Cross-allergies affect a significant proportion of the population, and contribute to detrimental health and socioeconomic impacts, yet allergen immunotherapies often target a single allergen source disregarding cross-reactive allergens from other sources. Here we introduce an immunization approach developed for improved desensitization in cross-allergic patients using a consensus allergen (cnsLTP1), which contains orthologous non-specific lipid transfer proteins (nsLTP) derived from relevant fruit and pollen allergens. In BALB/c mice, vaccination via either mRNA-lipid nanoparticle (LNP) vehicle or traditional protein formulation induces cnsLTP1-specific IgGs capable of recognizing and binding to multiple nsLTPs. These IgGs block allergen binding by patient serum IgEs and prevent humanized rat basophil degranulation in vitro. Meanwhile, in an allergic mouse model, the mRNA-LNP formulation is tolerated and induces allergen-specific IgG responses but does not ameliorate subsequent allergen challenge responses. Regardless, this cross-allergen mRNA-LNP-based immunotherapy may have translation value once route of administration, formulation and/or dosing are optimized.

Human tonsils from the nasopharyngeal mucosa mount frontline antibody responses, including IgD secretion by IgD+IgM- plasma cells (IgD-PCs). The developmental origins and functional significance of these IgD responses remain poorly understood. Here, we show that most IgD-PCs clonally emerge from a heterogeneous population of IgD class-switched IgD+IgM- memory (IgD-ME) B cells that reside within the epithelial, subepithelial, and interfollicular areas of the nasopharyngeal mucosa and share transcriptional and phenotypic properties with atypical B cells. These IgD-ME B cells arise from a mutation-intensive pathway that involves integrated innate and adaptive signals and engenders reactivities to respiratory commensal bacteria, common environmental antigens, and allergens. Such reactivities weaken in germline IgD revertants. Thus, the secreted IgD response heavily relies on nasopharyngeal mucosal IgD-ME B cells via a germinal center-imprinted mutational program that presumably enhances mucosal homeostasis and environmental tolerance.

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.

SCFA evaluation in serum of MM patients from the first cohort 28-day post CAR-T cell infusion, using gas chromatography-mass spectrometry methodology.

Supplementary Figure S15 identifies significantly different relative abundances of bacterial families in the gut microbiota of multiple myeloma (MM) patients compared to healthy donors (HD). This figure presents mean relative abundances ± SD for various bacterial families, with individual dots representing MM patients or healthy donors, and statistical significance indicated by asterisks based on Mann-Whitney test results.

BACKGROUND AND OBJECTIVES:Consuming baked milk (BM) may accelerate tolerance in cow's milk-allergic (CMA) children. In high-risk patients, controlled BM-based oral food challenge (BM-OFC) is recommended, as the benefits can outweigh the risks of a prolonged exclusion diet. Objectives: To identify predictive biomarkers for BM-OFC outcomes in a cohort at high risk of anaphylaxis and compare the OFC thresholds for baked and pasteurized cow´s milk protein (CMP). METHODS:We performed a prospective study of children (≥12 months to <6 years) with a history of CMA. Testing at diagnosis involved prick testing, specific IgE (sIgE) for CM and components, sIgG4, and the basophil activation test (BAT). Patients underwent a BM-OFC aiming for a cumulative dose of 1 g of CM protein. BM-tolerant children subsequently underwent a CM-OFC to confirm CMA. RESULTS:The study population comprised 50 patients (66% with a history of anaphylaxis). A reaction was recorded during BM-OFC in 36% of patients (39% with anaphylaxis). The median reactivity threshold was 138 mg of CMP. Risk factors for BM allergy included history of anaphylaxis, age >3 years, elevated CM-sIgE and casein-sIgE, and a positive BAT result. The cut-offs were as follows: >5 mm for skin prick testing with casein, ≥8.5 kUA/L for CM-sIgE, and ≥5.7 kUA/L for casein-sIgE. These made it possible to distinguish BM-allergic patients from CMA patients who tolerated BM. Among BM-tolerant patients, the CM-OFC threshold was 270 mg, with 43.8% reacting to <100 mg (40% with anaphylaxis). CONCLUSIONS:BM-OFC is not risk-free. Nevertheless, two-thirds of high-risk CMA children were BM-tolerant and benefited from early introduction of BM products. Patient selection can be guided by biomarkers and a prior history of anaphylaxis to baked goods. The reactivity threshold to pasteurized milk was less than half of the tolerated dose of BM (1000 mg).

Supplementary Figure S17 highlights statistically significant differences in fecal metabolite abundance between multiple myeloma patients and healthy donors. This figure presents mean fecal metabolite abundance ±SD for various metabolites, with individual dots representing MM patients or healthy donors, and statistical significance indicated by asterisks based on Mann-Whitney test results.

SCFA evaluation in serum of MM patients from the first cohort at the apheresis day, using gas chromatography-mass spectrometry methodology

Quantification of soluble BCMA in serum from MM patients in the first cohort on the day of apheresis, measured by ELISA.

Supplementary Figure S6 characterizes the taxa and metabolites associated with CD8+ T cells in both the apheresis product and the final CAR T-cell product. The figure specifically shows associations with Tc1 cells, Tc17 cells, and memory subsets, indicating negative associations in blue and positive associations in red.

Supplementary Figure S14 examines the pre-CAR T-cell infusion gut microbiota taxonomic profiles based on the patients' hospital of origin. This figure includes a principal component analysis (PCA) plot showing gut microbiota composition by hospital, arrows indicating the influence of variables on patient separation, the Reciprocal Simpson diversity index of the gut microbiome, and a stacked bar plot of mean relative abundance of bacterial families across different clinical trial sites.

Supplementary Figure S3 presents the pre-CAR T-cell infusion gut fecal metabolite profiles detected in multiple myeloma patients, showing means ± standard deviation for each metabolite.

Supplementary Figure S4 illustrates the pre and post-CAR T-cell infusion systemic short-chain fatty acid profiles in multiple myeloma patients, specifically detailing levels of acetate, propionate, butyrate, isobutyrate, and formate.

Parameters used for the clinical data-based model.

Percentages of CD4 and CD8 T cells (gated inside CD3+ T cells) in the apheresis and infusion CAR-T cell products.

Supplementary Figure S23 shows a network of correlations between gut microbial families (green nodes) and metabolites (yellow nodes) associated with clinical response improvement. Green lines denote positive correlations, while red lines indicate negative correlations, with line intensity reflecting the Spearman correlation coefficient (ρ).

Multiple myeloma remains incurable despite advances in immunotherapies like chimeric antigen receptor (CAR) T-cell therapy. This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized B-cell maturation antigen (BCMA)-directed CAR-T therapy ARI0002h. Stool metabolites, particularly succinate, were associated with CAR T-cell phenotypes and persistence in patients. In CAR T-cell culture, succinate supplementation enhanced CD4+ central memory phenotype and respiratory capacity. In a murine myeloma model, a succinate-enhancing diet significantly improved CAR T-cell persistence and showed a trend toward better tumor control. Furthermore, Acidaminococcaceae, Monoglobaceae, or Akkermansiaceae, along with specific metabolites, were associated with CAR T-cell clinical outcomes. These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by days 100 and 180 after infusion. These findings suggest that metabolites and gut microbiota correlate with CAR T-cell therapy responses and can be a valuable tool for risk assessment.Significance: This study integrates microbial profiles into response models, providing a tool to identify patients with multiple myeloma who may benefit from BCMA-directed CAR T-cell therapy optimization by identifying bacterial taxa and metabolites associated with CAR T-cell persistence and therapeutic outcomes.