Canakinumab Anti-inflammatory Thrombosis Outcomes Study Research Articles

Effect of Clonal Hematopoiesis Mutations and Canakinumab Treatment on Incidence of Solid Tumors in the CANTOS Randomized Clinical Trial.

Clonal hematopoiesis (CH) is more common in older persons and has been associated with an increased risk of hematological cancers and cardiovascular diseases. The most common CH mutations occur in the DNMT3A and TET2 genes and result in increased proinflammatory signaling. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (NCT01327846) evaluated the neutralizing anti-IL1β antibody canakinumab in 10,061 randomized patients with a history of myocardial infarction and persistent inflammation; DNA samples were available from 3,923 patients for targeted genomic sequencing. We examined the incidence of non-hematological malignancy by treatment assignment and CH mutations and estimated the cumulative incidence of malignancy events during trial follow-up. Patients with TET2 mutations treated with canakinumab had the lowest incidence of non-hematological malignancy across cancer types. The cumulative incidence of at least one reported malignancy was lower for patients with TET2 mutations treated with canakinumab versus those treated with placebo. These findings support a potential role for canakinumab in cancer prevention and provide evidence of IL1β blockade cooperating with CH mutations to modify the disease course. Prevention Relevance: We reveal that administering canakinumab is associated with a decrease in non-hematological malignancies among patients with clonal hematopoiesis (CH) mutations. These findings underscore canakinumab's potential in preventing cancer and provide proof of IL1β blockade collaborating with CH mutations to enhance its clinical benefits. See related Spotlight, p. 399.

Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial

AbstractCanakinumab, a monoclonal antibody targeting proinflammatory cytokine interleukin-1β (IL-1β), improved hemoglobin levels while preventing recurrent cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This cardiovascular (CV) preventive effect was greater in patients with TET2 mutations associated with clonal hematopoiesis (CH). The current proteogenomic analysis aimed to understand the clinical response to canakinumab and underlying proteomic profiles in the context of CH and anemia. The analysis included 4595 patients from the CANTOS study who received either canakinumab or placebo and evaluated multiplexed proteomics (4785 proteins) using SomaScan and targeted deep sequencing for CH mutations. Incident anemia was more common in the presence of CH mutations but reduced by canakinumab treatment. Canakinumab treatment was significantly associated with higher hemoglobin increment in patients with concurrent CH mutations and anemia than patients with CH mutations without anemia or without CH mutations. Compared with those without CH mutations, the presence of CH mutations was associated with proteomic signatures of inflammation and defense response to infection, as well as markers of high-risk CV disease which was further enhanced by the presence of anemia. Canakinumab suppressed hepcidin, proinflammatory cytokines, myeloid activation, and complement pathways, and reversed pathologically deregulated pathways to a greater extent in patients with CH mutations and anemia. These molecular findings provide evidence of the clinical use of IL-1β blockade and support further study of canakinumab for patients with concurrent anemia and CH mutations. This study was registered at www.clinicaltrials.gov as #NCT01327846.

Abstract 12593: Associations of Serum Uric Acid and Cardiovascular Events in a Clinical Trial of IL-1β Blockade

Background: Serum uric acid (SUA) associates with CV events, mortality, and gout. We assessed whether SUA predicts CV risk in a trial of IL-1β inhibition with canakinumab, a therapy known to reduce both CV events and gout. Aims: To validate associations between SUA and CV risk in a large cohort with chronic CAD and determine whether these associations were altered by IL-1β blockade or baseline renal function. Methods: The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) randomized 10,061 patients with prior MI and hsCRP ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo subcutaneously every four weeks. SUA levels were obtained at baseline. Cox proportional hazards models compared the outcomes of major adverse cardiovascular events (MACE), CV death (CVD), and all-cause mortality (ACM) among those with baseline SUA ≤ 6.8 mg/dL, 6.8- 9.0 mg/dL, and ≥ 9.0 mg/dL (format: HR (95% CI); p). This analysis was repeated separately within canakinumab, placebo, eGFR ≥ 60 mL/min, and eGFR < 60 mL/min sub-groups. Results: High SUA associated with MACE (1.66 (1.38-1.99); p<0.0001), CVD (2.52 (1.98-3.21); p<0.0001), and ACM (2.43 (2.01-2.94); p<0.0001) compared to low SUA. These associations were minimally attenuated after adjustment for age, sex, BMI, smoking, hypertension, diabetes, LDL-C, and hsCRP. After further adjusting for eGFR and diuretic use, high SUA independently predicted CVD and ACM. In the IL-1β blockade arm, high SUA associated with MACE (1.82 (1.46-2.26); p<0.0001), CVD (2.80 (2.10-3.73); p<0.0001), and ACM (2.72 (2.17-3.40); p<0.0001). In participants with normal eGFR, high SUA associated with CVD and ACM, but not MACE. Conclusions: These data from a large cohort of patients with chronic CAD confirm that individuals with elevated SUA have increased CV risk despite aggressive medical therapies. IL-1β blockade did not modify these associations. Future trials may consider inclusion of patients with high SUA and CKD as a method to increase absolute risk.

