Sophia N. Karagiannis

Purpose Physical activity (PA) can improve health and treatment outcomes in cancer patients. However, patients with advanced cancer undergoing immune checkpoint inhibitor (ICI) therapy often experience debilitating side-effects that impact PA participation. Because PA experiences in patients with advanced cancer undergoing ICI therapy are not well known, in this study we aimed to explore their perceptions and lived experiences. Method Twelve adults with advanced urological (bladder or renal) cancer undergoing ICI therapy at a tertiary cancer centre, London, UK, participated in individual semi-structured qualitative interviews. A topic guide facilitated discussions. Interviews were audio-recorded and transcribed verbatim. Data was inductively analysed following Braun and Clarke’s six-phases of Thematic Analysis. Results In-person interviews lasting 34–69 min revealed four main themes: 1) Purpose of PA participation, 2) Factors influencing PA participation (facilitators/barriers), 3) Limited ameliorative support from healthcare professionals, and 4) Desired PA support. Overall, participants reported suboptimal PA levels attributed to inadequate PA knowledge and cancer/ICI treatment-related side-effects such as fatigue and pain. PA facilitators included self-motivation, positive valance, and healthcare professionals support regarding PA benefits and safety. Conclusions Structured PA is a promising strategy for managing cancer and treatment-related side-effects during ICI therapy; however, findings from this study indicate that it is underutilised. Patients undergoing ICI therapy have distinct PA needs, necessitating personalised support. Integrating PA interventions, such as PA counselling and timely referrals to cancer exercise/rehabilitation specialists into cancer care pathways, is essential. Further research should explore optimal strategies to enhance PA participation and maximise its benefits during ICI treatment.

Background: Nearly half of patients with melanoma do not respond to immune checkpoint inhibitors (CPIs) and many develop immune-related adverse events (irAEs), often forcing treatment discontinuation, and underscoring the need to predict and monitor outcomes. Responses may depend on both B cell and T cell activity. Methods: We performed high-dimensional mass cytometry profiling of coexisting peripheral B cell and key T cell states in treatment-naïve patients and healthy individuals, and paired longitudinal samples from CPI-treated patients, with clinical annotations to define immune correlates of outcomes. Results: CPI-naive patients exhibited reduced CD19+ B cells, reduced B cell (CD21, IL-2, CXCR5) and T cell (CD38, CD27) activation markers, alongside enriched naïve (CD21lo) and double-negative (DN2)-like B cells, CD95+IL-10+plasmablasts, consistent with extrafollicular responses. Concurrently, programmed cell death protein 1 (PD-1)+ and proliferation marker protein-67 (Ki67)+ T cell expansion indicates ongoing activation with features of proliferative exhaustion. Active disease featured increased regulatory CD95 expression on B cells and expanded T follicular helper-like and activated DN (CD4−CD8−) T cells, indicating sustained antigen stimulation. Pretreatment, elevated PD-1+ T cells predicted irAEs, whereas VEGF (vascular endothelial growth factor)+TGF-β (transforming growth factor-β)+ DN T cells were enriched in patients without subsequent toxicity. Pretreatment, plasmablasts, transitional B cells, Forkhead box protein P3 (FoxP3)+ and central memory-like CD8+ T cells correlated with worse overall survival; naïve CD21lo B cells, PD-1+CD8+ T cells and CD4+follicular helper-like T cells predicted shorter event-free survival; CD4+ memory T cells predicted better prognosis, implicating dysregulated differentiation and sustained activation in adverse outcomes. On-treatment, naïve CD21hi B cells, plasmablasts, activated CD8+ and central memory-like CD4+ T cells expanded, indicating de novo humoral responses and cytotoxic T cell invigoration. On-treatment, increased class-switched memory (IgG2+) B and activated T cells predicted improved survival, while persistent naïve and DN B cells were associated with poorer outcomes. Anti-PD-1 monotherapy expanded naïve (CD21hi) B cells and global T cells. Anti-PD-1/anti-LAG-3 (lymphocyte-activation gene 3) combination contracted memory B cells. Conclusions: Melanoma displays aberrant peripheral B and T cell activation, maturation and exhaustion, prominent in active disease. Treatment-induced class-switched B cells and T cell invigoration predict clinical benefit and naïve/DN B cells signify resistance. Coordinated B and T cell responses, especially recurrent extrafollicular B cell and exhausted/regulatory T cell states emerge as candidate indicators of outcome.

