Immunotherapy advances最新文献

Introduction: B cells have a central regulatory role in various diseases. While macrophages are found in the disease microenvironment and interact with tissue and diverse immune cells, their relationship with B cells remains poorly explored.

Methods: This study used an asthma animal model and macrophage depletion and demonstrated a significant exacerbation of asthma symptoms upon macrophage removal, coupled with a marked reduction in IL-10⁺ B-cell expression.

Results: Further analysis revealed that the macrophages interacting with IL-10⁺ B cells in the asthma microenvironment were of the M2 subtype. Furthermore, our sequencing data indicated a potential mechanism wherein M2 macrophages promote IL-10⁺ B-cell activity through the TGF-β pathway and oxidative phosphorylation pathways.

Conclusion: These findings suggest that M2 macrophages modulate IL-10⁺ B cells, ultimately mitigating asthma symptoms in mouse models.

Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer therapy and improved patient outcomes in a range of cancers. ICIs enhance anti-tumour immunity by targeting the inhibitory checkpoint receptors CTLA-4, PD-1, PD-L1, and LAG-3. Despite their success, efficacy, and tolerance vary between patients, raising new challenges to improve these therapies. These could be addressed by the identification of robust biomarkers to predict patient outcome and a more complete understanding of how ICIs affect and are affected by the tumour microenvironment (TME). Despite being the first ICIs to be introduced, anti-CTLA-4 antibodies have underperformed compared with antibodies that target the PD-1/PDL-1 axis. This is due to the complexity regarding their precise mechanism of action, with two possible routes to efficacy identified. The first is a direct enhancement of effector T-cell responses through simple blockade of CTLA-4-'releasing the brakes', while the second requires prior elimination of regulatory T cells (T_REG) to allow emergence of T-cell-mediated destruction of tumour cells. We examine evidence indicating both mechanisms exist but offer different antagonistic characteristics. Further, we investigate the potential of the soluble isoform of CTLA-4, sCTLA-4, as a confounding factor for current therapies, but also as a therapeutic for delivering antigen-specific anti-tumour immunity.

This study aims to develop a human lung immune challenge model using inhaled Resiquimod (R848), a Toll-like receptor 7/8 agonist, to investigate inflammatory mechanisms involved in the human respiratory mucosa in health and disease. This approach seeks to induce innate immune anti-viral responses in the lungs and blood, with a suitable dose of inhaled R848 that is clinically tolerable. The study will include healthy volunteers and individuals with asthma. The primary outcome is a change in CXCL10, a biomarker representative of anti-viral responses, at 24 hours post-exposure. Secondary outcomes include changes in lung function, physiological parameters, and inflammatory markers, including C-reactive protein and eosinophil counts. This trial involves a single ascending dose, randomized, single-blind, placebo-controlled design. Participants will receive R848 via nebulization in escalating doses from 0.1 to 100 µg/ml or saline placebo. Safety assessments include spirometry, vital signs, and blood samples to monitor systemic and lung-specific immune responses. The study will contribute to understanding immune pathways in asthma and provide a platform for testing novel anti-inflammatory therapeutics. The protocol has been approved by relevant ethics committees and will be disseminated via peer-reviewed publications and open-access data repositories.

The HIC-Vac network is a unique association of researchers focussed on the development and use of human infection challenge (HIC, otherwise known as controlled human infection models or CHIM) studies for vaccine and therapeutic development, particularly for pathogens of high global impact. The fifth annual meeting of the HIC-Vac network was held on 1-3 November 2023. The theme of the meeting was capacity-building in endemic settings particularly in low- and middle-income countries (LMIC), where pathogens cause the greatest morbidity and mortality. In this report we highlight the strengths and limitations of HIC and expansion of such studies into endemic settings, noting that immune responses and vaccine efficacy differ across diverse settings and populations. The consensus was that HIC studies must not be restricted to high income settings if they are to be relevant to LMIC populations. This report summarizes the work presented at the HIC-Vac annual meeting, highlighting current and future challenge models, challenge agent manufacture, public engagement, ethics, and industry perspectives.

