCR)-based cell therapies have shown clinical efficacy across many cancer types and represent an attractive strategy for targeting solid tumors. However, the immunosuppressive tumor microenvironment, downregulation of target antigen and HLA, and the need for an autologous source limit the efficacy and the accessibility of TCR-Tc therapies. Early clinical trials have shown the potential of natural killer cells (NKs) as a therapy to treat hematological and solid cancers. Allogeneic NKs, engineered to express a TCR, represent a novel and promising strategy overcoming the limitations of T and NKs therapies. Here we describe the development of a product consisting of NKs engineered to express an affinity-enhanced TCR recognizing MAGE-A4, a clinically validated tumor antigen expressed across several solid tumors. The introduction of the TCR does not disrupt the innate functionality of NKs and adds TCR-mediated specific killing of antigen-positive targets. In fact, the innate potential of the NKs appears to be enhanced by the presence of the CD3-TCR complex, creating NKs with increased potency. TCR-NKs are faster, more potent than TCR-Tc and retain killing activity in the absence of TCR target antigen thus potentially overcoming tumor heterogeneity and/or antigen loss. Lastly, TCR-NKs are not activated when co-cultured with normal cells, displaying a safe profile. Combining the innate cytotoxicity of NKs with MAGE-A4-specific targeting of an affinity-enhanced TCR, results in a potent and safe cellular product representing a promising and novel therapeutic off-the-shelf paradigm for the treatment of many solid cancers.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"6 1","pages":"ltaf036"},"PeriodicalIF":4.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12755921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890660","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 1 experimental medicine study of anti-CD3 monoclonal antibody in rheumatoid arthritis.","authors":"Catherine A Lawson, Rachel Harry, Bridget Griffiths, Geoff Hale, Herman Waldmann, John D Isaacs","doi":"10.1093/immadv/ltaf034","DOIUrl":"10.1093/immadv/ltaf034","url":null,"abstract":"<p><strong>Introduction: </strong>An Fc-mutated chimeric aglycosyl anti-CD3 monoclonal antibody (mAb), otelixizumab, has been used successfully to treat renal transplant rejection and type 1 diabetes, with reduced toxicity compared with traditional anti-CD3 therapies such as OKT3. The aim of this study was to seek preliminary safety data for otelixizumab in rheumatoid arthritis (RA).</p><p><strong>Methods: </strong>A small Phase 1 experimental medicine study was performed in six participants with RA. The primary outcome measure was safety, with a focus on first-dose cytokine release reactions and extent of CD3⁺ lymphopenia. Cytokine release was quantified using ELISA, and lymphocyte subsets by flow cytometry. <i>In vitro</i> whole blood assays were used to interrogate the mechanisms underlying the first-dose cytokine release reaction. Clinical progress following therapy was monitored as an exploratory outcome.</p><p><strong>Results: </strong>All participants experienced a moderate first-dose cytokine release reaction. There was transient lymphopenia but no T-cell depletion, and a temporary CD8⁺ T-cell lymphocytosis occurred in all participants. In those who completed therapy, a sustained reduction in CRP following treatment was noted. In an <i>in vitro</i> whole blood assay, designed to mirror <i>in vivo</i> cytokine release, there was a trend for reduced cytokine production in seropositive RA compared with seronegative RA, psoriatic arthritis, or healthy controls.</p><p><strong>Conclusions: </strong>At the dosing regimen used, otelixizumab was associated with an unexpected and significant first-dose reaction in participants with RA.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltaf034"},"PeriodicalIF":4.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12724074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145829192","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}