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"Chan, Timothy"
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The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
Checkpoint inhibitor-based immunotherapies that target cytotoxic T lymphocyte antigen 4 (CTLA4) or the programmed cell death 1 (PD1) pathway have achieved impressive success in the treatment of different cancer types. Yet, only a subset of patients derive clinical benefit. It is thus critical to understand the determinants driving response, resistance and adverse effects. In this Review, we discuss recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, PD1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome. We focus on recently identified molecular and cellular determinants of response. A better understanding of how these variables cooperate to affect tumour–host interactions is needed to optimize the implementation of precision immunotherapy.This Review discusses recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, programmed cell death 1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome.
Journal Article
Inverse Optimization: Closed-Form Solutions, Geometry, and Goodness of Fit
In classical inverse linear optimization, one assumes that a given solution is a candidate to be optimal. Real data are imperfect and noisy, so there is no guarantee that this assumption is satisfied. Inspired by regression, this paper presents a unified framework for cost function estimation in linear optimization comprising a general inverse optimization model and a corresponding goodness-of-fit metric. Although our inverse optimization model is nonconvex, we derive a closed-form solution and present the geometric intuition. Our goodness-of-fit metric,
ρ
, the
coefficient of complementarity
, has similar properties to
R
2
from regression and is quasi-convex in the input data, leading to an intuitive geometric interpretation. While
ρ
is computable in polynomial time, we derive a lower bound that possesses the same properties, is tight for several important model variations, and is even easier to compute. We demonstrate the application of our framework for model estimation and evaluation in production planning and cancer therapy.
This paper was accepted by Yinyu Ye, optimization.
Journal Article
سر الثراء = The secret to wealth : دراسات
في هذا الكتاب المذهل سر الثراء الجزء الثالث قام كلا من سونيل تولسياني وبراين تريسي بجمع قادة اليوم القادمين من جميع أنحاء العالم للكشف عن إستراتيجياتهم المتطورة لمساعدتك على أن تصبح ثريا بشكل كبير. داخل هذه الصفحات، ستجد تقنيات وأدوات لتغيير الحياة لتحقيق أحلامك. سواء كنت تريد أن تصبح رائد أعمال ومليونير فائق الثروة، أو تشتري العقارات دون استخدام أموالك الخاصة، أو تتقاعد ثريا في سن أصغر، أو تقوم بجذب عملائك ذوي الدخل المرتفع، أو إعداد نفسك لتربح مبالغ ضخمة من الدخل السلبي، فهذا الكتاب مناسب لك تماما.
Book
Implementing artificial intelligence in Canadian primary care: Barriers and strategies identified through a national deliberative dialogue
With large volumes of longitudinal data in electronic medical records from diverse patients, primary care is primed for disruption by artificial intelligence (AI) technology. With AI applications in primary care still at an early stage in Canada and most countries, there is a unique opportunity to engage key stakeholders in exploring how AI would be used and what implementation would look like.
To identify the barriers that patients, providers, and health leaders perceive in relation to implementing AI in primary care and strategies to overcome them.
12 virtual deliberative dialogues. Dialogue data were thematically analyzed using a combination of rapid ethnographic assessment and interpretive description techniques.
Virtual sessions.
Participants from eight provinces in Canada, including 22 primary care service users, 21 interprofessional providers, and 5 health system leaders.
The barriers that emerged from the deliberative dialogue sessions were grouped into four themes: (1) system and data readiness, (2) the potential for bias and inequity, (3) the regulation of AI and big data, and (4) the importance of people as technology enablers. Strategies to overcome the barriers in each of these themes were highlighted, where participatory co-design and iterative implementation were voiced most strongly by participants.
Only five health system leaders were included in the study and no self-identifying Indigenous people. This is a limitation as both groups may have provided unique perspectives to the study objective.
These findings provide insight into the barriers and facilitators associated with implementing AI in primary care settings from different perspectives. This will be vital as decisions regarding the future of AI in this space is shaped.
