BackgroundExperimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. MethodsWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. ResultsAt 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in t...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1707914

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Understanding the tumor immune microenvironment (TIME) for effective therapy.

Inflammation and Cancer: Triggers, Mechanisms, and Consequences.

Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.

Targeting the NLRP3 inflammasome in inflammatory diseases

The interleukin-1 (IL-1) family of cytokines and receptors is unique in immunology because the IL-1 family and Toll-like receptor (TLR) families share similar functions. More than any other cytokine family, the IL-1 family is primarily associated with innate immunity. More than 95% of living organisms use innate immune mechanisms for survival whereas less than 5% depend on T- and B-cell functions. Innate immunity is manifested by inflammation, which can function as a mechanism of host defense but when uncontrolled is detrimental to survival. Each member of the IL-1 receptor and TLR family contains the cytoplasmic Toll-IL-1-Receptor (TIR) domain. The 50 amino acid TIR domains are highly homologous with the Toll protein in Drosophila. The TIR domain is nearly the same and present in each TLR and each IL-1 receptor family. Whereas IL-1 family cytokine members trigger innate inflammation via IL-1 family of receptors, TLRs trigger inflammation via bacteria, microbial products, viruses, nucleic acids, and damage-associated molecular patterns (DAMPs). In fact, IL-1 family member IL-1a and IL-33 also function as DAMPs. Although the inflammatory properties of the IL-1 family dominate in innate immunity, IL-1 family member can play a role in acquired immunity. This overview is a condensed update of the IL-1 family of cytokines and receptors.

Overview of the IL-1 family in innate inflammation and acquired immunity.

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

© BMJ Publishing Group Limited 2022. No commercial reuse. See rights and permissions. Published by BMJ. DESCRIPTION A patient in his 70s with a history of hypopharyngeal cancer presented with a 2 month history of progressive dysphagia and left mandible pain. On examination, he had severe trismus and leftsided mandibular swelling with tenderness. Flexible nasendoscopy revealed significant postradiotherapy changes at the tongue base and larynx, and a left vocal cord palsy; however, there were no signs of tumour recurrence. The patient has a history of a surgically excised T1 squamous cell carcinoma (SCC) of the soft palate and carcinoma in situ of the left tonsillar pillar in 2015. This was followed by T2N2b SCC of the left pyriform fossa treated with chemoradiotherapy in 2016, which included cisplatin and radiotherapy 65 Gy in 30 fractions. He had been asymptomatic since treatment. Initial contrast CT neck and thorax found no definite cause for his symptoms, recommending MRI neck with contrast for further investigation. This revealed inflammatory changes including joint space narrowing with bone and soft tissue oedema (figure 1), with a differential diagnosis of septic arthritis/osteomyelitis in the atlantoaxial joint or osteoradionecrosis (ORN). Initially, due to the involvement of both sides of the joint, the diagnosis of septic arthritis was favoured prompting admission for intravenous antibiotics. Discussion with radiology suggested that repeat imaging after initial treatment would be beneficial. Repeat MRI neck 1 week later showed more extensive changes in this region centred around the left atlantoaxial joint which was now eroded (figure 2), despite patient remaining well. After multidisciplinary discussion with radiology and neurosurgery, the patient was diagnosed with ORN of the C1 and C2 vertebra and discharged with 6 weeks of oral antibiotics, Miami J collar, and close clinical and radiological surveillance. The patient remained stable over the following months with repeat MRI neck imaging 1.5 months later showing no progression of the joint and soft tissue changes. He remains under close review to prevent recognised complications such as secondary osteomyelitis, spinal deformity and spinal cord compression. ORN of the cervical spine is a rare but serious consequence of radiation therapy for head and neck cancers with documented cases limited to a small number of published reports, with the most common documented side effect being dysphagia. 3 The difficulty in diagnosis for this particular patient lies in the lack of clearly identifiable ORN features on his imaging. Studies have compared various MR imaging characteristics of cervical ORN with recurrence of malignant disease, but little is documented in terms of differentiating features of cervical ORN Figure 1 Axial CT image showing soft tissue component between internal carotid artery and jugular vein. Figure 2 Coronal postcontrast MRI showing eroded left atlantoaxial joint.

/pdf/osteoradionecrosis-of-the-cervical-spine-an-uncommon-6zrtwuxl.pdf

Greg O'Neil

Papers

Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial

Osteoradionecrosis of the cervical spine: an uncommon complication of radiation therapy for hypopharyngeal cancer