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AIM - Antibodies to programmed death-1 receptor and its ligand (anti-PD-1/PD-L1) produce durable responses in many cancers. However, the long-term effects of anti-PD-1/PD-L1 blockade are not well defined. We identified the toxicities, health outcomes and health-related quality of life (HRQoL) amongst long-term survivors treated with anti-PD-1/PD-L1.
METHODS - We assessed 217 patients who received anti-PD-1/PD-L1 for melanoma, renal cell carcinoma or non-small-cell lung carcinoma between 2009 and 2017, with survival greater than two years after treatment. Patient and tumour characteristics, immune-related adverse events (irAEs), cardiometabolic parameters (glucose, blood pressure, body mass index [BMI]), body composition (using automated body composition analyser, computed tomography and Slice-o-matic software) and HRQoL outcomes were tracked.
RESULTS - Among the included patients, most were men (70.3%) and at anti-PD-1/PD-L1 initiation had an average age of 61.0 years and median BMI of 28.5. Median overall survival was not reached; 33 (15.2%) died during the follow-up primarily from progressive cancer (n = 28). At the last follow-up, most patients' Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose or BMI from baseline to two years after treatment initiation. Body composition showed increased adiposity (p = 0.05), skeletal muscle mass (p = 0.03) and skeletal muscle gauge (p = 0.04). We observed chronic irAEs at the last follow-up including hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%) and neuropathy (2.8%). New diagnoses of type 2 diabetes (6.5%) and hypertension (6.0%) were observed, with uncertain relationship to anti-PD-1/PD-L1. Patient-reported outcomes compared favourably with cancer and general populations, although younger age (p = 0.003) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL outcomes.
CONCLUSION - Durable responses to anti-PD-1/PD-L1 therapy and favourable HRQoL outcomes are encouraging. Chronic events may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.
Copyright © 2020 Elsevier Ltd. All rights reserved.
COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
The B cell CLL/lymphoma-2 (BCL-2) family of proteins control the mitochondrial pathway of apoptosis, also known as intrinsic apoptosis. Direct binding between members of the BCL-2 family regulates mitochondrial outer membrane permeabilization (MOMP) after an apoptotic insult. The ability of the cell to sense stress and translate it into a death signal has been a major theme of research for nearly three decades; however, other mechanisms by which the BCL-2 family coordinates cellular homeostasis beyond its role in initiating apoptosis are emerging. One developing area of research is understanding how the BCL-2 family of proteins regulate development using pluripotent stem cells as a model system. Understanding BCL-2 family-mediated regulation of mitochondrial homeostasis in cell death and beyond would uncover new facets of stem cell maintenance and differentiation potential.
© 2020 Elsevier Inc. All rights reserved.
Immune checkpoint inhibitors (ICI) are now routinely used in multiple cancers but may induce autoimmune-like side effects known as immune-related adverse events (irAE). Although classical autoimmune diseases have well-known risk factors, including age, gender, and seasonality, the clinical factors that lead to irAEs are not well-defined. To explore these questions, we assessed 455 patients with advanced melanoma treated with ICI at our center and a large pharmacovigilance database (VigiBase). We found that younger age was associated with a similar rate of any irAEs but more frequent severe irAEs and more hospitalizations (OR, 0.97 per year). Paradoxically, however, older patients had more deaths and increased length of stay (LOS) when hospitalized. This was partially due to a distinct toxicity profile: Colitis and hepatitis were more common in younger patients, whereas myocarditis and pneumonitis had an older age distribution both in our center and in VigiBase. This pattern was particularly apparent with combination checkpoint blockade with ipilimumab and nivolumab. We did not find a link between gender or seasonality on development of irAEs in univariate or multivariate analyses, although winter hospitalizations were associated with marginally increased LOS. This study identifies age-specific associations of irAEs.
©2020 American Association for Cancer Research.
Tuberculosis (TB) remains a major infectious disease worldwide. TB treatment displays a biphasic bacterial clearance, in which the majority of bacteria clear within the first month of treatment, but residual bacteria remain nonresponsive to treatment and eventually may become resistant. Here, we have shown that Mycobacterium tuberculosis was taken up by mesenchymal stem cells (MSCs), where it established dormancy and became highly nonresponsive to isoniazid, a major constituent of directly observed treatment short course (DOTS). Dormant M. tuberculosis induced quiescence in MSCs and promoted their long-term survival. Unlike macrophages, where M. tuberculosis resides in early-phagosomal compartments, in MSCs the majority of bacilli were found in the cytosol, where they promoted rapid lipid synthesis, hiding within lipid droplets. Inhibition of lipid synthesis prevented dormancy and sensitized the organisms to isoniazid. Thus, we have established that M. tuberculosis gains dormancy in MSCs, which serve as a long-term natural reservoir of dormant M. tuberculosis. Interestingly, in the murine model of TB, induction of autophagy eliminated M. tuberculosis from MSCs, and consequently, the addition of rapamycin to an isoniazid treatment regimen successfully attained sterile clearance and prevented disease reactivation.
Subversion of endoplasmic reticulum (ER) function is a feature shared by multiple intracellular bacteria and viruses, and in many cases this disruption of cellular function activates pathways of the unfolded protein response (UPR). In the case of infection with , the etiologic agent of brucellosis, the unfolded protein response in the infected placenta contributes to placentitis and abortion, leading to pathogen transmission. Here we show that infection of pregnant mice led to death of infected placental trophoblasts in a manner that depended on the VirB type IV secretion system (T4SS) and its effector VceC. The trophoblast death program required the ER stress-induced transcription factor CHOP. While NOD1/NOD2 expression in macrophages contributed to ER stress-induced inflammation, these receptors did not play a role in trophoblast death. Both placentitis and abortion were independent of apoptosis-associated Speck-like protein containing a caspase activation and recruitment domain (ASC). These studies show that uses its T4SS to induce cell-type-specific responses to ER stress in trophoblasts that trigger placental inflammation and abortion. Our results suggest further that in the T4SS and its effectors are under selection as bacterial transmission factors. infects the placenta of pregnant cows, where it replicates to high levels and triggers abortion of the calf. The aborted material is highly infectious and transmits infection to both cows and humans, but very little is known about how causes abortion. By studying this infection in pregnant mice, we discovered that kills trophoblasts, which are important cells for maintaining pregnancy. This killing required an injected bacterial protein (VceC) that triggered an endoplasmic reticulum (ER) stress response in the trophoblast. By inhibiting ER stress or infecting mice that lack CHOP, a protein induced by ER stress, we could prevent death of trophoblasts, reduce inflammation, and increase the viability of the pups. Our results suggest that injects VceC into placental trophoblasts to promote its transmission by abortion.
Copyright © 2019 Byndloss et al.
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.