Publications by authors named "Benjamin W Ewanchuk"

9 Publications

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Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials.

Eur J Cancer 2021 Jul 8;151:115-125. Epub 2021 May 8.

Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada. Electronic address:

Background: Immuno-oncology (IO)-based therapies have been approved based on randomised clinical trials, yet a significant proportion of real-world patients are not represented in these trials. We sought to compare the outcomes of trial-ineligible vs. -eligible patients with advanced solid tumours treated with first-line (1L) IO therapy.

Patients And Methods: Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and the Alberta Immunotherapy Database, patients with advanced RCC, non-small-cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition-based therapy were included. Trial eligibility was retrospectively determined as per commonly used exclusion criteria. The outcomes of interest were overall survival (OS), overall response rate (ORR), treatment duration (TD) and time to next treatment (TTNT).

Results: A total of 395 of 1241 (32%) patients were deemed trial-ineligible. The main reasons for ineligibility based on preselected exclusion criteria were Karnofsky performance status <70%/Eastern Cooperative Oncology Group performance status >1 (40%, 158 of 395), brain metastases (32%, 126 of 395), haemoglobin < 9 g/dL (16%, 63 of 395) and estimated glomerular filtration rate <40 mL/min (15%, 61 of 395). Between the ineligible vs. eligible groups, the median OS, ORR, median TD and median TTNT were 10.2 vs. 39.7 months (p < 0.01), 36% vs. 47% (p < 0.01), 2.7 vs. 6.9 months (p < 0.01) and 6.0 vs. 16.8 months (p < 0.01), respectively. Subgroup analyses showed statistically significant inferior OS, TD and TTNT for trial-ineligible vs. -eligible patients across all tumour types. Adjusted hazard ratios for death in RCC, NSCLC and melanoma were 1.84 (95% confidence interval [CI] 1.22-2.77), 2.21 (95% CI 1.58-3.11) and 1.82 (95% CI 1.21-2.74), respectively..

Conclusions: Thirty-two percent of real-world patients treated with contemporary 1L IO-based therapies were ineligible for clinical trials. Although one-third of the trial-ineligible patients responded to treatment, the overall trial-ineligible population had inferior outcomes than trial-eligible patients. These data may guide patient counselling and temper expectations of benefit.
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http://dx.doi.org/10.1016/j.ejca.2021.04.004DOI Listing
July 2021

A non-immunological role for γ-interferon-inducible lysosomal thiol reductase (GILT) in osteoclastic bone resorption.

Sci Adv 2021 Apr 23;7(17). Epub 2021 Apr 23.

Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.

The extracellular bone resorbing lacuna of the osteoclast shares many characteristics with the degradative lysosome of antigen-presenting cells. γ-Interferon-inducible lysosomal thiol reductase (GILT) enhances antigen processing within lysosomes through direct reduction of antigen disulfides and maintenance of cysteine protease activity. In this study, we found the osteoclastogenic cytokine RANKL drove expression of GILT in osteoclast precursors in a STAT1-dependent manner, resulting in high levels of GILT in mature osteoclasts, which could be further augmented by γ-interferon. GILT colocalized with the collagen-degrading cysteine protease, cathepsin K, suggesting a role for GILT inside the osteoclastic resorption lacuna. GILT-deficient osteoclasts had reduced bone-resorbing capacity, resulting in impaired bone turnover and an osteopetrotic phenotype in GILT-deficient mice. We demonstrated that GILT could directly reduce the noncollagenous bone matrix protein SPARC, and additionally, enhance collagen degradation by cathepsin K. Together, this work describes a previously unidentified, non-immunological role for GILT in osteoclast-mediated bone resorption.
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http://dx.doi.org/10.1126/sciadv.abd3684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064644PMC
April 2021

Proceedings From The 11th Annual University Of Calgary Leaders In Medicine Research Symposium.

Clin Invest Med 2021 Mar 21;44(1):E42-57. Epub 2021 Mar 21.

Cumming School of Medicine, University of Calgary, Alberta, Canada.

