Blockade of TGF-ß and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses.

BACKGROUND: Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-ß (TGF-ß) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-ß and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models. METHODS: BA is a first-in-class bifunctional inhibitor of TGF-ß and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models. RESULTS: Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-ß and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls. CONCLUSIONS: Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.

Hearing Loss and Dementia: A Population-Based Cohort Study.

INTRODUCTION: Hearing loss (HL) is considered a potentially modifiable risk factor for dementia. We aimed to examine the relationship between HL and incident dementia diagnosis in a province-wide population-based cohort study with matched controls. METHODS: Administrative healthcare databases were linked to generate a cohort of patients who were aged ≥40 years at their first claimed hearing amplification devices (HAD) between April 2007 and March 2016 through the Assistive Devices Program (ADP) (257,285 with claims and 1,005,010 controls). The main outcome was incident dementia diagnosis, ascertained using validated algorithms. Dementia incidence was compared between cases and controls using Cox regression. Patient, disease, and other risk factors were examined. RESULTS: Dementia incidence rates (per 1,000 person-years) were 19.51 (95% confidence interval [CI]: 19.26-19.77) and 14.15 (95% CI: 14.04-14.26) for the ADP claimants and matched controls, respectively. In adjusted analyses, risk of dementia was higher in ADP claimants compared with controls (hazard ratio [HR]: 1.10 [95% CI: 1.09-1.12, p < 0.001]). Subgroup analyses showed a dose-response gradient, with risk of dementia higher among patients with bilateral HADs (HR: 1.12 [95% CI: 1.10-1.14, p < 0.001]), and an exposure-response gradient, with increasing risk over time from April 2007-March 2010 (HR: 1.03 [95% CI: 1.01-1.06, p = 0.014]), April 2010-March 2013 (HR: 1.12 [95% CI: 1.09-1.15, p < 0.001]), and April 2013-March 2016 (HR: 1.19 [95% CI: 1.16-1.23, p < 0.001]). CONCLUSION: In this population-based study, adults with HL had an increased risk of being diagnosed with dementia. Given the implications of HL on dementia risk, understanding the effect of hearing interventions merits further investigation.

Hearing aid utilization in Ontario - a population based study.

BACKGROUND: Hearing loss is one of the most common sensory impairments and hearing aids are the most common unmet assistive device need among individuals with a disability. The benefits of hearing interventions are well-documented as they are known to deter the sequalae of hearing loss including social isolation, poor mental health, falls and cognitive decline. Identifying trends in hearing aid users can provide valuable information for improving access to hearing loss interventions. METHODS: Data were retrieved from ICES databases that were used to generate a cohort of 372,448 individuals in Ontario, Canada, who first claimed hearing aids between April 2007 and March 2018 through the Assistive Devices Program. RESULTS: The data indicated that the frequency distribution of hearing aids has steadily inclined since 2007. The mean age of hearing aid users was 70.25 ± 14.70 years and higher neighbourhood income quintile was associated with greater hearing aid use (p < 0.001). Most first claims occurred after visiting primary care physicians (70.60%) compared with otolaryngology (13.39%). An examination of clinical comorbidities revealed hypertension (63.41%), and diabetes (24.93%) to be the most common. Regression analysis demonstrated a positive associated between age and most comorbidities. Furthermore, higher neighbourhood income quintiles were associated with a reduced risk of having the examined comorbidities. CONCLUSIONS: This study examines patient demographics and clinical comorbidities in a cohort of hearing aid users in Ontario. The results identify associations between demographics and comorbidities that provide information relevant for improving access to hearing interventions and clinical decision-making in primary care.Implications for RehabilitationScreening for hearing loss (using an audiogram) in elderly individuals that manage multiple comorbidities, and any patient with significant risk factors for hearing loss (e.g., noise exposure history, prior ototoxic medications, prior head injury, history of ear surgery, family history of hearing loss) will identify deficits and direct appropriate hearing interventions.Improving access to care in low-income communities should include community-based education around expectation management and communication strategies to reinforce proper use and care of hearing devices.Geographic proximity to hearing testing facilities and hearing aid dispensaries is a significant barrier to hearing rehabilitation strategies.