Background: B cells are increasingly recognized regulators of antitumor immunity in melanoma, yet their differentiation states, lineage dynamics, spatial organization and integration within the immune microenvironment, and how these are influenced with immunotherapy remain incompletely defined. Methods: We conducted deep profiling of tumor-resident B cell differentiation and evolutionary features in the melanoma tumor microenvironment using bulk, single-cell and spatial transcriptomic analyses, long-read antibody sequencing and mass cytometry (Cytometry by Time-Of-Flight, CyTOF). We characterized B cell differentiation trajectories, class-switching patterns, antibody isotype usage, signaling pathways, spatial niches against clinicopathological features and immune cell communication, before and after checkpoint blockade and in clinically defined responders and non-responders. Results: Melanoma-infiltrating B cells were enriched across primary and metastatic lesions, were preferentially associated with immune-rich tumors and correlated with T and natural killer (NK) cell densities. Long-read immunoglobulin sequencing demonstrated recurrent class switch recombination (CSR) trajectories with predominant IgG and IgA isotype usage, confirmed by bulk transcriptomic analyses. Across independent single-cell and bulk transcriptomic datasets we identified conserved class-switching, B cell receptor (BCR) activation, and pseudotime analyses showed differentiation trajectories progressing from naïve and memory states toward interferon (IFN)-driven terminal differentiation trajectories that persisted before and after immunotherapy. CyTOF analyses independently confirmed proliferative, germinal center (GC)-like, memory and class-switched B cell subsets, suggesting conserved inflammatory differentiation endpoints. Spatial transcriptomic deconvolution identified IFN-rich B cells within tertiary lymphoid structures (TLS). Following immunotherapy, B cells retained class-switched trajectories, displayed enriched GC-associated profiles, enhanced crosstalk with T cells and Dendritic Cells (DCs) and preserved or induced IFN-rich IgM + /IgD + or IgG4 + phenotypes, suggesting persistence or emergence of non-class switched and atypical class-switched isotype profiles. Transcriptomic analyses of B cells pointed to upregulated antigen-driven stimulation and BCR signaling, whereas in non-responders displayed IFN-rich B cells, IFN-associated genes, and IFN-pathway enrichment. Conclusions: Melanoma-infiltrating B cells follow class-switched differentiation trajectories culminating in IFN signaling, atypical antibody expressing states that persist or emerge after immunotherapy, aligning dynamic B cell evolution and atypical lineage traits with immunotherapy.

Introduction: Novel predictive biomarkers are needed to optimize immunotherapy-based treatment response in non-small cell lung carcinoma (NSCLC). T cell modulatory features may limit the ability of T cells to mount effective anti-tumor responses and could predict immune fitness and responsiveness to therapy. We investigated the prognostic and predictive value of CD8+ T cells with an exhausted phenotype, specifically those co-expressing Programmed Death 1 (PD-1) and T cell factor 1 (TCF-1), in peripheral blood of NSCLC patients before any systemic treatment. Methods: Two patient cohorts were analyzed: a) 32 patients with early and locally advanced disease (stage I–IIIA; cohort A) who did not receive immunotherapy, and b) 47 patients with advanced disease (stage IIIB-IV) who received chemo-immunotherapy. Multicolor flow cytometry was used to assess CD8+ T cell subpopulations co-expressing PD-1 and TCF-1. Results: PD-1+TCF1+ progenitor (early) exhausted T cells were found at high frequencies in all NSCLC patients compared with healthy donors, regardless of tumor stage. In cohort A, patients with high levels of CD3+CD8+PD-1+TCF1+ T cells had significantly improved DFS (p= 0.038), while those with high CD3+CD8+PD-1+TCF1− T cells had significantly worse DFS (p= 0.028). In cohort B, high levels of CD3+CD8+PD-1+TCF1+ T cells were associated with shorter PFS (p= 0.027). No association with OS was observed in cohort A. Conversely, in cohort B, high CD3+CD8+PD-1+TCF1+ T cell levels correlated with shorter OS (p= 0.045), while high CD3+CD8+PD-1+TCF1− T cell levels correlated with longer OS (p= 0.010). Conclusion: Therefore, here we show that circulating PD-1⁺TCF1+ T cells correlated differentially with treatment outcome in early and late NSCLC stage patients.

