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Cytokines are small proteins that modulate the activity of the immune system. Because of their potent immunomodulatory properties, some recombinant cytokines have undergone clinical development and have gained marketing authorization for the therapy of certain forms of cancer. Recombinant cytokines are typically administered at ultralow doses, as many of them can cause substantial toxicity even at submilligram quantities. In an attempt to increase the therapeutic index, fusion proteins based on tumor-homing antibodies (also called "immunocytokines") have been considered, and some products in this class have reached late-stage clinical trials. While antibody-cytokine fusions, which preferentially localize in the neoplastic mass, can activate tumor-resident leukocytes and may be more efficacious than their nontargeted counterparts, such products typically conserve an intact cytokine activity, which may prevent escalation to curative doses. To further improve tolerability, several strategies have been conceived for the development of antibody-cytokine fusions with "activity-on-demand", acting on tumors but helping spare normal tissues from undesired toxicity. In this article, we have reviewed some of the most promising strategies, outlining their potential as well as possible limitations.

Background: Anti-PD-1 antibodies have revolutionized cancer immunotherapy due to their ability to induce long-lasting complete remissions in a proportion of patients. Current research efforts are attempting to identify biomarkers and suitable combination partners to predict or further improve the activity of immune checkpoint inhibitors. Antibody-cytokine fusions are a class of pharmaceuticals that showed the potential to boost the anticancer properties of other immunotherapies. Extradomain A-fibronectin (EDA-FN), which is expressed in most solid and hematological tumors but is virtually undetectable in healthy adult tissues, is an attractive target for the delivery of cytokine at the site of the disease., Methods: In this work, we describe the generation and characterization of a novel interleukin-7-based fusion protein targeting EDA-FN termed F8(scDb)-IL7. The product consists of the F8 antibody specific to the alternatively spliced EDA of FN in the single-chain diabody (scDb) format fused to human IL-7., Results: F8(scDb)-IL7 efficiently stimulates human peripheral blood mononuclear cells in vitro. Moreover, the product significantly increases the expression of T Cell Factor 1 (TCF-1) on CD8+T cells compared with an IL2-fusion protein. TCF-1 has emerged as a pivotal transcription factor that influences the durability and potency of immune responses against tumors. In preclinical cancer models, F8(scDb)-IL7 demonstrates potent single-agent activity and eradicates sarcoma lesions when combined with anti-PD-1., Conclusions: Our results provide the rationale to explore the combination of F8(scDb)-IL7 with anti-PD-1 antibodies for the treatment of patients with cancer., Competing Interests: Competing interests: DN is a cofounder and shareholder of Philogen (www.philogen.com), a Swiss-Italian Biotech company that operates in the field of ligand-based pharmacodelivery. CDN, EProdi, RD, DR, EG and EPuca are employees of Philochem AG, a daughter company of Philogen acting as discovery unit of the group., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Mediastinitis remains one of the most serious complications of cardiac surgery. The reported incidence is 1-4%, while the related mortality varies from 10-47%., Case Presentation: A patient with triple vessel disease (TVD) was hospitalized at our clinic for coronary artery bypass graft (CABG) surgery. The preoperative examination results were normal. We performed standard CABG under extracorporeal circulation. The patient had a favorable postoperative course. On the fifth postoperative day, the wound showed seropurulent drainage. The treatment of the patient's wound continued with open dressing, negative wound pressure device, debridement, minimal muscle plasticity, and total bilateral muscle pectoral flap plasticity. The infecting microorganism was identified as multidrug-resistant Acinetobacter baumani, and systemic antibiotic therapy was initiated. The patient had "per secundum closure" of the wound after all these efforts. The wound healed completely 2 months after discharge, and the patient was in good health., Conclusions: Mediastinitis is associated with high mortality and high financial and human costs. The occurrence of this high-risk complication can be prevented through constant vigilance at every step from admission to discharge., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Selman Dumani, Edmond Puca, Ermal Likaj, Stavri Llazo, Edlira Rruci, Vera Beca, Ali Refatllari, Arben Baboci.)

