Non-pharmaceutical interventions to optimize cancer immunotherapy.

The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and one's own vulnerability and mortality might be counterproductive and not doing justice to the complexity of human nature. Unlike cytotoxic and lympho-depleting treatments, immune-engaging therapies strengthen the immune system and are typically less harmful for patients. Thus, cancer patients receiving checkpoint inhibitors are not viewed as being vulnerable per se, at least not in immunological and physical terms. This perspective article advocates a holistic approach to cancer immunotherapy, with an empowered patient in the center, focusing on personal resources and receiving domain-specific support from healthcare professionals. It summarizes recent evidence on non-pharmaceutical interventions to enhance the efficacy of immune checkpoint blockade and improve quality of life. These interventions target behavioral factors such as diet, physical activity, stress management, circadian timing of checkpoint inhibitor infusion, and waiving unnecessary co-medication curtailing immunotherapy efficacy. Non-pharmaceutical interventions are universally accessible, broadly applicable, instantly actionable, scalable, and economically sustainable, creating value for all stakeholders involved. Most importantly, this holistic framework re-emphasizes the patient as a whole and harnesses the full potential of anticancer immunity and checkpoint blockade, potentially leading to survival benefits. Digital therapeutics are proposed to accompany the patients on their mission toward change in lifestyle-related behaviors for creating optimal conditions for treatment efficacy and personal growth.

Smartphone-based cough monitoring as a near real-time digital pneumonia biomarker.

Background: Cough represents a cardinal symptom of acute respiratory tract infections. Generally associated with disease activity, cough holds biomarker potential and might be harnessed for prognosis and personalised treatment decisions. Here, we tested the suitability of cough as a digital biomarker for disease activity in coronavirus disease 2019 (COVID-19) and other lower respiratory tract infections. Methods: We conducted a single-centre, exploratory, observational cohort study on automated cough detection in patients hospitalised for COVID-19 (n=32) and non-COVID-19 pneumonia (n=14) between April and November 2020 at the Cantonal Hospital St Gallen, Switzerland. Cough detection was achieved using smartphone-based audio recordings coupled to an ensemble of convolutional neural networks. Cough levels were correlated to established markers of inflammation and oxygenation. Measurements and main results: Cough frequency was highest upon hospital admission and declined steadily with recovery. There was a characteristic pattern of daily cough fluctuations, with little activity during the night and two coughing peaks during the day. Hourly cough counts were strongly correlated with clinical markers of disease activity and laboratory markers of inflammation, suggesting cough as a surrogate of disease in acute respiratory tract infections. No apparent differences in cough evolution were observed between COVID-19 and non-COVID-19 pneumonia. Conclusions: Automated, quantitative, smartphone-based detection of cough is feasible in hospitalised patients and correlates with disease activity in lower respiratory tract infections. Our approach allows for near real-time telemonitoring of individuals in aerosol isolation. Larger trials are warranted to decipher the use of cough as a digital biomarker for prognosis and tailored treatment in lower respiratory tract infections.

Nighttime Continuous Contactless Smartphone-Based Cough Monitoring for the Ward: Validation Study.

