scholarly journals A computational multiscale agent-based model for simulating spatio-temporal tumour immune response to PD1 and PDL1 inhibition

2017 ◽  
Vol 14 (134) ◽  
pp. 20170320 ◽  
Author(s):  
Chang Gong ◽  
Oleg Milberg ◽  
Bing Wang ◽  
Paolo Vicini ◽  
Rajesh Narwal ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Temporal Dynamics ◽  
Checkpoint Inhibitors ◽  
Tumour Progression ◽  
Cytotoxic T Cells ◽  
Three Dimensional ◽  
Agent Based Model ◽  
Agent Based ◽  
Tumour Development

When the immune system responds to tumour development, patterns of immune infiltrates emerge, highlighted by the expression of immune checkpoint-related molecules such as PDL1 on the surface of cancer cells. Such spatial heterogeneity carries information on intrinsic characteristics of the tumour lesion for individual patients, and thus is a potential source for biomarkers for anti-tumour therapeutics. We developed a systems biology multiscale agent-based model to capture the interactions between immune cells and cancer cells, and analysed the emergent global behaviour during tumour development and immunotherapy. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during tumour progression, as well as three-dimensional spatial distributions of these cells. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and antigen strength, a spectrum of pretreatment spatial patterns of PDL1 expression is generated in our simulations, resembling immuno-architectures obtained via immunohistochemistry from patient biopsies. By correlating these spatial characteristics with in silico treatment results using immune checkpoint inhibitors, the model provides a framework for use to predict treatment/biomarker combinations in different cancer types based on cancer-specific experimental data.

scholarly journals Temporal dynamics of viral load and false negative rate influence the levels of testing necessary to combat COVID-19 spread

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katherine F. Jarvis ◽  
Joshua B. Kelley
Keyword(s):  
Viral Load ◽  
Temporal Dynamics ◽  
Reproduction Number ◽  
False Negative ◽  
False Negative Rate ◽  
Agent Based Model ◽  
Agent Based ◽  
Viral Spread ◽  
Negative Rate

AbstractColleges and other organizations are considering testing plans to return to operation as the COVID-19 pandemic continues. Pre-symptomatic spread and high false negative rates for testing may make it difficult to stop viral spread. Here, we develop a stochastic agent-based model of COVID-19 in a university sized population, considering the dynamics of both viral load and false negative rate of tests on the ability of testing to combat viral spread. Reported dynamics of SARS-CoV-2 can lead to an apparent false negative rate from ~ 17 to ~ 48%. Nonuniform distributions of viral load and false negative rate lead to higher requirements for frequency and fraction of population tested in order to bring the apparent Reproduction number (Rt) below 1. Thus, it is important to consider non-uniform dynamics of viral spread and false negative rate in order to model effective testing plans.

scholarly journals Agent based models to investigate cooperation between cancer cells

2015 ◽  
Author(s):  
Joao Xavier ◽  
William Chang
Keyword(s):  
Growth Factor ◽  
Cancer Cells ◽  
Solid Tumor ◽  
Kin Selection ◽  
Evolution Of Cooperation ◽  
Emergent Properties ◽  
Agent Based Model ◽  
Agent Based ◽  
Chemical Gradients ◽  
Close Proximity

We present a type of agent-based model that uses off-lattice spheres to represent individual cells in a solid tumor. The model calculates chemical gradients and determines the dynamics of the tumor as emergent properties of the interactions between the cells. As an example, we present an investigation of cooperation among cancer cells where cooperators secrete a growth factor that is costly to synthesize. Simulations reveal that cooperation is favored when cancer cells from the same lineage stay in close proximity. The result supports the hypothesis that kin selection, a theory that explains the evolution of cooperation in animals, also applies to cancers.

scholarly journals An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5314
Author(s):  
Kathleen M. Storey ◽  
Trachette L. Jackson
Keyword(s):  
Three Dimensional ◽  
Spatial Location ◽  
Adaptive Strategy ◽  
Treatment Modalities ◽  
Agent Based Model ◽  
Agent Based ◽  
Oncolytic Viral Therapy ◽  
Landscape Characteristics ◽  
Adaptive Immune ◽  
Viral Therapy

Oncolytic viral therapies and immunotherapies are of growing clinical interest due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. These treatment modalities provide promising alternatives to the standard of care, particularly for cancers with poor prognoses, such as the lethal brain tumor glioblastoma (GBM). However, uncertainty remains regarding optimal dosing strategies, including how the spatial location of viral doses impacts therapeutic efficacy and tumor landscape characteristics that are most conducive to producing an effective immune response. We develop a three-dimensional agent-based model (ABM) of GBM undergoing treatment with a combination of an oncolytic Herpes Simplex Virus and an anti-PD-1 immunotherapy. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We utilize the spatially explicit nature of the ABM to determine optimal viral dosing in both the temporal and spatial contexts. After proposing an adaptive viral dosing strategy that chooses to dose sites at the location of highest tumor cell density, we find that, in most cases, this adaptive strategy produces a more effective treatment outcome than repeatedly dosing in the center of the tumor.