On November 8th, 2019, the Cumming School of Medicine at the University of Calgary hosted the 11th annual Leaders in Medicine (LIM) Research Symposium. Dr. Donald A. Redelmeier, Professor at the University of Toronto and Canada Research Chair in Medical Decision Sciences, served as the keynote speaker with a talk entitled "Pitfalls of Reasoning and Clinical Medicine". In addition, there were five oral and 64 poster presentations. These presentations covered topics ranging from health promotion to neuroimaging. The event celebrated the continuing success and diversity of the LIM program and the training of clinician-scientists at the University of Calgary.
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http://dx.doi.org/10.25011/cim.v44i1.35079DOI Listing
March 2021

Evaluation of the modified immune prognostic index to prognosticate outcomes in metastatic uveal melanoma patients treated with immune checkpoint inhibitors.

Cancer Med 2021 04 16;10(8):2618-2626. Epub 2021 Mar 16.

Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.

Background: Metastatic uveal melanoma (MUM) is associated with poor survival and inferior response to immune checkpoint inhibitor (ICI) therapy when compared with metastatic cutaneous melanoma. Currently, prognostic biomarkers are lacking to guide treatment decisions.

Patients And Methods: We conducted a multicenter, retrospective cohort study using a centralized, province-wide cancer database in Alberta, Canada. We identified 37 patients with histologically confirmed MUM who received at least one dose of single-agent pembrolizumab or nivolumab, or combination therapy nivolumab and ipilimumab. A modified immune prognostic index (IPI), based on the previously reported lung immune prognostic index, was used to stratify patients into favorable and poor IPI groups. Survival analyses were conducted using the Kaplan-Meier method and Cox proportional hazards models, adjusting for baseline age (≥60) and ECOG performance status, to assess the associations between IPI and overall survival (OS). Time to treatment failure (TTF) was also assessed using the Kaplan-Meier method. The association between IPI and objective response rate was examined using chi-squared tests. Logistic regression was used to determine the association between IPI and immune-related adverse events (irAEs).

Results: Median OS was 15.6 (range 0.6-57.6) months with 45.9% 1-year survival rate at a median follow-up of 11.8 months. We found that a favorable IPI was significantly associated with OS [median 30.5 (12.0-not reached) months in the favorable IPI group compared with 4.6 (2.1-16.0) months in the poor IPI group (p = 0.001)] (HR=4.81, 95% CI; 1.64-14.10, p = 0.004), TTF [median 5.1 (95% CI; 2.1-10.4) months in the favorable IPI group compared with 3.7 (95% CI; 1.4-6.4) months in the poor IPI group (p = 0.0191)], and irAE (HR=6.67, 95% CI; 1.32-33.69, p = 0.0220).

Conclusions: The modified IPI may be a useful tool in clinical practice for identifying MUM patients who are more likely to experience irAEs and realize a survival benefit from ICI treatment.
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http://dx.doi.org/10.1002/cam4.3784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026925PMC
April 2021

Exploring the role of physical activity and exercise for managing vascular comorbidities in people with multiple sclerosis: A scoping review.

Mult Scler Relat Disord 2018 Nov 24;26:19-32. Epub 2018 Aug 24.

Interdisciplinary School of Health Sciences, Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Electronic address:

Introduction: Vascular comorbidities are prevalent among people with multiple sclerosis (MS) and have adverse disease-related consequences. In the general population, physical activity (PA) and exercise training have proven beneficial at all levels of vascular disease risk management. People with MS exhibit particularly low rates of PA; therefore, PA represents a modifiable health behavior for potentially managing vascular comorbidity risk in MS, and in turn, reducing disease burden. However, points of evidence justifying such an approach have yet to be summarized.

Objective: To conduct a scoping review of existing evidence linking PA and exercise training to potential modification of vascular comorbidities and related risk factors in people with MS.

