Immunotherapy advances最新文献

Introduction: PACIFIC trial demonstrates improved progression-free survival (PFS) and overall survival (OS) in patients with locally advanced non-small-cell lung cancer (NSCLC) treated with platinum-based concurrent chemoradiotherapy (CRT) and adjuvant Durvalumab immunotherapy.

Methods: We retrospectively reviewed 72 consecutive patients with locally advanced NSCLC treated with platinum-based concurrent CRT, who were potentially eligible for adjuvant Durvaluamb treatment (PDL1 ≥1% or inadequate). We analysed PFS, OS, treatment toxicity, and the impact of PDL1 on these outcomes.

Results: The cohort median follow-up was 20 months. Fifty-five patients received adjuvant Durvalumab. The median OS (mOS) has not been reached. OS at 24 months was 67.8% for patients received Durvalumab. The median PFS (mPFS) for patients received Durvalumab was 30 months. PDL1 status (1-49% vs. ≥50%) did not affect outcome in our cohort. Sixteen patients stopped Durvalumab due to immune toxicity. At 24 months, 49% of these patients were still alive versus 76% of the patients who completed 12 months of treatment. The mOS for patients who stopped Durvalumab due to immune toxicity was 16 months, P = .0032. Seventeen patients did not receive adjuvant treatment due to insufficient performance status following CRT and mOS was 6 months.

Conclusions: Our real-world experience demonstrates possibility to achieve similar outcomes to PACIFIC trial. PDL1 status did not affect clinical outcome in our cohort. Patients who stopped adjuvant Durvalumab treatment due to toxicity and those who were not deemed suitable to proceed with adjuvant Durvalumab after CRT, had poorer outcomes. This indicates that careful case selection remains essential.

Introduction: The clinical efficacy of Janus kinase inhibitors (JAKinibs) is highly variable and their safety profiles are poorly understood.

Methods: We established two flow cytometry panels for the assessment of two promising leukocyte biomarkers: signal transducer and activator of transcription (STAT) phosphorylation and cytokine receptor expression. We evaluated the first panel, which assesses phosphorylation levels for STAT1, STAT3, and STAT5 after cytokine stimulation, with or without in vitro pretreatment with JAKinibs, in 10 healthy donors. We then evaluated the second panel, which assesses cytokine receptor expression on T cells and B cells, in five healthy donors.

Results: Stimulation with interleukin (IL)-2 or IL-7 increased STAT5 phosphorylation in T cells but not in B cells or monocytes. IL-6 stimulation induced STAT3 phosphorylation in monocytes and CD4 T cells and, to a lesser extent, in CD8 T cells, but not in B cells. IL-21 stimulation led to STAT3 phosphorylation in T cells and, to a lesser extent, in B cells, but not in monocytes. Interferon-α stimulation increased STAT1 phosphorylation in all cell types. STAT phosphorylation levels were lower after pretreatment with JAKinibs. A dose-response curve was plotted, confirming the correlation between JAKinib concentration and STAT phosphorylation inhibition. The second panel showed that each cell type displayed a distinct pattern of cytokine receptors expression, and that this pattern might be modified by in vitro treatment with JAKinibs.

Conclusion: This preliminary study confirms the utility of flow cytometry for monitoring the biological effects of JAKinibs. Further studies on treated patients are now required to evaluate the clinical value of these two flow cytometry panels.

Tumour-associated macrophages (TAM) are present in the majority of tumours, where they comprise one of the most abundant cell types, influencing tumour progression, metastasis, therapy resistance, and relapse. Hence, there is a great interest in targeting TAMs to improve and complement anti-cancer treatments. However, further studies are needed to validate the potential of exploiting TAM cell surface markers for cancer immunotherapy. Here, we review the function of TAMs, their involvement in tumorigenesis, metastasis, and therapy resistance. Furthermore, we summarize the current landscape of key TAM cell surface receptors that are being investigated as potential targets for cancer immunotherapy, highlighting the promise and challenges associated with these approaches.

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.