Journal Article
Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy
Functional diversity of the highly polymorphic human leukocyte antigen class I (
HLA
-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an
HLA
-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes
1
–
3
. However, the effect of sequence divergence between
HLA
-I alleles—a quantifiable measure of
HLA
-I evolution—on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between
HLA
-I alleles of each patient’s genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at
HLA
-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex–peptide complex, which dictates ICI efficacy. The data link divergent
HLA
allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of
HLA
-mediated immunity.
The degree of sequence divergence between patient MHC class I alleles influences the response to immune checkpoint blockade therapy independently of tumor mutational burden.
Journal Article
Generalized Inverse Multiobjective Optimization with Application to Cancer Therapy
We generalize the standard method of solving inverse optimization problems to allow for the solution of inverse problems that would otherwise be ill posed or infeasible. In multiobjective linear optimization, given a solution that is not a weakly efficient solution to the forward problem, our method generates objective function weights that make the given solution a near-weakly efficient solution. Our generalized inverse optimization model specializes to the standard model when the given solution is weakly efficient and retains the complexity of the underlying forward problem. We provide a novel interpretation of our inverse formulation as the dual of the well-known Benson's method and by doing so develop a new connection between inverse optimization and Pareto surface approximation techniques. We apply our method to prostate cancer data obtained from Princess Margaret Cancer Centre in Toronto, Canada. We demonstrate that clinically acceptable treatments can be generated using a small number of objective functions and inversely optimized weights-current treatments are designed using a complex formulation with a large parameter space in a trial-and-error reoptimization process. We also show that our method can identify objective functions that are most influential in treatment plan optimization.
Journal Article
Characteristics and outcomes of hospital admissions for COVID-19 and influenza in the Toronto area
Patient characteristics, clinical care, resource use and outcomes associated with admission to hospital for coronavirus disease 2019 (COVID-19) in Canada are not well described.
We described all adults with COVID-19 or influenza discharged from inpatient medical services and medical–surgical intensive care units (ICUs) between Nov. 1, 2019, and June 30, 2020, at 7 hospitals in Toronto and Mississauga, Ontario. We compared patient outcomes using multivariable regression models, controlling for patient sociodemographic factors and comorbidity level. We validated the accuracy of 7 externally developed risk scores to predict mortality among patients with COVID-19.
There were 1027 hospital admissions with COVID-19 (median age 65 yr, 59.1% male) and 783 with influenza (median age 68 yr, 50.8% male). Patients younger than 50 years accounted for 21.2% of all admissions for COVID-19 and 24.0% of ICU admissions. Compared with influenza, patients with COVID-19 had significantly greater in-hospital mortality (unadjusted 19.9% v. 6.1%, adjusted relative risk [RR] 3.46, 95% confidence interval [CI] 2.56–4.68), ICU use (unadjusted 26.4% v. 18.0%, adjusted RR 1.50, 95% CI 1.25–1.80) and hospital length of stay (unadjusted median 8.7 d v. 4.8 d, adjusted rate ratio 1.45, 95% CI 1.25–1.69). Thirty-day readmission was not significantly different (unadjusted 9.3% v. 9.6%, adjusted RR 0.98, 95% CI 0.70–1.39). Three points-based risk scores for predicting in-hospital mortality showed good discrimination (area under the receiver operating characteristic curve [AUC] ranging from 0.72 to 0.81) and calibration.
During the first wave of the pandemic, admission to hospital for COVID-19 was associated with significantly greater mortality, ICU use and hospital length of stay than influenza. Simple risk scores can predict in-hospital mortality in patients with COVID-19 with good accuracy.
Journal Article
CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy
Cancer immunotherapy restores or enhances the effector function of CD8
+
T cells in the tumour microenvironment
1
,
2
. CD8
+
T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin–granzyme and Fas–Fas ligand pathways
3
,
4
. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide
5
,
6
. Although it has been investigated in vitro
7
,
8
, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios
9
,
10
. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8
+
T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8
+
T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate–cystine antiporter system x
c
−
, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system x
c
−
was negatively associated, in cancer patients, with CD8
+
T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
Interferon-γ induces ferroptotic cell death in tumours by suppressing cystine uptake and promoting lipid peroxidation.
Journal Article