Introduction: Antigen processing and presentation are vital processes of the adaptive immunity. These processes involve a series of intracellular and extracellular events, including the enzymology within cells during antigen processing, the loading and presentation of antigenic peptides on major histocompatibility complexes, the recruitment of T cells, their interaction with antigen-presenting cells, and the expression of adhesion, co-stimulatory and co-inhibitory molecules at the T cell immunological synapse. These events collectively fine-tune and sustain antigen recognition and T cell function. Dysregulation of this machinery can profoundly impact the efficacy of cancer immunotherapy. Imaging technologies have emerged as powerful tools for elucidating the mechanisms underlying antigen processing and presentation. By providing complementary perspectives into the cellular and molecular interactions at play, imaging has significantly enhanced our understanding of these complex immunological events in cancer. Such insights can improve the monitoring of immunotherapy responses, facilitate the identification of effective treatments, and aid in predicting patient outcomes.

Methods: This review explores the role of imaging in studying antigen processing and presentation in the context of cancer.

Conclusion: It highlights key considerations for developing imaging tools and biomarkers to detect components of these pathways. Additionally, it examines the strengths and limitations of various imaging approaches and discusses their potential for clinical translation.

In the past decade, T-cell-based immunotherapies have grown to become some of the most promising treatments for cancer. Following the success of immune checkpoint inhibitors, other T-cell-based therapies emerged including CAR-T cells and bispecific T-cell engagers (BiTEs). BiTEs have the unique ability to crosslink T cells and tumor cells independently of major histocompatibility complex (MHC) restriction. They do not rely on TCR specificity or the CD4+/CD8+ costimulatory molecules, overcoming tumor MHC downregulation and low-affinity TCR binding. However, like many other immunotherapies, BiTEs have shown limited success beyond the treatment of hematological malignancies. BiTEs for the treatment of solid tumors still face challenges. Studies in gastrointestinal tumors have revealed Fc toxicity, short half-lives, and immunotoxicity, leading to Fc-silenced half-life extended BiTEs with humanized single-chain variable fragments. Studies in prostate tumors, lung tumors, and malignant gliomas have identified promising targets in PSMA, DLL3, and EGFRvIII, respectively, but also highlighted the problems of on-target off-tumor and BiTE-specific toxicities and inaccessible or immunosuppressive tumor microenvironments. Ongoing research to overcome these limitations remains an interesting field to follow, as BiTEs have the potential to be a powerful tool, especially when used in combination with other immunotherapies.

Purpose: Despite the proven clinical benefits of cytokine therapy in cancer treatment, systemic administration of cytokines such as IL-12 is constrained by dose-limiting toxicities and short half-lives. To address these challenges, we explored a localized cytokine delivery strategy using engineered neoantigen-reactive T (NRT) cells as carriers in a murine model of osteosarcoma.

Materials and methods: We used a neoantigen from K7M2 osteosarcoma cells to retrovirally transduce NRT cells to express an inducible form of IL-12. We evaluated the engineered NRT cells' antitumor activity and the production of IL-12 and IFN-γ upon in vitro co-culture with tumor cells. We systemically administered NRT-IL-12 cells in a mouse model of osteosarcoma to assess their impact on tumor growth and survival.

Results: In vitro assays demonstrated that the engineered NRT cells exhibited enhanced antitumor activity and produced elevated levels of IL-12 and IFN-γ. In the mouse model of osteosarcoma, systemic administration of NRT-IL-12 cells resulted in a significant reduction in tumor growth and an increase in survival rates compared to the administration of control NRT cells. Further analysis revealed that NRT-IL-12 cells induced a profound increase in CD8+ T-cell infiltration and a decrease in Treg cells within the tumor microenvironment.