An Agent-Based Model of the Spread of Devil Facial Tumor Disease in an Isolated Population of Tasmanian Devils

2012 ◽  
Vol 4 (4) ◽  
pp. 1-16
Author(s):  
Charles E. Knadler
Keyword(s):  
Life History ◽  
Cancer Cells ◽  
Tasmanian Devil ◽  
Isolated Population ◽  
Agent Based Model ◽  
Disease Mechanism ◽  
Agent Based ◽  
In The Wild ◽  
Devil Facial Tumor Disease

The Tasmanian devil population is being reduced in the wild at an alarming rate due to an epidemic, which is the result of an unusual disease mechanism. Infected animals “inject” cancer cells into other devils, which then clone the cells, developing tumors. These tumors are invariably fatal. Field observers have developed hypotheses that include a life- history change for the species. It is hypothesized that this change has the potential to improve the population’s survivability. An agent-based model of Tasmanian devils is used to evaluate these hypotheses. The model results suggest that the devils’ intra-gender aggression as well as their aggressive mating practices render the life-history change hypotheses’ correctness improbable.

scholarly journals Cancer associated-fibroblast-derived exosomes in cancer progression

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chao Li ◽  
Adilson Fonseca Teixeira ◽  
Hong-Jian Zhu ◽  
Peter ten Dijke
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Chemotherapy Resistance ◽  
Cell Types ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblast

AbstractTo identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

Immune Checkpoint Regulators: A New Era Toward Promising Cancer Therapy

2020 ◽  
Vol 20 (6) ◽  
pp. 429-460
Author(s):  
Mohammed Shaaban ◽  
Heba Othman ◽  
Takwa Ibrahim ◽  
Mariam Ali ◽  
Mohamed Abdelmoaty ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Historical Background ◽  
New Era ◽  
Cancer Management ◽  
Immunosuppressive Tumor Microenvironment ◽  
Specific Proteins ◽  
Immune Editing

During the last century, our battle against cancer has been inaugurated upon three main approaches; surgery, radiation and chemotherapy. The latest findings on the effectiveness of immunotherapy in cancer management offer a ray of hope after decades of research and studies on the best treatment methods. Immunotherapy has proven effective in the surveillance and destruction of cancer- causing cells, demonstrating its ability to suppress cancer through controlling the wellestablished immune-editing process. Immuno-editing is a process that comprises three principal elements; elimination, equilibrium, and escape, and is paramount to the comprehension of checkpoint inhibition. Cancer cells employ various approaches to evade the elimination step leading to its immune- escape. The escape mechanism encompasses the up-regulation of negative co-signals that block successful activation of cancer-eradicating immune cells, developing cytokine background that favors the immunosuppressive tumor microenvironment (TME), or dropping the expression of tumor- specific proteins known as neo-antigens, therefore reducing the immunogenic activity against cancer cells. Today, checkpoint inhibitors are considered as a primary approach in our fight against cancer. Strategies targeting the inhibitory roles of checkpoint inhibitors have been shown effective against different cancer types and stages, and some already gained the FDA’s approval. This review seeks to comprehensively cover the historical background as well as the most recent updates for the role of immune checkpoint regulators in the maintenance of immune homeostatic balance as well as keeping the tumorigenic cells in check.

Current status of treatment with immune checkpoint inhibitors in the field of gynecological oncology

2019 ◽  
pp. 1-2
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Clinical Medicine ◽  
Checkpoint Inhibitors ◽  
Cell System ◽  
Current Status ◽  
Living Body ◽  
Foreign Objects

In our living body, foreign objects are eliminated by the function of immunity. On the other hand, cancer cells are known to have a mechanism to break the immune cell system that is trying to attack cancer in order to escape from the attack of immune cells. “Immune checkpoint inhibitors” prevent cancer cells from breaking the immune system. Therefore, the “immune checkpoint inhibitor” is a drug that induces the immune function to attack the original cancer. Currently, PD-1 antibody, PD-L1 antibody and CTLA-4 antibody are used in clinical medicine as anti-cancer drugs. In this paper, the authors discuss the clinical use of immune checkpoint inhibitors in gynecological tumors.

scholarly journals Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Gut ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 127-138 ◽  
Author(s):  
Erik S Knudsen ◽  
Vishnu Kumarasamy ◽  
Sejin Chung ◽  
Amanda Ruiz ◽  
Paris Vail ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Multispectral Imaging ◽  
Checkpoint Inhibitors ◽  
Tumour Progression ◽  
Interferon Response ◽  
Immune Checkpoints ◽  
Mek Inhibition ◽  
Tumour Control

ObjectiveThis study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer.DesignPatient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment.ResultsWe found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors.ConclusionsTogether, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.

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