Examining the efficacy of localised gemcitabine therapy for the treatment of pancreatic cancer using a hybrid agent-based model.

The prognosis for pancreatic ductal adenocarcinoma (PDAC) patients has not significantly improved in the past 3 decades, highlighting the need for more effective treatment approaches. Poor patient outcomes and lack of response to therapy can be attributed, in part, to a lack of uptake of perfusion of systemically administered chemotherapeutic drugs into the tumour. Wet-spun alginate fibres loaded with the chemotherapeutic agent gemcitabine have been developed as a potential tool for overcoming the barriers in delivery of systemically administrated drugs to the PDAC tumour microenvironment by delivering high concentrations of drug to the tumour directly over an extended period. While exciting, the practicality, safety, and effectiveness of these devices in a clinical setting requires further investigation. Furthermore, an in-depth assessment of the drug-release rate from these devices needs to be undertaken to determine whether an optimal release profile exists. Using a hybrid computational model (agent-based model and partial differential equation system), we developed a simulation of pancreatic tumour growth and response to treatment with gemcitabine loaded alginate fibres. The model was calibrated using in vitro and in vivo data and simulated using a finite volume method discretisation. We then used the model to compare different intratumoural implantation protocols and gemcitabine-release rates. In our model, the primary driver of pancreatic tumour growth was the rate of tumour cell division. We were able to demonstrate that intratumoural placement of gemcitabine loaded fibres was more effective than peritumoural placement. Additionally, we quantified the efficacy of different release profiles from the implanted fibres that have not yet been tested experimentally. Altogether, the model developed here is a tool that can be used to investigate other drug delivery devices to improve the arsenal of treatments available for PDAC and other difficult-to-treat cancers in the future.

The Role of Antigen-Competitive Dynamics in Regulating the Immune Response.

The clonal expansion of T cells during an infection is tightly regulated to ensure an appropriate immune response against invading pathogens. Although experiments have mapped the trajectory from expansion to contraction, the interplay between mechanisms that control this response is not fully understood. Based on experimental data, we propose a model in which the dynamics of CD4+ T cell expansion is controlled through the interactions between T cells and antigen-presenting cells, where T cell stimulation is proportional to antigen availability, and antigen availability is regulated through downregulation of antigen by T cells. This antigen-dependent-feedback mechanism operates alongside an intrinsic reduction in cell proliferation rate that may also be responsible for slowing expansion. Our model can successfully predict T cell recruitment rates into division, expansion, and clonal burst size per cell when initial precursors are varied or when T cells are introduced late into an ongoing immune response. Importantly, the findings demonstrate that a feedback mechanism between T cells and antigen-presenting cells, along with a reduction in cell proliferation rate, can explain the ability of the immune system to adapt its response to variations in initial conditions or changes that occur later in the response, ensuring a robust yet controlled line of defence against pathogens.

The role of viral infectivity in oncolytic virotherapy outcomes: A mathematical study.

A model capturing the dynamics between virus and tumour cells in the context of oncolytic virotherapy is presented and analysed. The ability of the virus to be internalised by uninfected cells is described by an infectivity parameter, which is inferred from available experimental data. The parameter is also able to describe the effects of changes in the tumour environment that affect viral uptake from tumour cells. Results show that when a virus is inoculated inside a growing tumour, strategies for enhancing infectivity do not lead to a complete eradication of the tumour. Within typical times of experiments and treatments, we observe the onset of oscillations, which always prevent a full destruction of the tumour mass. These findings are in good agreement with available laboratory results. Further analysis shows why a fully successful therapy cannot exist for the proposed model and that care must be taken when designing and engineering viral vectors with enhanced features. In particular, bifurcation analysis reveals that creating longer lasting virus particles or using strategies for reducing infected cell lifespan can cause unexpected and unwanted surges in the overall tumour load over time. Our findings suggest that virotherapy alone seems unlikely to be effective in clinical settings unless adjuvant strategies are included.