Probiotics which do not result in the development and spread of microbial resistance are among the candidate replacements for antibiotics previously used as growth promotors. In this study the effect of in-feed supplementation of the butyrate producing Butyricicoccus pullicaecorum strain 25-3T on performance, intestinal microbiota and prevention of necrotic enteritis (NE), a disease caused by Clostridium perfringens was evaluated in broilers. For the performance study, day old Ross 308 chicks were randomly allocated into two treatment groups and fed either a non-supplemented diet or a diet supplemented with 109 cfu lyophilized B. pullicaecorum per kg feed for 40 days. On day 40 broilers administered B. pullicaecorum had a significant lower bodyweight (2675 g vs. 2762 g; p = 0.0025) but supplementation of B. pullicaecorum decreased the feed conversion ratio significantly (1.518 vs. 1.632; p < 0.0001). Additionally, ingestion of the Butyricicoccus strain significantly lowered the abundance of Campylobacter spp. in the caecum and Enterococcus and Escherichia/Shigella spp. in the ileum at day 40. In feed supplementation of B. pullicaecorum in the NE trials resulted in a significant decrease in the number of birds with necrotic lesions compared with the untreated control group. These studies show that supplementation of B. pullicaecorum is able to improve feed conversion, to reduce the abundance of some potentially important pathogens in the caeca and ileum and to contribute to the prevention of NE in broilers, making the strain a potential valuable probiotic.

Cancer immunotherapy can induce durable antitumor responses. However, many patients poorly respond to such therapies. Here we describe a generic antitumor therapy that is based on the intratumor delivery of mRNA that codes for the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein. This intervention stalls primary tumor growth and protects against distal and disseminated tumor formation in syngeneic mouse melanoma and colon carcinoma models. Moreover, MLKL-mRNA treatment combined with immune checkpoint blockade further improves the antitumor activity. MLKL-mRNA treatment rapidly induces T cell responses directed against tumor neo-antigens and requires CD4+ and CD8+ T cells to prevent tumor growth. Type I interferon signaling and Batf3-dependent dendritic cells are essential for this mRNA treatment to elicit tumor antigen-specific T cell responses. Moreover, MLKL-mRNA treatment blunts the growth of human lymphoma in mice with a reconstituted human adaptive immune system. MLKL-based treatment can thus be exploited as an effective antitumor immunotherapy.

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An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I IFN has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1,000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon (AFN)-targeting Clec9Aþ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AFNs provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker. Significance: Targeted type I interferon elicits powerful antitumor efficacy, similar to wild-type IFN, but without any toxic side effects. Cancer Res; 78(2); 463-74. Ó2017 AACR.