The benefit from immune checkpoint inhibitors is tempered by immunologic toxicities, which involve diverse organs, have varying biology, onset time, and severity. Herein, we identify important areas of controversy and open research questions in the field of immune-related toxicity. Immune checkpoint inhibitors and immune-related adverse events in cancer therapyThe oncology field has been historically dominated by cytotoxic chemotherapy. Immune checkpoint inhibitors (ICI) represent a significant step forward in the clinical practice of medical oncologists. With responses across several tumour types, immunotherapy has resulted in durable responses for selected patients and even a tentative re-introduction of the word 'cure' 1 .However, it is not only the efficacy of ICIs that distinguishes them from chemotherapy. These treatments are also linked to a new cadre of side effects, termed immune-related adverse events (irAEs). Immune-related toxicities are autoimmune conditions that can affect any organ in the body after ICI administration, with natural histories that are distinct from their de novo autoimmune disease counterparts. Thus, these toxicities represent a varied challenge in clinical practice and a steep learning curve to diagnose and manage. Rather than managing the familiar nausea, immunosuppression and anaemia, we now face underactive pituitary glands, inflamed bowel segments and hepatitis (Table 1). A decade on from the first immunotherapy approval, how much do we know about these cryptic harms and how do we balance their risk with the undeniable benefits of immunotherapy?There are some fundamental principles we now understand about irAEs. Immune-related toxicities vary in terms of their time of onset, severity, and underlying biology. They affect a broad range of organs and thus require a tailored management approach. They can occur at any time during a patient's treatment course, most commonly in the first 3 months of treatment, but sometimes long after ICI has been discontinued. Second, despite this heterogeneity of presentation, the management of irAEs is centred around treatment with glucocorticoids. Most symptomatic irAEs (except endocrinopathies) are managed with several weeks of glucocorticoid treatment, with good effect. Third, while most irAEs resolve, some become chronic and may require lifelong therapy such as hormonal supplementation or immunosuppression.More importantly, there are several aspects of irAEs that we do not understand and which are the source of several controversies in the field.Several high-impact publications have demonstrated a positive association between the development of irAEs and anti-tumour responses to ICIs, across tumour types 2,3 . In addition, we have seen incremental gains in survival outcomes as patients develop numerically more irAEs 4 . It is hypothesised that both the anti-tumour response and the development of irAEs are representative of a robust immune reaction, where self-reactive T cells infiltrate both tumours and the organs that develop irAEs. However, o...
BackgroundNatural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output.MethodsSingle-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controlsResultsIn addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-β (TGFβ) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFβ processing pathway, was increased on NK cells from some patients. Blocking the GARP–TGFβ axis recapitulated the effects of TGFβ neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time.ConclusionsTGFβ contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFβ and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.
Antibodies directed against the beta chain of the T cell receptor (anti-Vbeta antibodies) are useful to identify the Vbeta repertoire of T cells in various diseases and to quantify numbers of Vbeta-bearing T cells. The goals of this study were to identify Vbeta+ cases of leukemic phase cutaneous T cell lymphoma (CTCL) and to compare the percentage of positive calls with other measures of blood tumor burden, i.e., lymphocyte subsets with a CD4+CD7- and CD4+CD26- phenotype and Sezary cell counts. Thirty-three of 49 (67%) cases of leukemic CTCL reacted with an anti-Vbeta antibody. When combined with reports from the literature, the frequency of Vbeta5 (probably Vbeta5.1) usage was relatively high when compared with Vbeta2 that is also frequently expressed by normal CD4+ T cells. The percentage of Vbeta+ cells correlated to the percentage of CD4+CD7- and CD4+CD26- cells for cases in which the neoplastic cells were deficient in expression of CD7 and CD26, respectively, but not the Sezary cell count. We hypothesize that the increased Vbeta5.1 usage in CTCL may be the result of depletion of Vbeta2 and other Vbeta-bearing T cells by staphylococcal superantigens prior to neoplastic transformation, resulting in a relative increase in the frequency of Vbeta5.1 usage in CTCL.