The Controversies of Coronary Artery Disease in End-Stage Kidney Disease Patients: A Narrative Review.

Cardiovascular disease (CVD) accounts for more than 50% of deaths among patients with end-stage kidney disease (ESKD). Approximately 40-50% of ESKD patients have clinically significant coronary artery disease (CAD) due to atherosclerosis which accounts for a significant proportion of CVD risk. However, other CVD pathologies including myocardial fibrosis, vascular calcification and arterial stiffening play important contributory roles. The pathophysiology of CAD in ESKD is distinct from the general population. ESKD patients is typically have diffuse multi-vessel involvement with increased calcification that involves both intimal and medial layers of the arterial wall. There is a complex interplay between an increased burden of traditional Framingham risk factors and exposure to non-traditional risk factors including chronic inflammation and dialysis per se. Established treatments for CAD risk factors including cholesterol lowering with statin therapy have attenuated effects and ESKD patients also have worse outcomes after revascularisation. Recent trials such as the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) have established that direct modulation of inflammation improves CVD outcomes in the general population, which may prove to be a potential attractive therapeutic target in ESKD patients. Multiple retrospective observational studies comparing mortality outcomes between haemodialysis (HD) and peritoneal dialysis (PD) patients have been inconclusive. Randomised trials on this issue of clinical equipoise are clearly warranted but are unlikely to be feasible. Screening for stable CAD in asymptomatic ESKD patients remains a clinical dilemma which is unique to chronic dialysis patients being assessed for kidney transplantation. This has become particularly relevant in light of the recent ISCHEMIA-CKD trial which demonstrated no difference between optimal medical therapy and revascularisation upon CVD outcomes or mortality. The optimal strategy for screening is currently being investigated in the ongoing large international multi-centre CARSK trial. Here we discuss the pathophysiology, risk modification, treatment, screening and future directions of CAD in ESKD.

Inflammasomes and Atherosclerosis: a Mixed Picture.

The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.

Association between inflammation, body mass index, and long-term outcomes in patients after percutaneous coronary intervention: A large cohort study.

Association between inflammation, body mass index, and long-term outcomes in patients after percutaneous coronary intervention: A large cohort study.

Canakinumab's Effect Against Subsequent Gout Flares and High-Sensitivity C-Reactive Protein Levels: A Causal Mediation Analysis.

The objective of this study was to quantify the value of early suppression of high-sensitivity C-reactive protein (hsCRP) levels as a biomarker of the protective role of canakinumab against future gout flares. We conducted a post hoc causal mediation analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study for gout flares. The 3-month change in the log hsCRP level was the mediator of interest. We used linear regression for the hsCRP level mediator and Cox or Weibull regression for gout-flare outcomes, combining them in causal mediation analysis. We examined the cohort overall, as well as stratified by prevalent gout at baseline. We analyzed 9,221 patients without prevalent gout and 747 with prevalent gout. The Cox regression hazard ratio (HR) for a gout flare was 0.50 (95% confidence interval [95% CI] 0.37-0.68) comparing canakinumab with placebo, of which 6% was explained by the mediated effect through hsCRP level reduction in the first 3 months. In the prevalent-gout subgroup, the HR was 0.58 (95% CI 0.36-0.95), of which 31% was explained by the mediated effect through hsCRP level reduction. The Weibull analysis gave a proportion-mediated estimate of 47%. The indirect effect via hsCRP level reductions was unclear in the subgroup without prevalent gout. The first 3-month reduction in hsCRP level was not a good biomarker for canakinumab's protective effect on future gout flares in the overall cohort. Among patients with prevalent gout, there may be a potential role for early hsCRP level reduction as a biomarker for interleukin-1β inhibitors' future gout-flare benefit.