BACKGROUND: Clinical deterioration can go unnoticed in hospital wards for hours. Mobile technologies such as wearables and smartphones enable automated, continuous, noninvasive ward monitoring and allow the detection of subtle changes in vital signs. Cough can be effectively monitored through mobile technologies in the ward, as it is not only a symptom of prevalent respiratory diseases such as asthma, lung cancer, and COVID-19 but also a predictor of acute health deterioration. In past decades, many efforts have been made to develop an automatic cough counting tool. To date, however, there is neither a standardized, sufficiently validated method nor a scalable cough monitor that can be deployed on a consumer-centric device that reports cough counts continuously. These shortcomings limit the tracking of coughing and, consequently, hinder the monitoring of disease progression in prevalent respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19 in the ward. OBJECTIVE: This exploratory study involved the validation of an automated smartphone-based monitoring system for continuous cough counting in 2 different modes in the ward. Unlike previous studies that focused on evaluating cough detection models on unseen data, the focus of this work is to validate a holistic smartphone-based cough detection system operating in near real time. METHODS: Automated cough counts were measured consistently on devices and on computers and compared with cough and noncough sounds counted manually over 8-hour long nocturnal recordings in 9 patients with pneumonia in the ward. The proposed cough detection system consists primarily of an Android app running on a smartphone that detects coughs and records sounds and secondarily of a backend that continuously receives the cough detection information and displays the hourly cough counts. Cough detection is based on an ensemble convolutional neural network developed and trained on asthmatic cough data. RESULTS: In this validation study, a total of 72 hours of recordings from 9 participants with pneumonia, 4 of whom were infected with SARS-CoV-2, were analyzed. All the recordings were subjected to manual analysis by 2 blinded raters. The proposed system yielded a sensitivity and specificity of 72% and 99% on the device and 82% and 99% on the computer, respectively, for detecting coughs. The mean differences between the automated and human rater cough counts were -1.0 (95% CI -12.3 to 10.2) and -0.9 (95% CI -6.5 to 4.8) coughs per hour within subject for the on-device and on-computer modes, respectively. CONCLUSIONS: The proposed system thus represents a smartphone cough counter that can be used for continuous hourly assessment of cough frequency in the ward.

Compartmentalization of the host microbiome: how tumor microbiota shapes checkpoint immunotherapy outcome and offers therapeutic prospects.

The host microbiome is polymorphic, compartmentalized, and composed of distinctive tissue microbiomes. While research in the field of cancer immunotherapy has provided an improved understanding of the interaction with the gastrointestinal microbiome, the significance of the tumor-associated microbiome has only recently been grasped. This article provides a state-of-the-art review about the tumor-associated microbiome and sheds light on how local tumor microbiota shapes anticancer immunity and influences checkpoint immunotherapy outcome. The direct route of interaction between cancer cells, immune cells, and microbiota in the tumor microenvironment is emphasized and advocates a focus on the tumor-associated microbiome in addition to the spatially separated gut compartment. Since the mechanisms underlying checkpoint immunotherapy modulation by tumor-associated microbiota remain largely elusive, future research should dissect the pathways involved and outline strategies to therapeutically modulate microbes and their products within the tumor microenvironment. A more detailed knowledge about the mechanisms governing the composition and functional quality of the tumor microbiome will improve cancer immunotherapy and advance precision medicine for solid tumors.

OMIP 077: Definition of all principal human leukocyte populations using a broadly applicable 14-color panel.

This Optimized Multicolor Immunofluorescence Panel was designed to identify and quantify all principal leukocyte populations in human blood using a minimum number of markers. We achieved this goal using a carefully selected combination of 14 surface markers compatible with standard flow cytometric instruments and accessible to a particularly large research community. Optimized for use in whole blood, this panel allows polymorphonuclear cell identification, supports live cell recovery, and is well-suited for absolute cell counting applications in the original in vivo volume. Panel performance and the separation of populations are high, and virtually no cells remain undefined after gating. Besides the identification of neutrophils, eosinophils, basophils, T cells, natural killer cells, B cells, plasma cells, monocytes, myeloid dendritic cells and plasmacytoid dendritic cells, this panel also covers progenitor cells and may therefore be attractive for stem cell researchers. Envisioned applications of this panel include immune monitoring within clinical trials, initial discovery to inform subset-targeted panels, and clinical diagnostics. In summary, this panel offers a broadly applicable platform for immune cell identification, quantification and characterization in human samples, particularly whole blood.

Local tumor microbial signatures and response to checkpoint blockade in non-small cell lung cancer.