How to identify balance disorders and reduce fall risk.

A multifactorial risk assessment, correction of hearing impairment, exercise, and an optimized home environment can help prevent imbalance-related falls.

Predictors of Postoperative Complications in Vestibular Schwannoma Surgery-A Population-Based Study.

OBJECTIVE: To investigate preoperative patient demographics and comorbidities in relation with postsurgical complications following vestibular schwannoma surgery. STUDY DESIGN: Retrospective population-based cohort study. SETTING: All hospitals in the Canadian province of Ontario. PATIENTS: This study includes 1,456 patients who underwent vestibular schwannoma surgery from April 1, 2002 to March 31, 2018 in Ontario, Canada. INTERVENTION/OUTCOME MEASURES: For all surgical patients, the demographic data, preoperative comorbidities, and postoperative complications were evaluated. Postoperative complications were examined immediately following surgery in the hospital as well as 1 year following the hospital discharge. RESULTS: The most common comorbidities in this cohort were hypertension (30.22%), diabetes (9.48%), asthma (13.53%), and chronic obstructive pulmonary disease (6.73%). Diabetes was the most impactful comorbidity and was associated with higher risk of myocardial infarction (RR = 4.58, p < 0.01), pneumonia (RR = 1.80, p = 0.02), dysphagia (RR = 1.58, p < 0.01), and meningitis (RR = 3.62, p < 0.01). Analysis of surgical approaches revealed that the translabyrinthine approach, compared with the open craniotomy approach, was negatively associated with postoperative complications including pneumonia (RR = 0.43, p < 0.01), urinary tract infection (RR = 0.55, p = 0.01), dysphagia (RR = 0.66, p < 0.01), and readmission (RR = 0.45, p < 0.01). CONCLUSION: This study examines patient demographics, preoperative comorbidities, and postoperative complications in patients who have undergone vestibular schwannoma surgery. The results highlight associations between patient characteristics and postoperative outcomes that can aid in preoperative decision-making and counselling.

Approach to hearing loss.

OBJECTIVE: To provide family physicians with a practical evidence-based approach to the management of patients with hearing loss. SOURCES OF INFORMATION: MEDLINE and PubMed databases were searched for English-language hearing loss research, review articles, and guidelines published between 1980 and 2020. Most of the retrieved articles provided level II or III evidence. MAIN MESSAGE: Hearing loss is one of the most common sensory impairments worldwide and causes great detriment to a patient's overall well-being by affecting physical health, finances, social inclusion, and mental health. A robust clinical assessment of hearing loss includes a history and physical examination that effectively characterizes the deficit as conductive, sensorineural, or mixed. Patients presenting with red flags (such as sudden unilateral sensorineural hearing loss) must be urgently referred to otolaryngology-head and neck surgery or immediately assessed in the emergency department. Many nonurgent presentations of hearing loss will also require referral for further audiological assessment, diagnosis, and management. CONCLUSION: As primary care providers, family physicians are well equipped to manage the psychological concerns associated with hearing loss and to reinforce conservative treatment strategies. Frequently, referral or urgent workup, including imaging, is necessary to confirm a patient's diagnosis and initiate management in order to prevent further complications.

Aborder la perte auditive.