Canakinumab Effects on Erythropoiesis, Cardiovascular Risk, and Clonal Hematopoiesis: Proteogenomic Analysis of the Cantos Randomized Clinical Trial

Canakinumab is a monoclonal antibody that directly neutralizes interleukin (IL)-1β. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) - a randomized, double-blind, placebo-controlled trial that enrolled 10,061 patients with previous myocardial infarction and high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L - canakinumab prevented recurrent cardiovascular (CV) events (Ridker et al. NEJM 2017). Anemia of inflammation (AI) presents with mild to moderate anemia in the setting of systemic inflammatory conditions. The pathogenesis of AI involves deregulation of iron homeostasis via hepcidin and inflammatory cytokines such as IL-1β, IL-6, and TNF-α, resulting in skewed myeloid differentiation and decreased erythrocyte lifespan via enhanced erythrophagocytosis (Ganz et al. NEJM 2019). A CANTOS exploratory study revealed that canakinumab reduces the incidence of anemia and improves hemoglobin levels (Vallurupalli et al. Ann Intern Med. 2020). Among mutations associated with clonal hematopoiesis (CH), patients with TET2 variants had fewer major adverse CV events than those without CH mutations (Svensson et al. JAMA Cardiol. 2022). CH mutations in TET2 were associated with higher IL-1β levels (Bick et al. Nature 2020), generating the hypothesis that inhibition of IL-1β may provide preferential benefits to patients with CH mutations. To determine the association between CH mutations and clinical response to canakinumab and evaluate the underlying molecular mechanisms of anemia response, a proteogenomic study was performed in 13080 plasma samples from 4595 CANTOS participants, including highly multiplexed proteomics (4785 proteins) and targeted deep sequencing of CH mutations with variant allele fraction≥ 2% (Figure A). Longitudinal and cross-sectional analyses were performed in pre- and post-treatment samples from patients with at least one pre-treatment sample (baseline). CH mutations were associated with older age, anemia at baseline, and higher baseline IL-6 and TNF-α levels (all OR's >1.4 and p<0.003). Among patients without baseline anemia, canakinumab treatment prevented incidental anemia, compared to those treated with a placebo (without CH mutation: HR=0.72; 95% CI=0.61-0.84; P < 0.001, with CH mutations: HR=0.77; 95% CI=0.49-1.19; P =0.24). In individuals treated with canakinumab, however, those with CH mutations were more likely to develop incidental anemia compared to patients without CH mutations (HR=1.56; 95% CI=1.18-2.07; P=0.002). Conversely, among patients with baseline anemia, canakinumab treatment significantly improved hemoglobin levels in patients with CH mutations compared to a placebo (P< 0.001), whereas a significant difference was not found in hemoglobin levels of patients without CH mutations (Figure B). Enhanced hemoglobin response over time to canakinumab was observed in patients with concurrent baseline anemia and CH mutations, particularly in DNMT3A and TET2, compared to no CH mutations (all CH mutations, DNMT3A and TET2,P = 0.022, 0.004, 0.078 respectively). We observed that canakinumab treatment reversed multiple nodes of abnormal erythropoiesis associated with AI. Canakinumab treatment was associated with lower hepcidin and inflammatory cytokines (IL-6 and TNF-α) and down-regulation of pathways for complement activation and phagocytosis, which may prolong RBC lifespan and promote erythropoiesis. Higher odds of having both an increase in hemoglobin and a decrease in hepcidin (OR=1.88; 95% CI=1.62 - 2.17; P<0.001 ) and both an increase in hemoglobin and a decrease in IL-6 (OR=3.46; 95%CI=3.00 - 4.00; P<0.001) were observed with canakinumab treatment compared to placebo. The characterization of proteomic profiles in patients with CH mutations revealed novel biological links in dysregulation of RBC homeostasis, cardiovascular risk biomarkers, inhibitory immune molecules, and bone morphogenetic protein antagonists, which were reversed by canakinumab treatment more significantly in patients with TET2 mutations. Collectively this data provides direct clinical evidence that patients with concurrent anemia and CH mutations can benefit from canakinumab treatment by suppressing CH-mediated activation of the IL-1β/IL-6 axis and reversing ineffective erythropoiesis via multiple mechanisms, and the type of CH mutations may be associated with distinct clinical and biological response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cancer and cardiovascular disease: can understanding the mechanisms of cardiovascular injury guide us to optimise care in cancer survivors?