In cancer patients, the clinical response to checkpoint-based immunotherapy is associated with the composition and functional quality of the host microbiome. While the relevance of the gut microbiome for checkpoint immunotherapy outcome has been addressed intensively, data on the role of the local tumor microbiome are missing. Here, we set out to molecularly characterize the local non-small cell lung cancer microbiome using 16S rRNA gene amplicon sequencing of bronchoscopic tumor biopsies from patients treated with PD-1/PD-L1-targeted checkpoint inhibitors. Our analyses showed significant diversity of the tumor microbiome with high proportions of Firmicutes, Bacteroidetes and Proteobacteria. Correlations with clinical data revealed that high microbial diversity was associated with improved patient survival irrespective of radiology-based treatment response. Moreover, we found that the presence of Gammaproteobacteria correlated with low PD-L1 expression and poor response to checkpoint-based immunotherapy, translating into poor survival. Our study suggests novel microbiome-specific/derived biomarkers for checkpoint immunotherapy response prediction and prognosis in lung cancer. In a broader sense, our data draw attention to the local tumor microbial habitat as an important addition to the spatially separated microbiome of the gut compartment.

Influence of Measurement Location on Reflectance Pulse Oximetry in Sleep Apnea Patients: Wrist vs. Upper Arm.

Peripheral oxygen saturation (SpO2) plays a key role in diagnosing sleep apnea. It is mainly measured via transmission pulse oximetry at the fingertip, an approach less suited for long-term monitoring over several nights.In this study we tested a more patient-friendly solution via a reflectance pulse oximetry device. Having previously observed issues with pulse oximetry at the wrist, we investigated in this study the influence of the location of our device (upper arm vs. wrist) to measure SpO2. Accuracy was compared against state-of-the-art fingertip SpO2 measurements during a full overnight polysomnography in nine patients with suspected sleep apnea.The upper arm location clearly showed a lower root mean square error ARMS = 1.8% than the wrist ARMS = 2.5% and a lower rate of automatic data rejection (19% vs 25%). Irrespective of the measurement location the accuracies obtained comply with the ISO standard and the FDA guidance for pulse oximeters. In contrast to the wrist, the upper arm location seemed to be more resilient to deteriorating influences such as venous blood.Reflectance pulse oximetry at the wrist remains challenging but the upper arm could provide remedy for more robust SpO2 estimates to reliably screen for sleep apnea and other diseases.Clinical Relevance- The performance of reflectance pulse oximetry measured at the upper arm during sleep is superior to measurements at the wrist which are perturbed by undesired large fluctuations suspected to be caused by venous blood. If confirmed, this could also apply to the optical measurement of other vital signs such as blood pressure.

Laser facilitated epicutaneous peptide immunization using dry patch technology.

The skin has been intensely investigated as a target tissue for immunization because it is populated by multiple types of antigen presenting cells. Directly addressing dendritic cells or Langerhans cells in vivo represents an attractive strategy for inducing T cell responses in cancer immunotherapy. We and others have studied fractional laser ablation as a novel method combining efficient delivery of macromolecules to the skin with an inherent adjuvant effect of laser illumination. In this proof of concept study, we demonstrate the feasibility of peptide delivery to the skin using the P.L.E.A.S.E. professional Erb:YAG fractional infrared laser together with EPIMMUN patches. In an ovalbumin mouse model we demonstrate that a dry patch formulation of SIINFEKL peptide in combination with CpG-ODN1826, but not imiquimod or polyI:C, induces potent cytotoxic T cell responses, which can be further boosted by co-delivery of the pan-helper T cell epitope PADRE.

Phase I Study to Assess Safety of Laser-Assisted Topical Administration of an Anti-TNF Biologic in Patients With Chronic Plaque-Type Psoriasis.