OBJECTIF: Fournir aux médecins de famille une approche pratique et fondée sur des données probantes pour la prise en charge de la perte auditive. SOURCES D'INFORMATION: Une recherche dans les bases de données MEDLINE et PubMed a relevé les revues de synthèse, recherches et lignes directrices publiées en anglais de 1980 à 2020. Les données probantes étaient de niveau II ou III dans la plupart des articles relevés. MESSAGE PRINCIPAL: La perte auditive est l'une des déficiences sensorielles les plus fréquentes dans le monde, et elle est grandement préjudiciable au bien-être général du patient, affectant sa santé physique, ses finances, son inclusion sociale et sa santé mentale. Une solide évaluation clinique de la perte auditive comprend une anamnèse et un examen physique qui caractérisent efficacement la perte auditive comme étant de transmission, neurosensorielle ou mixte. Les patients qui présentent des signes alarmants (comme une perte auditive neurosensorielle unilatérale soudaine) doivent être aiguillés d'urgence en oto-rhino-laryngologie et chirurgie cervico-faciale ou être évalués immédiatement au service des urgences. Beaucoup de cas non urgents de perte auditive nécessitent également une évaluation audiologique plus poussée, un diagnostic et la prise en charge. CONCLUSION: À titre de fournisseurs de soins de première ligne, les médecins de famille sont bien placés pour gérer les préoccupations psychologiques liées à la perte auditive et pour renforcer les stratégies thérapeutiques prudentes. Il est fréquemment nécessaire d'aiguiller le patient ou d'effectuer un bilan urgent, dont l'imagerie, pour confirmer le diagnostic et instaurer la prise en charge afin de prévenir d'autres complications.

Blockade of TGF-ß signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models.

Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-ß (TGF-ß) within ascites has been linked to poor prognosis. TGF-ß signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-ß receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-ß signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-ß signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-ß pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models.

Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis.

Amplification of HER2 leads to development of HER2-positive (HER2+) cancers with high rates of metastasis compared to other cancer subtypes. The goal of this study was to probe the vulnerability of HER2+ cancer cells to a filamentous actin (F-actin) severing and capping toxin. The growth and viability of human HER2+ breast cancer (HCC1954) and ovarian cancer (SKOV3) cell lines were significantly impaired upon treatment with the marine macrolide mycalolide B (Myc B) at doses above 100 nanomolar. Further testing of Myc B in combination with the antibody-drug conjugate Trastuzumab-emtansine (T-DM1) led to improved killing of SKOV3 cells compared to either treatment alone. At sub-lethal doses, treatment of HER2+ cancer cells with Myc B resulted in rapid loss of leading edge protrusions and formation of aggresomes containing F-actin and the actin regulatory protein Cortactin. This correlated with robust inhibition of HER2+ cancer cell motility and invasion with Myc B treatment. In SKOV3 tumor xenograft assays, intratumoral injections of Myc B impaired HER2+ tumor growth and metastasis, with maximal effects observed in combination with systemic delivery of Trastuzumab. Metastasis of SKOV3 cells to the lungs following tail vein injection was also reduced by Myc B. Together, these findings provide rationale for targeting F-actin in combination with existing therapies for HER2+ cancers to reduce metastasis.

MicroRNA-206 suppresses TGF-ß signalling to limit tumor growth and metastasis in lung adenocarcinoma.

MicroRNA-206 (miR-206) has demonstrated tumor suppressive effects in a variety of cancers. Numerous studies have identified aberrantly expressed targets of miR-206 that contribute to tumor progression and metastasis, however, the broader gene-networks and pathways regulated by miR-206 remain poorly defined. Here, we have ectopically expressed miR-206 in lung adenocarcinoma cell lines and tumors to identify differentially expressed genes, and study the effects on tumor growth and metastasis. In H1299 tumor xenograft assays, stable expression of miR-206 suppressed both tumor growth and metastasis in mice. Profiling of xenograft tumors using small RNA sequencing and a targeted panel of tumor progression and metastasis-related genes revealed a network of genes involved in TGF-ß signalling that were regulated by miR-206. Among these were the TGFB1 ligand, as well as direct transcriptional targets of Smad3. Other differentially expressed genes included components of the extracellular matrix involved in TGF-ß activation and signalling, including Thrombospondin-1, which is responsible for the activation of latent TGF-ß in the stroma. In cultured lung adenocarcinoma cells treated with recombinant TGF-ß, ectopic expression of miR-206 impaired canonical signalling, and expression of TGF-ß target genes linked to epithelial-mesenchymal transition. This was due at least in part to the suppression of Smad3 protein levels in lung adenocarcinoma cells with ectopic miR-206 expression. Together, these findings indicate that miR-206 can suppress tumor progression and metastasis by limiting autocrine production of TGF-ß, and highlight the potential utility of TGF-ß inhibitors for the treatment of lung adenocarcinomas.

Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis.

Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR+ CXC chemokines. The engineered molecules recognize functional epitopes of ELR+ CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics.

A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models.

Matrix metalloproteinase-14 (MMP-14) is a clinically relevant target in metastatic cancers due to its role in tumor progression and metastasis. Since active MMP-14 is localized on the cell surface, it is amenable to antibody-mediated blockade in cancer, and here we describe our efforts to develop novel inhibitory anti-MMP-14 antibodies. A phage-displayed synthetic humanized Fab library was screened against the extracellular domain of MMP-14 and a panel of MMP14-specific Fabs were identified. A lead antibody that inhibits the catalytic domain of MMP-14 (Fab 3369) was identified and treatment of MDA-MB-231 breast cancer cells with Fab 3369 led to significant loss of extracellular matrix degradation and cell invasion abilities. In mammary orthotopic tumor xenograft assays, MMP-14 blockade by IgG 3369 limited tumor growth and metastasis. Analysis of tumor tissue sections revealed that MMP-14 blockade limited tumor neoangiogenesis and hypoxia. Similar effects of MMP-14 blockade in syngeneic 4T1 mammary tumors were observed, along with increased detection of cytotoxic immune cell markers. In conclusion, we show that immunotherapies targeting MMP-14 can limit immune suppression, tumor progression, and metastasis in triple-negative breast cancer.

Advances and challenges in mucosal adjuvant technology.

Adjuvants play attractive roles in enhancement of immune response during vaccination; however, due to several challenges, only a limited number of adjuvants are licensed by health authorities. The lack of an effective mucosal adjuvant is even more significant as none of the licensed adjuvants revealed a strong enhancement in immune system after mucosal administration. Over the past two decades, several mucosal adjuvants have been developed to deliver antigens to the target cells in the mucosal immune system and increase specific immune responses. However, the safety and efficacy of these adjuvants for testing in human trials is still an important issue, requiring further study. In this article, we briefly review the challenges associated with most common mucosal adjuvants and discuss potential strategies for targeting the mucosal immune system.

Identification and validation of dysregulated metabolic pathways in metastatic renal cell carcinoma.

Metastatic renal cell carcinoma (mRCC) is a devastating disease with a 5-year survival rate of approximately 9 % and low response to chemotherapy and radiotherapy. Targeted therapies have slightly improved patient survival, but are only effective in a small subset of patients, who eventually develop resistance. A better understanding of pathways contributing to tumor progression and metastasis will allow for the development of novel targeted therapies and accurate prognostic markers. We performed extensive bioinformatics coupled with experimental validation on proteins dysregulated in mRCC. Gene ontology analysis showed that many proteins are involved in oxidation reduction, metabolic processes, and signal transduction. Pathway analysis showed metabolic pathways are altered in mRCC including glycolysis and pyruvate metabolism, the citric acid cycle, and the pentose phosphate pathway. RT-qPCR analysis showed that genes involved in the citric acid cycle were downregulated in metastatic RCC while genes of the pentose phosphate pathway were overexpressed. Protein-protein interaction analysis showed that most of the 198 proteins altered in mRCC clustered together and many were involved in glycolysis and pyruvate metabolism. We identified 29 reported regions of chromosomal aberrations in metastatic disease that correlate with the direction of protein dysregulation in mRCC. Furthermore, 36 proteins dysregulated in mRCC are predicted to be targets of metastasis-related miRNAs. A more comprehensive understanding of the pathways dysregulated in metastasis can be useful for the development of new therapies and novel prognostic markers. Also, multileveled analyses provide a unique "snapshot" of the molecular "environment" in RCC with prognostic and therapeutic implications.