Cancer and cardiovascular disease (CVD) are the leading causes of morbidity and mortality. Therefore, CVD deaths in cancer survivors remain a major challenge in improving cancer outcomes, especially in low and middle income countries (LMICs). Cancer and CVD share many common risk factors, both modifiable risk factors (obesity, diabetes and smoking) and non-modifiable factors such as inflammation. Additionally, some cancer therapies are associated with cardiac toxicity. These mechanisms drive increased CVD outcomes in cancer survivors, and understanding this relationship allows us to target therapies to combat such risks. Several commonly used pharmacotherapies for CVD demonstrate promise in cancer survivors for both primary and secondary prevention. Beta blockers and Angiotensin converting enzyme (ACE)-inhibitors have been shown in several studies to improve left ventricular ejection fraction (LVEF) in patients with already established LVEF decline following cancer therapy. Statin use during chemotherapy was associated with lower risk of heart failure and smaller declines in LVEF. Recent studies into the effects of anti-inflammatory medications on cardiovascular events in the non-cancer population have demonstrated promising results and may prove to be an area of further investigation and possible benefit in the cancer population [Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) and Colchicine Cardiovascular Outcomes Trial (COLCOT)]. Additionally, several other medications including PCSK9 inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 (GLP-1) agonists have been shown to modify inflammation, and therefore may provide cardiovascular benefits. While common pharmacotherapies used in CVD show promise in cancer survivors, their exact mechanisms remain poorly understood. Few studies evaluate their clinical effectiveness specifically in cancer survivors, as this patient population is excluded from most studies. Further investigation is warranted with more representation of cancer survivors before cost-effective recommendations are made. This is especially true in LMICs where resources are sparse for primary and secondary prevention in order to optimise care in this unique, high-risk population for CVD.

Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer.

K-ras–mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D–mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti–IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.

Osteopontin in Cardiovascular Diseases.

Unprecedented advances in secondary prevention have greatly improved the prognosis of cardiovascular diseases (CVDs); however, CVDs remain a leading cause of death globally. These findings suggest the need to reconsider cardiovascular risk and optimal medical therapy. Numerous studies have shown that inflammation, pro-thrombotic factors, and gene mutations are focused not only on cardiovascular residual risk but also as the next therapeutic target for CVDs. Furthermore, recent clinical trials, such as the Canakinumab Anti-inflammatory Thrombosis Outcomes Study trial, showed the possibility of anti-inflammatory therapy for patients with CVDs. Osteopontin (OPN) is a matricellular protein that mediates diverse biological functions and is involved in a number of pathological states in CVDs. OPN has a two-faced phenotype that is dependent on the pathological state. Acute increases in OPN have protective roles, including wound healing, neovascularization, and amelioration of vascular calcification. By contrast, chronic increases in OPN predict poor prognosis of a major adverse cardiovascular event independent of conventional cardiovascular risk factors. Thus, OPN can be a therapeutic target for CVDs but is not clinically available. In this review, we discuss the role of OPN in the development of CVDs and its potential as a therapeutic target.

Targeting IL-6 in patients at high cardiovascular risk

The understanding that atherosclerosis is a chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anti-cytokine therapies targeting interleukin signalling pathways could serve as adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease.1 The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) showed that targeting interleukin (IL)-1β reduced cardiovascular event rates without lowering lipids or blood pressure.

Therapeutic Implications of NLRP3-Mediated Inflammation in Coronary Artery Disease.