Ablative fractional laser treatment facilitates epidermal drug delivery, which might be an interesting option to increase the topical efficacy of biological drugs in a variety of dermatological diseases. This work aims at investigating safety and tolerability of this new treatment approach in patients with plaque-type psoriasis. Eight patients with plaque-type psoriasis were enrolled in this study. All patients received (i) ablative fractional laser microporation (AFL) of a psoriatic lesion with an Er:YAG laser + etanercept (ETA; Enbrel® solution for injection) (AFL-ETA), (ii) ETA alone on another lesion, and, if feasible, (iii) AFL alone on an additional lesion. Overall, all treatment arms showed a favorable safety profile. AFL-ETA improved the lesion-specific TPSS score by 1.75 vs. baseline, whereas ETA or AFL alone showed a TPSS score improvement of 0.75 points, a difference that was not statistically significant and might be attributable to differences in baseline scores. Topical administration of ETA to psoriatic plaques via AFL-generated micropores was generally well-tolerated. No special precautions seem necessary in future studies. Clinical benefit will need assessment in sufficiently powered follow-up studies.

Laser-facilitated epicutaneous immunization of mice with SARS-CoV-2 spike protein induces antibodies inhibiting spike/ACE2 binding.

The skin represents an attractive target tissue for vaccination against respiratory viruses such as SARS-CoV-2. Laser-facilitated epicutaneous immunization (EPI) has been established as a novel technology to overcome the skin barrier, which combines efficient delivery via micropores with an inherent adjuvant effect due to the release of danger-associated molecular patterns. Here we delivered the S1 subunit of the Spike protein of SARS-CoV-2 to the skin of BALB/c mice via laser-generated micropores with or without CpG-ODN1826 or the B subunit of heat-labile enterotoxin of E.coli (LT-B). EPI induced serum IgG titers of 1:3200 that could be boosted 5 to 10-fold by co-administration of LT-B and CpG, respectively. Sera were able to inhibit binding of the spike protein to its receptor ACE2. Our data indicate that delivery of recombinant spike protein via the skin may represent an alternative route for vaccines against Covid-19.

Tumour neoantigen mimicry by microbial species in cancer immunotherapy.

Tumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body's anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy.

Transcriptomic profiling reveals disease-specific characteristics of epithelial cells in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterized by progressive lung fibrosis ultimately resulting in respiratory failure and death. Recurrent micro-injuries to the alveolar epithelium and aberrant alveolar wound healing with impaired re-epithelialization define the initial steps of the pathogenic trajectory. Failure of timely alveolar epithelial repair triggers hyper-proliferation of mesenchymal cells accompanied by increased deposition of extracellular matrix into the lung interstitium. METHODS: We previously isolated fibrosis-specific mesenchymal stem cell (MSC)-like cells from lung tissue of patients with interstitial lung diseases. These cells produced factors bearing anti-fibrotic potential and changed their morphology from mesenchymal to epithelial upon culture in an epithelial cell (EC)-specific growth medium. Here, we set out to molecularly characterize these MSC-like cell-derived ECs using global gene expression profiling by RNA-sequencing. Moreover, we aimed at characterizing disease-specific differences by comparing the transcriptomes of ECs from IPF and non-IPF sources. RESULTS: Our results suggest that differentially expressed genes are enriched for factors related to fibrosis, hypoxia, bacterial colonization and metabolism, thus reflecting many of the hallmark characteristics of pulmonary fibrosis. IPF-ECs showed enrichment of both pro- and anti-fibrotic genes, consistent with the notion of adaptive, compensatory regulation. CONCLUSIONS: Our findings support the hypothesis of a functional impairment of IPF-ECs, which could possibly explain the poor clinical outcome of IPF that roughly compares to those of advanced-stage cancers. Our study provides a valuable resource for downstream mechanistic investigation and the quest for novel therapeutic IPF targets.

Classification of Sleep Apnea Severity by Electrocardiogram Monitoring Using a Novel Wearable Device.