Basophils, the least abundant leukocytes, are increasingly recognised as potent immunomodulators. Upon activation, they rapidly release preformed granule‐associated mediators including histamine and lipid mediators such as LTC ₄ , while cytokine production occurs over a longer timescale, contributing to downstream immune responses. Basophil activation is driven by IgE‐dependent FcεRI crosslinking or IL‐3, complement and Toll‐like receptor (TLR) pathways, enabling diverse effector responses, including type I hypersensitivity to allergens. Through IL‐4 and IL‐13 secretion, basophils bridge innate and adaptive immunity, promoting Th2 differentiation, B cell activation and recruiting eosinophils. Beyond allergy, basophils contribute to inflammation, angiogenesis, cancer immune surveillance and tumour progression. Basophils participate in IgE‐dependent type I hypersensitivity to small‐molecule drugs, chemotherapeutics and monoclonal antibodies, becoming activated when drugs cross‐link specific IgE–FcεRI complexes, driving rapid mediator release and amplifying Th2‐skewed inflammation. The basophil activation test (BAT), which quantifies activation markers, such as CD63 and CD203c, provides an ex vivo functional measurement of these responses and serves as a biomarker of IgE‐mediated hypersensitivity. In oncology, BAT is applied to predict and monitor hypersensitivity reactions, drug desensitisation and support IgE‐based therapeutics development. Collectively, basophils are emerging as pivotal immune regulators and BAT presents a mechanistic, clinically‐actionable tool for advancing precision medicine in AllergoOncology.

Antibody-drug conjugates (ADCs) are a leading area of targeted cancer therapeutics, typically combining a tumor-associated antigen-specific antibody conjugated to a toxic payload that targets key cellular mechanisms, such as mitosis and survival. The global ADC clinical trial landscape has been expanding significantly, with over 430 ADCs reaching early to late clinical studies in the past two decades, up from just 90 between 2004 and 2014. The US Food and Drug Administration (FDA) has so far approved 14 ADCs for use in clinical oncology. This growth is likely driven by significant advances in antibody technology and conjugation methods enabling more effective and precise delivery to cancer cells and more effective payloads that target vital cancer biology. Here, we review the ADCs that have reached clinical approval as well as current and emerging trends in ADC development, and we discuss these from multiple perspectives, including ADC mechanisms of action, emerging antigen targets, linker and conjugation chemistry, payloads, combination of ADC with checkpoint inhibitor immunotherapy, and antibody fragment crystallizable (Fc) engineering. We also consider how the field is evolving through the application of artificial intelligence (AI) and pathology-based biomarker discovery. Combined, innovative and emerging ADC design coupled with precision medicine and patient stratification strategies hold great promise to develop diverse and personalized cancer treatments with improved therapeutic indices and to enhance tolerability compared to traditional chemotherapy and current established ADCs. This review aims to assist researchers in exploring the evolution, characteristics, and development trends in ADC design and to provide new directions for future research.