Atherosclerosis is considered a chronic, inflammatory disease responsible for more than 15% of all global deaths, secondary to its complications of myocardial infarction, vascular disease, and stroke. Current treatment regimens consist of lipid-lowering pharmaceuticals, control of risk factors, and prevention of plaque rupture and thrombosis with antiplatelet agents. However, a significant burden on society remains due to the morbidity and mortality of coronary artery disease despite our best practices. In addition to dyslipidemia and hemostasis, inflammation has now moved to the proverbial forefront as the remaining obstacle to appropriate management of atherosclerosis. A complex dance of endothelial dysfunction, complement activation, and immune cell-mediated cytokine release underlie the pathogenesis of atherosclerotic plaque development, destabilization, and rupture. Cholesterol-induced sterile inflammation is thought to be central to this process via activation of a protein complex called the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome. The focus of this review article will be to examine the NLRP3 inflammasome, which directs the release of interleukin-1, leading to downstream pro-inflammatory effects, and its potential for therapeutic targeting using currently available and future tools in our pharmacologic arsenal. In particular, we focus on the results of several large, recently concluded clinical trials including the Canakinumab Antiinflammatory Thrombosis Outcome Study, Colchicine Cardiovascular Outcomes Trial, and the Low-Dose Colchicine Study, examining the efficacy of direct inhibition of interleukin-1 with canakinumab or a multimodal approach to inhibiting the NLRP3 inflammasome using colchicine, as well as an overview of novel small molecule inhibitors that are still in development.

Abstract PO033: Regulation of immune checkpoint proteins in NSCLC adenocarcinoma

Abstract Lung cancer is the leading cause of cancer-related deaths in both men and women. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC), with adenocarcinoma (adenoCa) being the main subtype. Well-defined mutational signatures of various lung cancer subtypes have been exploited for targeted therapies, but cancer cells often acquire resistance to these treatments, which could be mediated by the inflammatory tumor microenvironment (TME). Inflammation within the TME is known to promote cancer progression and therapy resistance. The inflammatory cytokine, interleukin-1 beta (IL-1β) is elevated in the TME of several cancers and correlates with poor outcomes. In NSCLC patients, serum IL-1β is elevated relative to normal subjects; within the same patient, IL-1β is elevated in the tumor relative to adjacent non-tumor tissue. Significantly, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) showed that blockade of IL-1 signaling could drastically reduce lung cancer incidence and mortality. Interestingly, we observed that NSCLC adenoCa cell lines H1838, H2228, H2347, HCC4150 and HCC827 have significantly higher basal expression of the Type 1 IL-1 receptor (IL-1R1), relative to immortalized normal Human Bronchial Epithelial Cell (HBEC-3KT) and Human Small Airway Epithelial Cell (HSAEC-1KT) lines, suggesting that adenoCa cells are primed to respond to IL-1 signaling. Cancer cells can promote immunosuppression through the expression of immune checkpoint proteins (ICPs). Previously, we identified several ICPs, including programmed death-ligand 1 (PD-L1), tryptophan 2,3-dioxygenase 2 (TDO2), indoleamine 2, 3-dioxygenase 1 (IDO1) and growth differentiation factor 15 (GDF15), that were developmentally upregulated by transcription factor nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) in human fetal lung epithelial cells during differentiation in culture. Importantly, genomic studies have revealed that &amp;gt;20% of lung adenoCa harbor mutations in NRF2 or its inhibitor KEAP1, which cause NRF2 activation. Lung adenoCa with signatures of increased NRF2 activation manifest reduced immune cell infiltration, suggesting that increased expression of NRF2 might create a more permissive immune cell environment, resulting in evasion and tolerance to the host immune system. Given that IL-1β induces ROS which can activate NRF2, we hypothesized that IL-1β present in the TME may enhance expression of NRF2 and ICPs in NSCLC adenoCa. We found that increased expression of ICPs in adenoCa cell lines H1838, H2228, H2347, HCC4150 and HCC827 compared to HBEC-3KT and HSAEC-1KT cells was correlated with significantly increased expression of NRF2. When these adenoCa cell lines were treated with IL-1β, we observed a marked induction in NRF2 and ICP mRNA and protein levels. Taken together our studies indicate that NSCLC adenoCa cells are primed to respond to IL-1 signaling which induces NRF2 and ICPs to promote tumor cell survival through immunosuppression. Citation Format: Afshan Fathima Nawas, Ritu Mishra, Carole R. Mendelson. Regulation of immune checkpoint proteins in NSCLC adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO033.