ObjectivesTo explore patient characteristics recorded at the initial consultation associated with a poor response to non-surgical multidisciplinary management of knee osteoarthritis (KOA) in tertiary care.DesignProspective multisite longitudinal study.SettingAdvanced practice physiotherapist-led multidisciplinary orthopaedic service within eight tertiary hospitals.Participants238 patients with KOA.Primary and secondary outcome measuresStandardised measures were recorded in all patients prior to them receiving non-surgical multidisciplinary management in a tertiary hospital service across multiple sites. These measures were examined for their relationship with a poor response to management 6 months after the initial consultation using a 15-point Global Rating of Change measure (poor response (scores −7 to +1)/positive response (scores+2 to+7)). Generalised linear models with binomial family and logit link were used to examine which patient characteristics yielded the strongest relationship with a poor response to management as estimated by the OR (95% CI).ResultsOverall, 114 out of 238 (47.9%) participants recorded a poor response. The odds of a poor response decreased with higher patient expectations of benefit (OR 0.74 (0.63 to 0.87) per 1/10 point score increase) and higher self-reported knee function (OR 0.67 (0.51 to 0.89) per 10/100 point score increase) (p<0.01). The odds of a poor response increased with a greater degree of varus frontal knee alignment (OR 1.35 (1.03 to 1.78) per 5° increase in varus angle) and a severe (compared with mild) radiological rating of medial compartment degenerative change (OR 3.11 (1.04 to 9.3)) (p<0.05).ConclusionsThese characteristics may need to be considered in patients presenting for non-surgical multidisciplinary management of KOA in tertiary care. Measurement of these patient characteristics may potentially better inform patient-centred management and flag the need for judicious monitoring of outcome for some patients to avoid unproductive care.
Critical Care 2017, 21(Suppl 1):P349 Introduction Imbalance in cellular energetics has been suggested to be an important mechanism for organ failure in sepsis and septic shock. We hypothesized that such energy imbalance would either be caused by metabolic changes leading to decreased energy production or by increased energy consumption. Thus, we set out to investigate if mitochondrial dysfunction or decreased energy consumption alters cellular metabolism in muscle tissue in experimental sepsis. Methods We submitted anesthetized piglets to sepsis (n = 12) or placebo (n = 4) and monitored them for 3 hours. Plasma lactate and markers of organ failure were measured hourly, as was muscle metabolism by microdialysis. Energy consumption was intervened locally by infusing ouabain through one microdialysis catheter to block major energy expenditure of the cells, by inhibiting the major energy consuming enzyme, N+/K + -ATPase. Similarly, energy production was blocked infusing sodium cyanide (NaCN), in a different region, to block the cytochrome oxidase in muscle tissue mitochondria. Results All animals submitted to sepsis fulfilled sepsis criteria as defined in Sepsis-3, whereas no animals in the placebo group did. Muscle glucose decreased during sepsis independently of N+/K + -ATPase or cytochrome oxidase blockade. Muscle lactate did not increase during sepsis in naïve metabolism. However, during cytochrome oxidase blockade, there was an increase in muscle lactate that was further accentuated during sepsis. Muscle pyruvate did not decrease during sepsis in naïve metabolism. During cytochrome oxidase blockade, there was a decrease in muscle pyruvate, independently of sepsis. Lactate to pyruvate ratio increased during sepsis and was further accentuated during cytochrome oxidase blockade. Muscle glycerol increased during sepsis and decreased slightly without sepsis regardless of N+/K + -ATPase or cytochrome oxidase blocking. There were no significant changes in muscle glutamate or urea during sepsis in absence/presence of N+/K + -ATPase or cytochrome oxidase blockade. ConclusionsThese results indicate increased metabolism of energy substrates in muscle tissue in experimental sepsis. Our results do not indicate presence of energy depletion or mitochondrial dysfunction in muscle and should similar physiologic situation be present in other tissues, other mechanisms of organ failure must be considered. , and long-term follow up has shown increased fracture risk [2]. It is unclear if these changes are a consequence of acute critical illness, or reduced activity afterwards. Bone health assessment during critical illness is challenging, and direct bone strength measurement is not possible. We used a rodent sepsis model to test the hypothesis that critical illness causes early reduction in bone strength and changes in bone architecture. Methods 20 Sprague-Dawley rats (350 ± 15.8g) were anesthetised and randomised to receive cecal ligation and puncture (CLP) (50% cecum length, 18G needle single pass through anterior and posterior wa...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.