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 P < 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.

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.

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. 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. 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. 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.

Cytokine-induced memory-like natural killer cells (CIMLNK) represent a novel form of adoptive cellular therapy that is easy to manufacture and readily available. These cells are generated after overnight stimulation of purified natural killer (NK) cells with interleukin-12 (IL-12), interleukin-15 (IL-15), and interleukin-18 (IL-18). While CIMLNK has demonstrated efficacy in patients with relapsed or refractory acute myeloid leukemia (AML), its potential application in B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. Tafasitamab (TAFA), a monoclonal antibody (mAb) directed against CD19, a surface antigen expressed on B-ALL cells, has been developed to augment anti-tumor efficacy through antibody-dependent cellular cytotoxicity (ADCC), a mechanism predominantly mediated by NK cells. Consequently, we sought to assess the susceptibility of B-ALL to the combination of CIMLNK and TAFA using three B-ALL cell lines: NALM6, SUP-B15, and RS4;11. The addition of TAFA significantly augmented the cytotoxic activity, degranulation capacity, and IFN-γ production of CIMLNK. TAFA-induced ADCC was found to be dose-dependent and was abolished after CD16 blockade. Furthermore, TAFA-mediated effects against NALM6 and SUP-B15 were more pronounced in CIMLNK compared to unstimulated NK cells. In vivo, the combination of CIMLNK and TAFA led to a more pronounced survival benefit in leukemia-bearing mice. In summary, our findings suggest that this combination holds promise as a potential alternative treatment option for patients with relapsed refractory B-ALL.

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.

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.

SummaryImmunogenicity against biologic medicines is ubiquitous, and it is traditionally measured by the final humoral response. However, the onset of a sustained immunogenic response begins at the cellular level with activation of T cells and maturation of naïve B cells into plasma cells. Ex vivo comparative immunogenicity assessment (EVCIA) of cellular immunogenicity in participants with moderate-to-severe chronic plaque psoriasis in the AVT02-GL-302 study, who received either reference product (RP) alone (non-switching arm) or switched between RP and AVT02 (switching arm) after 1:1 randomization at week 12. Peripheral blood mononuclear cells (PBMCs) were collected and cryopreserved from 28 participants at: baseline (before treatment) (week 1); pre-randomization (week 12); and week 16 and week 28 in both switching and non-switching arms. PBMCs were thawed and re-exposed to either medium alone (negative control), RP, AVT02, keyhole limpet hemocyanin (KLH) (positive control), RP+KLH, or AVT02+KLH. Samples from 10 participants (predetermined average cell viability of 75% across all timepoints) from each arm were analyzed for cytokine release after 24 hours and for Th-cell proliferation, 6 days post-seeding. Until week 28, cytokine release and Th-cell proliferation was similar at all time points in both switching and non-switching arms. Overall cellular immune response was elevated post-KLH re-exposure at all timepoints. The comparable ex vivo cellular immunogenicity between switching and non-switching arms complements the confirmation of interchangeability in the main study. Given the sensitivity of novel EVCIA, detecting cellular immunogenicity could be a potential outcome in predicting the immunogenicity of biologic medicines.

Immunotherapy treatment strategies have proven effective in a limited portion of patients, where identifying responders from non-responders to treatment remains a challenge. While some indications can be drawn from invasive biopsies, we need more accessible methods for predicting response and better correlates of response prior to starting therapy. Recent work has identified differences in immune composition at baseline in peripheral blood from melanoma patients responding to PD-1 blockade treatment. Through flow cytometric analysis of T cell receptors, phenotypical features of CD8+ and CD4+ T cells and Tregs could allow for the stratification of treatment response. Analysing T cells within peripheral blood could potentially allow for the stratification of PD-1 treatment response prior to therapy in different cancer settings.

There is an increasing number of immune-checkpoint inhibitors being developed and approved for cancer immunotherapy. Most of the new therapies aim to reactivate tumour-infiltrating T cells, which are responsible for tumour killing. However, in many tumours, the most abundant infiltrating immune cells are macrophages and myeloid cells, which can be tumour-promoting as well as tumouricidal. CD200R was initially identified as a myeloid-restricted, inhibitory immune receptor, but was subsequently also found to be expressed within the lymphoid lineage. Using a mouse model humanised for CD200R and PD-1, we investigated the potential of a combination therapy comprising nivolumab, a clinically approved PD-1 blocking antibody, and OX108, a CD200R antagonist. We produced nivolumab as a murine IgG1 antibody and validated its binding activity in vitro as well as ex vivo. We then tested the combination therapy in the immunogenic colorectal cancer model MC38 as well as the PD-1 blockade-resistant lung cancer model LLC1, which is characterised by a large number of infiltrating myeloid cells, making it an attractive target for CD200R blockade. No significant improvement of overall survival was found in either model, compared to nivolumab mIgG1 monotherapy. There was a trend for more complete responses in the MC38 model, but investigation of the infiltrating immune cells failed to account for this. Importantly, MC38 cells expressed low levels of CD200, whereas LLC1 cells were CD200-negative. Further investigation of CD200R-blocking antibodies in tumours expressing high levels of CD200 could be warranted.

Recurrence of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) after liver transplant (LT) is mediated by circulating tumour cells (CTCs) and exacerbated by the immunosuppressants required to prevent graft rejection. To circumvent the effects of immunosuppressants, we developed immunosuppressive drug-resistant armoured HBV-specific T-cell receptor-redirected T cells (IDRA HBV-TCR). However, their ability to eliminate HBV-HCC circulating in the whole blood has never been tested, and whether their lytic efficacy is compatible with the number of adoptively transferred T cells in vivo has never been measured. Hence, we developed a microscopy-based assay to quantify CTCs in whole blood. The assay was then used to quantify the efficacy of IDRA HBV-TCRs to lyse free-floating HBV-HCC cells in the presence of Tacrolimus and Mycophenolate Mofetil (MMF). We demonstrated that a panel of antibodies (AFP, GPC3, Vimentin, pan-Cytokeratin, and CD45) specific for HCC tumour antigens and immune cells can effectively differentiate HCC-CTCs in whole blood. Through dose-titration experiments, we observed that in the presence of immunosuppressive drugs, a minimum of 20 000 IDRA HBV-TCR T cells/ml of whole blood is necessary to lyse ~63.5% of free-floating HBV-HCC cells within 16 hours. In conclusion, IDRA HBV-TCR T cells can lyse free-floating HBV-HCC cells in whole blood in the presence of Tacrolimus and MMF. The quantity of IDRA-HBV TCR T cells required can be achieved by the adoptive transfer of 5 × 106 IDRA-HBV TCR-T cells/kg, supporting the utilisation of IDRA HBV-TCR T cells to eliminate CTCs as prophylaxis against recurrence after LT.