Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors.

BACKGROUND: Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of antigenic determinants on tumor cells. Creating an antigen-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an antigenic determinant is not known is a major challenge. METHODS: We use multiple cell line and poorly immunogenic syngeneic, autochthonous, and autologous mouse models to evaluate the efficacy of a novel combination immunotherapy named tripartite immunotherapy (TRI-IT). To elucidate TRI-ITs mechanism of action we use immune cell depletions and comprehensive tumor and immune infiltrate characterization by flow cytometry, RNA sequencing and diverse functional assays. RESULTS: We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells, cytokine-induced killer cells, Vγ9Vδ2-T-cells (γδ-T-cells) and T-cells enriched for tumor recognition (CTLs) display synergistic antitumor effects, which are further enhanced by cotreatment with anti-PD1 antibodies. Most strikingly, the full TRI-IT protocol, a combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, eradicates and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT coactivates adaptive cellular and humoral, as well as innate antitumor immune responses to mediate its antitumor effect without inducing off-target toxicity. CONCLUSIONS: Overall, TRI-IT is a novel, highly effective, antigen-agnostic, non-toxic combination immunotherapy. In this study, comprehensive insights into its preclinical efficacy, even in poorly immunogenic tumors, and mode of action are given, so that translation into clinical trials is the next step.

Anaphylaxis after consumption of pumpkin seeds in a 2-y-old child tolerant to its pulp: A case study.

OBJECTIVES: Pumpkin and its seeds are increasingly consumed by children for their potential health benefits. Each day, approximately 30% of teenagers consume nuts and seeds, including pumpkin seeds. However, there is some evidence that pumpkin seeds may exert allergenic effects and induce severe life-threatening anaphylaxis. Allergy to melon, cucumber, and zucchini, which belong to the same Cucurbitaceae family as pumpkin, are well known, opposite to pumpkin allergy. Few descriptions of allergic reactions associated with pumpkin have been published, especially in children. To date, three cases of pumpkin pulp and two seed cases have been reported among children. Our case report describes a case of pumpkin seed anaphylaxis in a child with good tolerance of pulp. METHODS: In the present study, a 2-y-old child experienced anaphylaxis, presenting with generalized urticaria, swollen lips, and increasing dyspnea after consuming pumpkin seeds. RESULTS: The patient's history showed that, although the child had been receiving an elimination diet because of an immunoglobulin E (IgE)-mediated food allergy to cow's milk and eggs, the basic dietary element was pumpkin pulp. The skin-prick test was positive for pumpkin seed (5 mm) but negative for pumpkin pulp (1 mm), and allergen-specific IgE was 1.34 kUA/L for seed and 0.37 kUA/L for pulp. The component-resolved diagnostics (CRD) found IgE to sesame seed, buckwheat, and walnut (storage proteins). Based on these findings, severe anaphylactic reaction to pumpkin seeds was identified. CONCLUSIONS: Pumpkin seed anaphylaxis can develop in a child with a tolerance to pumpkin pulp. Pumpkin seed allergens have not been well characterized. Homology between amino-acid sequences in storage proteins may indicate cross reactivity between different edible seeds and nuts.

[Food protein-induced enterocolitis syndrome (FPIES) - a rare disease with frequent symptoms - the practitioner's compendium].

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with varying degrees of severity. The acute form of the disease is manifested by vomiting, lethargy and pallor, which usually appear within 1-4 hours after food ingestion, and can lead to shock. The most common trigger foods are: cow's milk, soy, rice and oats. Chronic FPIES is typical for infants fed with cow's milk or soy infant formula and is manifested by chronic vomiting, diarrhea and failure to thrive. In the vast majority of patients with FPIES, the analysis of the clinical history is sufficient to diagnose and identify trigger foods. If the history is unclear, use an oral food challenge to help confirm the diagnosis. Long-term management of patients with FPIES involves elimination of the trigger foods, monitoring for FPIES resolution and caregivers' education. The majority of children acquire food tolerance at the age of 3-5.

Early risk factors for cow's milk allergy in children in the first year of life.

Background: Cow's milk allergy (CMA) is a key form of food allergy (FA). It was shown that the frequency of FA seems to have increased during the past 10-20 years, which led to the thought that FA may have different risk factors. Epigenetic regulations and environmental pre- and postnatal factors play a large role in contributing to allergy. Understanding the risk factors that pertain to the development of FA may help to provide reasonable recommendations for prevention of the disease. Objective: To assess the impact of perinatal and environmental risk factors on the incidence of CMA in children in the first year of life. Methods: The study group consisted of 138 infants with CMA and 101 healthy infants without allergy. CMA was confirmed by an elimination test and oral food challenge. To assess infant, parental, and environmental risk factors, we used a validated questionnaire survey. Results: The incidence of CMA was three times higher in infants with a positive family history for allergy (p < 0.001). An analysis revealed that mothers of children with CMA were fourfold more frequently university educated than mothers of children without allergy (p < 0.0001). The ages of the mothers from the study group were significantly higher than the ages of the mothers from the control group. Children from the study group were breast-fed for a significantly shorter time than children from the control group. The risk of CMA was threefold lower in children who had pets at home (p = 0.0002). The risk of IgE-mediated CMA was twofold higher than the risk of non-IgE-mediated CMA if the family had more children (p = 0.04) and as many as ninefold higher if multiorgan symptoms were detected (p = 0.01). Conclusion: A positive family history of allergy and mother's education increased the risk of CMA in children in the first year of life, whereas having pets at home and a longer period of breast-feeding decreased the risk.