Sleep apnea (SA) is a prevalent disorder diagnosed by polysomnography (PSG) based on the number of apnea-hypopnea events per hour of sleep (apnea-hypopnea index, AHI). PSG is expensive and technically complex; therefore, its use is rather limited to the initial diagnostic phase and simpler devices are required for long-term follow-up. The validity of single-parameter wearable devices for the assessment of sleep apnea severity is still debated. In this context, a wearable electrocardiogram (ECG) acquisition system (ECG belt) was developed and its suitability for the classification of sleep apnea severity was investigated using heart rate variability analysis with or without data pre-filtering. Several classification algorithms were compared and support vector machine was preferred due to its simplicity and overall performance. Whole-night ECG signals from 241 patients with a suspicion of sleep apnea were recorded using both the ECG belt and patched ECG during PSG recordings. 65% of patients had an obstructive sleep apnea and the median AHI was 21 [IQR: 7-40] h - 1 . The classification accuracy obtained from the ECG belt (accuracy: 72%, sensitivity: 70%, specificity: 74%) was comparable to the patched ECG (accuracy: 74%, sensitivity: 88%, specificity: 61%). The highest classification accuracy was obtained for the discrimination between individuals with no or mild SA vs. moderate to severe SA. In conclusion, the ECG belt provided signals comparable to patched ECG and could be used for the assessment of sleep apnea severity, especially during follow-up.

High RIG-I expression in ovarian cancer associates with an immune-escape signature and poor clinical outcome.

Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum-based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real-time quantitative PCR to assess the expression of retinoic acid-inducible gene-I (RIG-I) in primary tumor and healthy ovarian control tissues. RIG-I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG-I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG-I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type-II cancers and cancers with inactivating p53 mutations exhibited higher RIG-I expression. RIG-I levels were also elevated in cancers that recurred after remission or were platinum-refractory. Survival analyses disclosed RIG-I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG-I expression in the tumor microenvironment, including interferon production and a distinct immune-regulatory signature involving checkpoint molecules (PD-L1/PD-1), the RNA-editing enzyme ADAR1 and the regulatory T cell-specific transcription factor FoxP3. We conclude that high RIG-I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG-I expression may inform checkpoint blockade and/or RIG-I agonistic targeting in a subset of high-risk OC patients.

Applicability of a Textile ECG-Belt for Unattended Sleep Apnoea Monitoring in a Home Setting.

Sleep monitoring in an unattended home setting provides important information complementing and extending the clinical polysomnography findings. The validity of a wearable textile electrocardiography (ECG)-belt has been proven in a clinical setting. For evaluation in a home setting, ECG signals and features were acquired from 12 patients (10 males and 2 females, showing an interquartile range for age of 48-59 years and for body mass indexes (BMIs) of 28.0-35.5) over 28 nights. The signal quality was assessed by artefacts detection, signal-to-noise ratio, and Poincaré plots. To assess the validity, the data were compared to previously reported data from the clinical setting. It was found that the artefact percentage was slightly reduced for the ECG-belt from 9.7% ± 14.7% in the clinical setting, to 7.5% ± 10.8% in the home setting. The signal-to-noise ratio was improved in the home setting and reached similar values to the gel electrodes in the clinical setting. Finally, it was found that for artefact percentages above 3%, Poincaré plots are instrumental to evaluate the origin of artefacts. In conclusion, the application of the ECG-belt in a home setting did not result in a reduction in signal quality compared to the ECG-belt used in the clinical setting, and thus provides new opportunities for patient pre-screening or follow-up.

Fibroblasts in cancer: Defining target structures for therapeutic intervention.

The functional importance of the tumor stroma for cancer growth and progression is increasingly recognized, but has not resulted in notable therapeutic developments yet. Within the mesenchymal tumor microenvironment, cancer-associated fibroblasts take the center stage and fuel tumor progression in various ways including malignant cell potentiation, immune regulation and fibrosis. However, recent studies have demonstrated pronounced heterogeneity of the fibroblastic tumor stroma, which comprises a plethora of individual cell subsets with varying phenotypes and functions, some of which suppress malignant growth through immune engagement or crosstalk with the tumor vasculature. This article summarizes the various levels at which the fibroblastic tumor stroma may impact cancer progression and highlights potential target structures for future therapeutic intervention(s).