Honey bee venom (HBV) represents a unique interface between allergy and oncology, exemplifying how allergen‐derived molecules can be repurposed as anti‐cancer agents. Melittin, the principal component of HBV, accounts for 40%–50% of its dry weight and is responsible for most of its biological activity. Beyond its well‐established role as a potent allergen and mast cell activator, melittin displays broad anti‐tumour properties across multiple cancer models. Preclinical evidence demonstrates that melittin induces cancer cell death through membrane disruption, mitochondrial and death receptor–mediated apoptosis, ferroptosis, and inhibition of key oncogenic pathways, including PI3K/Akt/mTOR, NF‐κB, and HIF‐1α/VEGF signalling. Additional effects include suppression of angiogenesis, epithelial–mesenchymal transition, invasion, and metastatic dissemination, as well as modulation of the tumour immune microenvironment. However, the clinical translation of melittin is limited by its intrinsic haemolytic activity, systemic toxicity, and high allergenic potential. Advances in nanotechnology, targeted delivery systems, and venom‐inspired peptide engineering are addressing these barriers, enabling tumour‐selective delivery while reducing off‐target effects. This EAACI Task Force Position Paper integrates current evidence on melittin within the emerging field of AllergoOncology. It highlights its dual relevance for allergists and oncologists and outlines the translational challenges to be overcome and opportunities to enable safe clinical application.

Mast cells and basophils, historically defined by their pathogenic roles in allergic diseases and type I hypersensitivity, are increasingly recognized as influential participants in cancer biology. Emerging research in AllergoOncology highlights their plasticity, diverse functions, and significance beyond classical contributions to allergy. This review summarizes current evidence on their presence, activation states, and roles across multiple cancer types. We examine their interactions with other immune populations, their context‐dependent pro‐ and anti‐tumor functions, and their potential utility as biomarkers. Their pro‐tumor activities include secretion of Th2 cytokines, release of angiogenic mediators, and facilitation of extracellular matrix remodeling, all of which can support tumor progression. Conversely, these cells may also promote anti‐tumor immunity through effector mechanisms and recruitment of cytotoxic CD8 ⁺ T cells. Translational tools such as the basophil activation test (BAT) and the mast cell activation test (MAT) are emerging to help predict hypersensitivities to cancer treatments including immunotherapies. A deeper understanding of their dynamic roles within the tumor microenvironment (TME) and across anatomical locations may reveal previously underappreciated functions, prognostic value, and therapeutic opportunities.

Antibody–drug conjugates (ADCs) demonstrate therapeutic potential, but aggressive triple-negative breast cancers (TNBCs) require precise target selection and antibody optimisation. We identified chondroitin sulfate proteoglycan 4 (CSPG4) expression in neoadjuvant treatment-resistant TNBC to guide ADC development. Three anti-CSPG4 IgG1 antibodies with distinct variable regions (225.28S, 763.74, and 9.2.27) were engineered and compared. 225.28S IgG1 demonstrated the most efficient internalisation and potent cancer cell cytotoxicity when conjugated to the tubulin inhibitor MMAE. To determine the optimal isotype, we generated 225.28S IgG4 and directly compared it with 225.28S IgG1. The IgG1 isotype showed superior internalisation and killing activity as an MMAE-conjugated ADC. Conjugation of 225.28S IgG1 to the topoisomerase inhibitor DXd produced an ADC with a drug-to-antibody ratio (DAR) of 8. This ADC was capable of robust internalisation into cancer cells and tumour cell cytotoxicity in vitro, and significant growth restriction of two CSPG4-expressing TNBC patient-derived xenografts (PDX) implanted orthotopically in mouse mammary fat pads. Unconjugated 225.28S IgG1 also limited TNBC xenograft growth in immunodeficient mice engrafted with human immune cells, confirming Fc-mediated functional activity. These studies identify 225.28S IgG1 as the optimal clone and isotype, supporting a next-generation DXd-conjugated ADC as a promising therapeutic strategy for hard-to-treat CSPG4-expressing TNBC.