Methods: We searched five electronic databases (PubMed, Ovid MEDLINE, Embase, PsycINFO, and CINAHL Plus) from inception to November 2017, for articles involving relevant vascular comorbidities (obesity, hyperlipidemia, heart disease, hypertension, and diabetes) in people with MS in conjunction with measures of PA, physical fitness, sedentary behavior, or exercise training. Studies were limited to English-language and primary research articles. Data were extracted and summarized by comorbidity type and study design (observational vs. interventional).

Results: Our initial search identified 1028 articles; subsequent screening resulted in 34 articles meeting the final inclusion criteria, including both observational (n = 17) and interventional (n = 17) studies. Most of the articles reported on obesity (n = 29), although evidence surrounding hyperlipidemia (n = 5), arterial function and hypertension (n = 5), and diabetes (n = 5) was also identified. Data supporting a beneficial role for PA or exercise training could be drawn from each comorbidity category. Overall, 14 of the 17 observational studies identified (82.4%) reported an association between higher levels of PA or cardiorespiratory fitness, or decreased sedentary behavior, and better function of at least one risk factor related to vascular comorbid conditions in people with MS. The efficacy of exercise training in limiting vascular comorbidity risk and burden was dependent upon intervention type and duration, with 9 of 17 interventional studies (52.9%) reporting improvement in at least one relevant measure of vascular comorbidity in participants with MS.

Conclusions: Evidence points to a potential relationship between PA and exercise and risk factors related to vascular comorbidities in people with MS. PA and exercise training interventions may represent an effective therapeutic strategy for managing vascular comorbidities in people with MS, justifying further investigation.
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http://dx.doi.org/10.1016/j.msard.2018.08.022DOI Listing
November 2018

The phagosome and redox control of antigen processing.

Free Radic Biol Med 2018 09 22;125:53-61. Epub 2018 Mar 22.

Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1. Electronic address:

In addition to debris clearance and antimicrobial function, versatile organelles known as phagosomes play an essential role in the processing of exogenous antigen in antigen presenting cells. While there has been much attention on human leukocyte antigen haplotypes in the determination of antigenic peptide repertoires, the lumenal biochemistries within phagosomes and endosomes are emerging as equally-important determinants of peptide epitope composition and immunodominance. Recently, the lumenal redox microenvironment within these degradative compartments has been shown to impact two key antigenic processing chemistries: proteolysis by lysosomal cysteine proteases and disulfide reduction of protein antigens. Through manipulation of the balance between oxidative and reductive capacities in the phagosome-principally by modulating NADPH oxidase (NOX2) and γ-interferon-inducible lysosomal thiol reductase (GILT) activities-studies have demonstrated changes to antigen processing patterns leading to modified repertoires of antigenic peptides available for presentation, and subsequently, altered disease progression in T cell-driven autoimmunity. This review focuses on the mechanisms and consequences of redox-mediated phagosomal antigen processing, and the potential downstream implications to tolerance and autoimmunity.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.03.040DOI Listing
September 2018

The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response.

FASEB J 2018 03 3;32(3):1236-1249. Epub 2018 Jan 3.

Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

The synthetic supercooling drug, icilin, and its primary receptor target, the cation channel transient receptor potential (TRP) melastatin-8 (TRPM8), have been described as potent negative regulators of inflammation in the colon. The aim of this study was to determine whether the anti-inflammatory action of icilin could potentially be used to treat autoimmune neuroinflammatory disorders, such as multiple sclerosis (MS). During experimental autoimmune encephalomyelitis (EAE)-a CD4 T cell-driven murine model of MS-we found that both wild-type (WT) and TRPM8-deficient EAE mice were protected from disease progression during icilin treatment, as evidenced by delays in clinical onset and reductions in neuroinflammation. In vitro, icilin potently inhibited the proliferation of murine and human CD4 T cells, with the peripheral expansion of autoantigen-restricted T cells similarly diminished by the administration of icilin in mice. Attenuation of both TRPM8 and TRP ankyrin-1 T-cell proliferation by icilin was consistent with the WT phenotype, which suggests a mechanism that is independent of these channels. In addition, icilin treatment altered the expressional profile of activated CD4 T cells to one that was indicative of restricted effector function and limited neuroinflammatory potential. These findings identify a potent anti-inflammatory role for icilin in lymphocyte-mediated neuroinflammation and highlight clear pleiotropic effects of the compound beyond classic TRP channel activation.-Ewanchuk, B. W., Allan, E. R. O., Warren, A. L., Ramachandran, R., Yates, R. M. The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response.
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http://dx.doi.org/10.1096/fj.201700552RDOI Listing
March 2018

A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis.

