Cancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network, they can spread to distant secondary sites in the body. This process, known as metastatic spread , is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer . To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner—a multigrid, hybrid, individual-based approach. This framework accounts for the spatiotemporal evolution of mesenchymal- and epithelial-like cancer cells, membrane-type-1 matrix metalloproteinase (MT1-MMP) and the diffusible matrix metalloproteinase-2 (MMP-2), and for their interactions with the extracellular matrix. Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix-degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs such as MMP-2.

Cancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network (tumour-induced angiogenesis), they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer.To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner -a multi-grid, hybrid, individual-based approach. This framework accounts for the spatio-temporal evolution of mesenchymal-and epithelial-like cancer cells, as well as MT1-MMP and MMP-2 dynamics, and interactions with the extracellular matrix.Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs like MMP-2.Keywords Metastatic spread · Mathematical oncology · Tumour microenvironment · Individual-based model · Multi-grid framework LCF is funded by the Engineering and Physical Sciences Research Council (EPSRC). MAJC gratefully acknowledges the support of EPSRC Grant

Immunogenicity, defined as the ability to provoke an immune response, can be either wanted (i.e., vaccines) or unwanted. The latter refers to an immune response to protein or peptide therapeutics, characterized by the production of anti-drug antibodies, which may affect the efficacy and/or the safety profiles of these drugs. Consequently, evaluation of the risk of immunogenicity early in the development of biotherapeutics is of critical importance for defining their efficacy and safety profiles. Here, we describe and validate a fit-for-purpose FluoroSpot-based in vitro assay for the evaluation of drug-specific T cell responses. A panel of 24 biotherapeutics with a wide range of clinical anti-drug antibody response rates were tested in this assay. We demonstrated that using suitable cutoffs and donor cohort sizes, this assay could identify most of the compounds with high clinical immunogenicity rates (71% and 78% for sensitivity and specificity, respectively) while we characterized the main sources of assay variability. Overall, these data indicate that the dendritic cell and CD4+ T cell restimulation assay published herein could be a valuable tool to assess the risk of drug-specific T cell responses and contribute to the selection of clinical candidates in early development.

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Cancer invasion and metastatic spread to secondary sites in the body are facilitated by a complex interplay between cancer cells of different phenotypes and their microenvironment. A trade-off between the cancer cells’ ability to invade the tissue and to metastasize, and their ability to proliferate has been observed. This gives rise to the classification of cancer cells into those of mesenchymal and epithelial phenotype, respectively. Additionally, mixed phenotypic states between these two extremes exist. Cancer cells can transit between these states via epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal–epithelial transition (MET). These processes are crucial for both the local tissue invasion and the metastatic spread of cancer cells. To shed light on the role of these phenotypic states and the transitions between them in the invasive and metastatic process, we extend our recently published multi-grid, hybrid, individual-based mathematical metastasis framework (Franssen et al. 2019, A mathematical framework for modelling the metastatic spread of cancer. Bull. Math. Biol., 81, 1965). In addition to cancer cells of epithelial and of mesenchymal phenotype, we now also include those of an intermediate partial-EMT phenotype. Furthermore, we allow for the switching between these phenotypic states via EMT and MET at the biologically appropriate steps of the invasion-metastasis cascade. We also account for the likelihood of spread of cancer cells to the various secondary sites and differentiate between the tissues of the organs involved in our simulations. Finally, we consider the maladaptation of metastasized cancer cells to the new tumour microenvironment at secondary sites as well as the immune response at these sites by accounting for cancer cell dormancy and death. This way, we create a first mathematical multi-organ model that explicitly accounts for EMT-processes occurring at the level of individual cancer cells in the context of the invasion-metastasis cascade.

Immunogenicity against therapeutic proteins frequently causes attrition owing to its potential impact on pharmacokinetics, pharmacodynamics, efficacy, and safety. Predicting immunogenicity is complex because of its multifactorial drivers, including compound properties, subject characteristics, and treatment parameters. To integrate these, the Immunogenicity Simulator was developed using published, predominantly late-stage trial data from 15 therapeutic proteins. This single-blinded evaluation with subject-level data from 10 further monoclonals assesses the Immunogenicity Simulator's credibility for application during the drug development process.

Cancer invasion and metastatic spread to secondary sites in the body are facilitated by a complex interplay between cancer cells of different phenotypes and their microenvironment. A trade-off between the cancer cells' ability to invade the tissue and to metastasise, and their ability to proliferate has been observed. This gives rise to the classification of cancer cells into those of mesenchymal and epithelial phenotype, respectively. Additionally, mixed phenotypic states between these two extremes exist. Cancer cells can transit between these states via epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET). These processes are crucial both for the local tissue invasion and the metastatic spread of cancer cells. To shed light on the role of these phenotypic states and the transitions between them in the invasive and metastatic process, we extend our recently published multigrid, hybrid, individual-based mathematical metastasis framework (Franssen et al., 2019a). In addition to cancer cells of epithelial and of mesenchymal phenotype, we now also include those of an intermediate partial-EMT phenotype. Furthermore, we allow for the switching between these phenotypic states via EMT and MET at the biologically appropriate steps of the invasion-metastasis cascade. We also account for the likelihood of spread of cancer cells to the various secondary sites and differentiate between the tissues of the organs involved in our simulations. Finally, we consider the maladaptation of metastasised cancer cells to the new tumour microenvironment at secondary sites as well as the immune response at these sites by accounting for cancer cell dormancy and death. This way, we create a first mathematical multi-organ model that explicitly accounts for EMT-processes in individual cancer cells in the context of the invasion-metastasis cascade.

We develop a three-dimensional genuinely hybrid atomistic-continuum model that describes the invasive growth dynamics of individual cancer cells in tissue. The framework explicitly accounts for phenotypic variation by distinguishing between cancer cells of an epithelial-like and a mesenchymal-like phenotype. It also describes mutations between these cell phenotypes in the form of epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET). The model consists of a hybrid system of partial and stochastic differential equations that describe the evolution of epithelial-like and mesenchymal-like cancer cells, respectively, under the consideration of matrix-degrading enzyme concentrations and the extracellular matrix density. With the help of inverse parameter estimation and a sensitivity analysis, this three-dimensional model is then calibrated to an in vitro organotypic invasion assay experiment of oral squamous cell carcinoma cells.