Canakinumab for secondary prevention of coronary artery disease.

Cardiovascular disease manifestations (CVD) are the world's leading cause of death, and their impact on morbidity requires effective prevention strategies of recurrent adverse events. For decades, inflammation has been proposed as a key promoter for atherosclerosis and its complications. However, studies on the use of drugs to target the excess inflammation in CVD are limited. In 2017, the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial confirmed the key role of inflammation on atherosclerotic disease. Canakinumab is a monoclonal antibody that blocks an inflammatory pathway mediated by IL-1β. The results of the CANTOS trial opened a new era of investigating new therapeutics targeting inflammation for CVD secondary prevention. This review presents the canakinumab's pharmacology, current clinical development status and regulatory perspectives.

Anti-inflammatory Therapy for Coronary Atherosclerotic Heart Disease: Unanswered Questions Behind Existing Successes.

Coronary atherosclerotic heart disease is a serious threat to human health. The results of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study published in 2017 put an end to the perennial debate about the anti-inflammatory treatment of coronary atherosclerotic heart disease. In addition to interleukin 1β monoclonal antibody, interleukin 6 receptor antagonists and colchicine have also shown exciting results in clinical trials within the last 3 years. However, behind these successes, questions remain that need to be addressed. In this review, we summarize the successes and existing doubts of interleukin 1β antibodies, interleukin 6 receptor antagonists, and colchicine in the anti-inflammatory treatment of coronary atherosclerotic heart disease.

NLRP3 inflammasome as a key driver of vascular disease.

Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular innate immune receptor that recognizes a diverse range of stimuli derived from pathogens, damaged or dead cells, and irritants. NLRP3 activation causes the assembly of a large multiprotein complex termed the NLRP3 inflammasome, and leads to the secretion of bioactive interleukin (IL)-1β and IL-18 as well as the induction of inflammatory cell death termed pyroptosis. Accumulating evidence indicates that NLRP3 inflammasome plays a key role in the pathogenesis of sterile inflammatory diseases, including atherosclerosis and other vascular diseases. Indeed, the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study trial demonstrated that IL-1β-mediated inflammation plays an important role in atherothrombotic events and suggested that NLRP3 inflammasome is a key driver of atherosclerosis. In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, in particular in atherosclerosis, vascular injury, aortic aneurysm, and Kawasaki disease vasculitis, and discuss NLRP3 inflammasome as a therapeutic target for these disorders.

Thromboses and COVID-19: reducing inflammation in addition to thromboprophylaxis.

Thromboses and COVID-19: reducing inflammation in addition to thromboprophylaxis.

Update on the Inflammatory Hypothesis of Coronary Artery Disease.

The pathogenesis and progression of coronary artery disease (CAD) is now known to be largely driven by inflammation on top of the well-accepted role for the disequilibrium between cholesterol deposition and removal from the arterial wall. Recent clinical trials have supported the inflammatory hypothesis of CAD and will be discussed in this review. The clinical trial Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) found that treatment with canakinumab, an anti-interleukin-1β agent, resulted in a reduction in non-fatal myocardial infarction, non-fatal stroke, or death. This provided evidence for the inflammatory hypothesis of CAD. However, canakinumab is not cost-effective for widespread therapy and more cost-effective treatments are warranted. The Cardiovascular Inflammation Reduction Trial (CIRT), Colchicine Cardiovascular Outcomes Trial (COLCOT), and Low-Dose Colchicine 2 (LoDoCo2) are recent clinical trials that increased the understanding of the inflammatory hypothesis of CAD. Cost-effective therapies targeting inflammation are the future of preventative CAD treatment. Additional clinical trials with anti-inflammatory and anti-cytokine agents would help delineate the most beneficial target for CAD prevention.

Inhibition of IL1β by Canakinumab May Be Effective against Diverse Molecular Subtypes of Lung Cancer: An Exploratory Analysis of the CANTOS Trial

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer. SIGNIFICANCE: These findings suggest that targeting the IL1β inflammatory pathway might be critical in reducing tumor-promoting inflammation and lung cancer incidence.