J Neuroinflammation 2017 05 10;14(1):103. Epub 2017 May 10.

Snyder Institute for Chronic Disease, University of Calgary, Calgary, AB, T2N 4 N1, Canada.

Background: Hypomethylation of the cathepsin Z locus has been proposed as an epigenetic risk factor for multiple sclerosis (MS). Cathepsin Z is a unique lysosomal cysteine cathepsin expressed primarily by antigen presenting cells. While cathepsin Z expression has been associated with neuroinflammatory disorders, a role for cathepsin Z in mediating neuroinflammation has not been previously established.

Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in both wildtype mice and mice deficient in cathepsin Z. The effects of cathepsin Z-deficiency on the processing and presentation of the autoantigen myelin oligodendrocyte glycoprotein, and on the production of IL-1β and IL-18 were determined in vitro from cells derived from wildtype and cathepsin Z-deficient mice. The effects of cathepsin Z-deficiency on CD4+ T cell activation, migration, and infiltration to the CNS were determined in vivo. Statistical analyses of parametric data were performed by one-way ANOVA followed by Tukey post-hoc tests, or by an unpaired Student's t test. EAE clinical scoring was analyzed using the Mann-Whitney U test.

Results: We showed that mice deficient in cathepsin Z have reduced neuroinflammation and dramatically lowered circulating levels of IL-1β during EAE. Deficiency in cathepsin Z did not impact either the processing or the presentation of MOG, or MOG- specific CD4+ T cell activation and trafficking. Consistently, we found that cathepsin Z-deficiency reduced the efficiency of antigen presenting cells to secrete IL-1β, which in turn reduced the ability of mice to generate Th17 responses-critical steps in the pathogenesis of EAE and MS.

Conclusion: Together, these data support a novel role for cathepsin Z in the propagation of IL-1β-driven neuroinflammation.
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http://dx.doi.org/10.1186/s12974-017-0874-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424360PMC
May 2017

Ligation of FcγR Alters Phagosomal Processing of Protein via Augmentation of NADPH Oxidase Activity.

Traffic 2016 07 13;17(7):786-802. Epub 2016 May 13.

Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, Calgary, Canada.

Proteolysis and the reduction of disulfides, both major components of protein degradation, are profoundly influenced by phagosomal redox conditions in macrophages. We evaluated the activation of phagocytic receptors that are known to influence activation of the phagocyte NADPH oxidase (NOX2), and its effect on phagosomal protein degradation. Population-based and single phagosome analyses of phagosomal chemistries in murine macrophages revealed that activation of NOX2 via the Fcγ receptor (FcγR) during phagocytosis decreased rates of proteolysis and disulfide reduction. Immunoglobulin G (IgG)-stimulated reactive oxygen species (ROS) production and the inhibition of phagosomal proteolysis and disulfide reduction were dependent on NOX2, FcγR and protein kinase C (PKC)/spleen tyrosine kinase (Syk) signaling. In contrast, low levels of ROS production were observed following the phagocytosis of unopsonized beads, which resulted in higher rates of phagosomal proteolysis and disulfide reduction. Phagosomes displayed autonomy with respect to FcγR-mediated differences in NOX2 activation and proteolysis, as phagosomes containing unopsonized cargo retained low NOX2 activation and high proteolysis even in the presence of phagosomes containing IgG-opsonized cargo in the same macrophage. These results show that opsonization of phagocytic cargo results in vastly different phagosomal processing of proteins through the FcγR-triggered, PKC/Syk-dependent local assembly and activation of NOX2.
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http://dx.doi.org/10.1111/tra.12396DOI Listing
July 2016