Immunotherapy advances最新文献

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 in vitro 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. In silico models further complement these systems by enabling high-throughput neoantigen prediction and therapy simulation. In vivo 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, in silico, and in vivo 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.

Introduction: 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.

Methods and results: 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.

Conclusion: 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.

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.

Introduction: 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).

Methods: 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. In vitro 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.

Results: 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 in vitro whole blood assay, designed to mirror in vivo cytokine release, there was a trend for reduced cytokine production in seropositive RA compared with seronegative RA, psoriatic arthritis, or healthy controls.

Conclusions: At the dosing regimen used, otelixizumab was associated with an unexpected and significant first-dose reaction in participants with RA.

The in vivo visualization of inflammatory processes offers not only the possibility of localizing disease but also of monitoring its progression over time. Among available imaging modalities, combined ¹H/¹⁹F MRI has emerged as a powerful technique, as it enables the detection of inflammation with minimal background signal. Beyond diagnosis, however, there is increasing interest in using this platform to initiate targeted therapeutic interventions. The integration of these two components-diagnosis and therapy-is commonly referred to as theranostics. In this review, we provide an overview of the potential of fluorine-based MRI and highlight a range of targeted theranostic applications across different disease models. Particular emphasis is placed on recent strategies to manipulate neutrophils during acute colitis, which have demonstrated significant improvements in disease outcome.

Cancer vaccines offer transformative potential in oncology, especially with advances in mRNA technologies. To accelerate advances in cancer vaccine research and capitalize on its COVID-19 vaccine leadership, the UK Government has launched the UK Vaccine Innovation Pathway (VIP) through a partnership between the National Institute for Health and Care Research (NIHR), NHS England, and pharmaceutical partners. Its innovative approaches to trial delivery have enabled a 500% increase in patient recruitment with 33 trials open or recently closed across 85 sites and 11 cancer types. Working alongside the Cancer Vaccine Launchpad (CVLP), which pre-screens patients across 55 NHS sites, VIP offers streamlined trial set-up, decentralized delivery, and equity-focused design. The UK's approach aligns scientific innovation with rapid clinical deployment, creating a scalable, patient-centred model for delivering individualized therapies. This article outlines the strategic framework, outcomes, and lessons from the VIP and CVLP to inform future national strategies in cancer vaccine deployment.

Background: Immune checkpoint inhibitor treatment in non-small cell lung cancer (NSCLC) expands to early stages of disease. The neoadjuvant setting allows to investigate the mechanism-of-action of immune therapy using molecular imaging and tissue analysis. We investigated the safety and feasibility of programed cell death ligand-1 (PD-L1) PET-imaging with ⁸⁹Zr-labeled avelumab and neoadjuvant avelumab treatment in resectable NSCLC. Secondly, [⁸⁹Zr]Zr-DFO-avelumab accumulation was correlated with features of the tumor immune microenvironment and pathological response.

Methods: This Phase I-II study (NCT03514719) enrolled 20 patients with Stage Ia-IIIa NSCLC who received two cycles of avelumab (10 mg/kg Q2W) prior to surgery. In the imaging optimization part, [⁸⁹Zr]Zr-DFO-avelumab PET was performed with protein doses of 2, 10, or 50 mg avelumab and imaging at Day 2 and 4 postinjection. Subsequent patients were scanned with 10 mg [⁸⁹Zr]Zr-DFO-avelumab at Day 4. Tracer-accumulation was correlated to PD-L1 expression and immune cell densities on pretreatment biopsies.

Results: [⁸⁹Zr]Zr-DFO-avelumab PET/CT was successfully performed in 23/24 patients. 19/20 patients started neoadjuvant avelumab treatment, with no delays or conversions of surgical procedures. Six patients showed pathologic response, including two major pathologic responses. [⁸⁹Zr]Zr-DFO-avelumab tumor-accumulation was not correlated to PD-L1 expression, but did correlate with regulatory T-cell density (r = 0.72, P = .030) and pathologic response (r = 0.56, P = .036); and was inversely correlated with CD303+ plasmacytoid dendritic cell density (r = -0.72, P = .030). SUV_peak on baseline [¹⁸F]FDG-PET correlated with pretreatment PD-L1 expression but not with [⁸⁹Zr]Zr-DFO-avelumab accumulation nor with pathologic response.

Conclusion: [⁸⁹Zr]Zr-DFO-avelumab PET imaging is a safe and feasible approach in early-stage NSCLC. Higher [⁸⁹Zr]Zr-DFO-avelumab tumor-accumulation at baseline strongly correlates with features of a suppressive tumor immune environment and response to neoadjuvant avelumab.

[This corrects the article DOI: 10.1093/immadv/ltaf001.].

Background: Anti-CD20 antibodies are first-line treatments for B cell malignancies. Natural killer (NK) cells are important mediators of anti-CD20 antibody efficacy in humans through antibody-dependent cellular cytotoxicity (ADCC). In B cell malignancies, the lymph nodes are a critical site of pathology and the T cell-derived signals CD40L and IL-4 within the lymph node microenvironment can mediate tumour proliferation, survival and resistance to pro-apoptotic therapy. CD40L and IL-4 have recently been shown to inhibit NK cell activation against chronic lymphocytic leukaemia (CLL) cells via the HLA-E:NKG2A immune checkpoint axis. However, the effect of these signals on NK cell-mediated ADCC of malignant B cells is unclear.

Methods: Using a combination of clinical samples, murine models, flow cytometry, immunoblotting, immunohistochemistry, ELISA, bioinformatics and functional assays, we examined the impact of lymph node-mimicking conditions on NK cell-mediated ADCC against malignant B cells. Exogenous CD40L and IL-4 were used to mimic T-B cell interactions in 2D malignant B cell cultures, in addition to a 3D spheroid model of T cell-dependent CLL proliferation.

Results: CD40L and IL-4 increased HLA-E expression on the surface of primary CLL cells and non-Hodgkin's lymphoma (NHL) cell lines, and this decreased NK cell-mediated ADCC via ligation of the inhibitory receptor NKG2A. High HLA-E surface expression was observed in lymph node FFPE sections of CLL and NHL patients and in a 3D ex vivo lymph node-mimicking model of CLL. NKG2A blockade potentiated NK cell-mediated ADCC against malignant B cells treated with CD40L and IL-4 and improved anti-CD20 antibody therapy in a murine model of B cell lymphoma.

Conclusion: These results reveal a novel mechanism of resistance to anti-CD20 therapy in B cell malignancies and demonstrate that the combination of anti-NKG2A with anti-CD20 could improve the treatment of patients with CLL or NHL.

Glioblastoma (GBM) is a devastating malignant disease with a remarkably low 5-year survival rate and invariably poor prognosis. Current conventional treatment options (surgery, targeted radiotherapy, and a limited number of chemotherapies) are rarely entirely effective, leading to the majority of GBM patients experiencing disease recurrence shortly after primary treatment. Thus far, immunotherapeutic approaches towards GBM treatment have been largely unsuccessful due to the tumour site and profoundly immunosuppressive tumour microenvironment (TME). However oncolytic virus therapy (OVT) has been recently developed and licenced for the treatment of cancers and has the potential to switch the TME to become immune-reactive. This has been shown to both directly reduce tumour burden while also enhancing responsiveness to other therapies. In this review, we review the challenges faced by standard immunotherapies in GBM and outline the various approaches to OV treatment of GBM. We highlight the promise of OVT for targeting GBM by critically assessing the outcomes from recent clinical trials.