Introduction: Tigecycline has a broad spectrum of activity, including activity against drug-resistant Gram-positive and -negative microorganisms. Its side effects are significant, but hypoglycemia is a rare finding during treatment. We aim to present an event of severe hypoglycemia in a patient with type 2 diabetes mellitus with replacement renal therapy, and hemodialysis after initiating tigecycline., Case Presentation: A 54-year-old female diagnosed with type 2 diabetes mellitus was under treatment with basal-bolus insulin therapy and oral antihypertensive drugs. She started hemodialysis 24 months ago. She complained of recurrent fever for the last seven months and was treated with several antibiotics. In two separate blood cultures, she tested positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Based on the antibiogram, we started treatment with tigecycline 100 mg/day. After 6-8 hours from the first dose, the patient is complicated with events of hypoglycemia and then continues with severe hypoglycemia (40-47 mg/dL). The patient continued to have hypoglycemia for about 16-18 hours after the last dose. We didn't find any reasons to explain the cause of episodes of hypoglycemia. She did not have high blood insulin levels (insulin 4.11 mIU/L [range 2.6-24.9]). We followed her for six months and the patient did not experience episodes of hypoglycemia., Conclusions: The association of severe hypoglycemia with tigecycline treatment is a very rare event and published papers on this topic are limited. Clinicians should be aware of this rare event when administering tigecycline and should routinely check blood glucose level during the treatment., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Entela Puca, Edmond Puca, Klei Vrekaj, Dea Puca.)

Background: Blood culture-negative endocarditis (BCNE) is a diagnostic challenge, therefore our objective was to pinpoint high-risk cohorts for BCNE., Methods: The study included adult patients with definite endocarditis. Data were collected via the Infectious Diseases International Research Initiative (ID-IRI). The study analysing one of the largest case series ever reported was conducted across 41 centers in 13 countries. We analysed the database to determine the predictors of BCNE using univariate and logistic regression analyses., Results: Blood cultures were negative in 101 (11.65 %) of 867 patients. We disclosed that as patients age, the likelihood of a negative blood culture significantly decreases (OR 0.975, 95 % CI 0.963-0.987, p < 0.001). Additionally, factors such as rheumatic heart disease (OR 2.036, 95 % CI 0.970-4.276, p = 0.049), aortic stenosis (OR 3.066, 95 % CI 1.564-6.010, p = 0.001), mitral regurgitation (OR 1.693, 95 % CI 1.012-2.833, p = 0.045), and prosthetic valves (OR 2.539, 95 % CI 1.599-4.031, p < 0.001) are associated with higher likelihoods of negative blood cultures. Our model can predict whether a patient falls into the culture-negative or culture-positive groups with a threshold of 0.104 (AUC±SE = 0.707 ± 0.027). The final model demonstrates a sensitivity of 70.3 % and a specificity of 57.0 %., Conclusion: Caution should be exercised when diagnosing endocarditis in patients with concurrent cardiac disorders, particularly in younger cases., Competing Interests: None to declare., (© 2024 Published by Elsevier Ltd.)

Metastatic colorectal cancer remains a leading cause of cancer-related deaths, with a 5-year survival rate of only 15%. T cell-engaging bispecific antibodies (TCBs) represent a class of biopharmaceuticals that redirect cytotoxic T cells toward tumor cells, thereby turning immunologically "cold" tumors into "hot" ones. The carcinoembryonic antigen (CEA) is an attractive tumor-associated antigen that is overexpressed in more than 98% of patients with colorectal cancer. In this study, we report the comparison of four different TCB formats employing the antibodies F4 (targeting human CEA) and 2C11 (targeting mouse CD3ε). These formats include both antibody fragment-based and IgG-based constructs, with either one or two binding specificities of the respective antibodies. The 2 + 1 arrangement, using an anti-CEA single-chain diabody fused to an anti-CD3 single-chain variable fragment, emerged as the most potent design, showing tumor killing at subnanomolar concentrations across three different CEA+ cell lines. The in vitro activity was three times greater in C57BL/6 mouse colon adenocarcinoma cells (MC38) expressing high levels of CEA compared with those expressing low levels, highlighting the impact of CEA density in this assay. The optimal TCB candidate was tested in two different immunocompetent mouse models of colorectal cancer and showed tumor growth retardation. Ex vivo analysis of tumor infiltrates showed an increase in CD4+ and CD8+ T cells upon TCB treatment. This study suggests that bivalent tumor targeting, monovalent T-cell targeting, and a short spatial separation are promising characteristics for CEA-targeting TCBs., (©2024 American Association for Cancer Research.)

Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named "Intra-Cork") to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice., (© 2024. The Author(s).)