Conclusion: Our study presents a novel and efficacious strategy for osteosarcoma immunotherapy by harnessing NRT cells as targeted cytokine delivery vehicles.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, Pfizer/BioNTech BNT162b2, and Moderna mRNA-1273 vaccines were central to the global pandemic control measures.

Methods: Here, we conducted a systematic review and meta-analysis to evaluate their real-world vaccine effectiveness (VE). Our study focussed on those that reported the efficacy of these vaccines against COVID-19 hospitalization. Hospitalization was chosen as the primary outcome as it directly reflects the ability of the vaccine to prevent severe disease. A literature search was undertaken using Medline and Embase on 25 February 2024. From this, 50 studies out of 18,347 articles were included for further analysis.

Results: High VE against hospitalization was reported for both the BNT162b2 and mRNA-1273 COVID-19 vaccines when used either as a primary vaccination series (2-dose) or following an additional booster dose (3-dose). Meta-analysis indicated that the pooled VE estimates for each of these vaccination protocols ranged from 84% to 86%, suggesting strong protectiveness. Our data also imply that booster doses can restore waning effectiveness, with no significant differences observed in VE between the 2-dose and 3-dose protocols. However, subgroup analysis revealed an association between the presence of the Omicron variant and a drop in VE, indicating that future emerging SARS-CoV-2 virus variants could similarly affect VE.

Conclusions: Our review underscores the importance of ongoing research to ensure vaccine strategies remain effective against evolving variants. Our study also identified the need for expanding data collection to include underrepresented populations.

The phosphoinositide-3-kinase (PI3K) pathway function is crucial to the normal development, differentiation, and function of immune cells including B, T, and NK cells. Following the description of two cohorts of patients with an inboirn error of immunity (also known as primary immunodeficiency) with gain-of-function variants in the PIK3CD gene a decade ago, the disease entity activated PI3K delta syndrome (APDS) was named. Since then, many more patients with PIK3CD variants have been described, and loss-of-function variants in PIK3R1 and PTEN have also been linked to APDS. Importantly, the availability of small molecules that inhibit the PI3K pathway has enabled targeted treatment of APDS patients. In this review, we define (i) the PI3K pathway and its role in inborn errors of immunity; (ii) the clinical and immunological presentation of APDS1 (PIK3CD GOF), APDS2 (PIK3R1 LOF), and related disorders; (iii) Diagnostic approaches to identify and functionally validate the genetic causes of disease; (iv) therapeutic interventions to target PI3K hyperactivation; and finally (v) current challenges and future perspectives that require attention for the optimal treatment of patients with APDS and APDS-L diseases.

Background: PRAME (Preferentially expressed Antigen in Melanoma) is a cancer-testis antigen expressed in several tumor indications, representing an attractive anticancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME⁺ tumors could be a novel immunotherapeutic option. We confirm that PRAME protein is expressed in cutaneous melanoma, including rare subtypes with limited treatment options, as well as primary and metastatic lung, breast, endometrial, and ovarian tumors. Furthermore, PRAME is expressed homogeneously across tumors with distinct oncogenic mutations, mutation burden, PD-L1 expression, immune infiltration, and features of immune checkpoint resistance. Immunopeptidomic analysis of primary tumors detected HLA class I-restricted PRAME peptides.

Methods: A TCR recognizing PRAME peptide SLLQHLIGL was engineered to high affinity and fused to a CD3 engaging domain to create a TCRxCD3 bispecific molecule (Immune-mobilizing monoclonal TCR Against Cancer, ImmTAC®) with the ability to redirect polyclonal T cells to efficiently kill PRAME⁺ cells.

Rs: The degree of T cell activation was positively correlated with peptide-HLA abundance, with as few as 10 epitopes per cell sufficient for target cell killing. Impaired ImmTAC®-redirected cytotoxicity of exhausted T cells was rescued using an anti-PD-1 antibody, supporting the use of a combination strategy to treat tumors with active PDL1-PD1 axes.

Conclusions: Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple cancer indications.