Telemedicine for Continuous Positive Airway Pressure in Sleep Apnea. A Randomized, Controlled Study.

Rationale: Continuous positive airway pressure (CPAP) is the standard treatment for the obstructive sleep apnea syndrome (OSAS), but long-term adherence remains a challenge. In a pilot study, we observed that telemedicine combined with telemetrically triggered interventions was associated with improved CPAP adherence in the first month of treatment.Objectives: In the current randomized, controlled phase III trial, we aimed to collect pivotal data for the use of telemedicine in CPAP treatment of patients with OSAS.Methods: Symptomatic patients with OSAS were randomized to a telemedicine or control arm and initiated CPAP treatment. Phone calls were triggered in the telemedicine group during the first month of treatment upon either poor use or excessive mask leakage. Patients were followed for 6 months. Measures of CPAP use at 6 months were the main study endpoints.Results: Among 240 patients enrolled, 71 (30%) discontinued CPAP treatment over the course of the study. The primary outcome measure, the proportion of nights with CPAP use greater than 1 hour, was not statistically different in the telemedicine group (92.0%) versus the control group (88.2%) (P = 0.565). The daily hours of CPAP use at 6 months also did not differ significantly between the telemedicine group (5.6 h) and the control group (4.8 h) (P = 0.663). However, in a post hoc analysis, telemedicine led to increased device use in a subgroup of patients with a mild form of disease (5.6 h vs. 3.4 h; P = 0.026). The telemedicine-based intervention had a positive impact on sleep-related quality of life as measured with the Quebec Sleep Questionnaire (5.55 vs. 5.49 at 1 mo [P = 0.020]; 5.61 vs. 5.46 at 6 mo [P = 0.013]).Conclusions: A telemetrically triggered intervention in the first month of treatment did not improve CPAP use in the study population overall, but it had positive effects in patients with a mild form of OSAS and led to an improvement in sleep-related quality of life.Clinical trial registered with www.clinicaltrials.gov (NCT01715194).

Ovarian Cancer Stem Cell Heterogeneity.

Ovarian carcinoma features pronounced clinical, histopathological, and molecular heterogeneity. There is good reason to believe that parts of this heterogeneity can be explained by differences in the respective cell of origin, with a self-renewing fallopian tube secretory cell being likely responsible for initiation of an overwhelming majority of high-grade serous ovarian carcinomas (i.e., type II tumors according to the recent dualistic classification), whereas there are several mutually non-exclusive possibilities for the initiation of type I tumors, including ovarian surface epithelium stem cells, endometrial cells, or even cells of extra-Müllerian origin. Interestingly, both fallopian tube self-renewing secretory cells and ovarian surface epithelium stem cells seem to be characterized by an overlapping array of stemness signaling pathways, especially Wnt/ß-catenin. Apart from this variability in the respective cell of origin, the particular clinical behavior of ovarian carcinoma strongly suggests an underlying stem cell component with a crucial impact. This becomes especially evident in high-grade serous ovarian carcinomas treated with classical chemotherapy, which entails a gradual evolution of chemoresistant disease without any apparent selection of clones carrying obvious chemoresistance-associated mutations. Several cell surface markers (e.g., CD24, CD44, CD117, CD133, and ROR1) as well as functional approaches (ALDEFLUOR™ and side population assays) have been used to identify and characterize putative ovarian carcinoma stem cells. We have recently shown that side population cells exhibit marked heterogeneity on their own, which can hamper their straightforward therapeutic targeting. An alternative strategy for stemness-depleting interventions is to target the stem cell niche, i.e., the specific microanatomical structure that secures stem cell maintenance and survival through provision of a set of stem cell-promoting and differentiation-antagonizing factors. Besides identifying direct or indirect therapeutic targets, profiling of side population cells and other ovarian carcinoma stem cell subpopulations can reveal relevant prognostic markers, as exemplified by our recent discovery of the Vav3.1 transcript variant, which filters out a fraction of prognostically unfavorable ovarian carcinoma cases.