Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.

Pathology: cancer cells compress intratumour vessels.

The delivery of therapeutic drugs to solid tumours may be impaired by structural and functional abnormalities in blood and lymphatic vessels. Here we provide evidence that proliferating cancer cells cause intratumour vessels to compress and collapse. By reducing this compressive mechanical force and opening vessels, cytotoxic cancer treatments have the potential to increase blood perfusion, thereby improving drug delivery.

A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy.

The traditional view of angiogenesis emphasizes proliferation and migration of vessel wall-associated endothelial cells. However, circulating endothelial progenitor cells have recently been shown to contribute to tumor angiogenesis. Here we quantify the relative contributions of endothelial and endothelial progenitor cells to angiogenesis using a mathematical model. The model predicts that during the early stages of tumor growth, endothelial progenitors have a significant impact on tumor growth and angiogenesis, mediated primarily by their localization in the tumor, not by their proliferation. The model also shows that, as the tumor grows, endothelial progenitors adhere preferentially near the tumor periphery, coincident with the location of highest vascular density, supporting their potential utility as vectors for targeted delivery of therapeutics. Model simulations of various antiangiogenic strategies show that those therapies that effectively target both endothelial and endothelial progenitor cells, either by restoring the balance between angiogenic stimulators and inhibitors or by targeting both types of cells directly, are most effective at delaying tumor growth. The combination of continuous low-dose chemotherapy and antiangiogenic therapy is predicted to have the most significant effect on therapeutic outcome. The model offers new insight into tumor angiogenesis with implications for the rational design of antiangiogenic therapy.

Antibody-directed effector cell therapy of tumors: analysis and optimization using a physiologically based pharmacokinetic model.

The failure of the cellular immune response to stop solid tumor growth has been the subject of much research. Although the mechanisms for tumor evasion of immune response are poorly understood, one viable explanation is that tumor-killing lymphocytes cannot reach the tumor cells in sufficient quantity to keep the tumor in check. Recently, the use of bifunctional antibodies (BFAs) has been proposed as a way to direct immune cells to the tumor: one arm of the antibody is specific for a known tumor-associated antigen and the other for a lymphocyte marker such as CD3. Injecting this BFA should presumably result in cross-linking of lymphocytes (either endogenous or adoptively transferred) with tumor cells, thereby enhancing therapy. Results from such an approach, however, are often disappointing--frequently there is no benefit gained by using the BFA. We have analyzed the retargeting of endogenous effector cells by BFA using a physiologically based whole-body pharmacokinetic model that accounts for interactions between all relevant species in the various organs and tumor. Our results suggest that the design of the BFA is critical and the binding constants of the antigen and lymphocyte binding epitopes need to be optimized for successful therapy.

Systemic distribution and tumor localization of adoptively transferred lymphocytes in mice: comparison with physiologically based pharmacokinetic model.

The mechanisms by which tumors are able to evade cellular immune responses are still largely unknown. It is likely, however, that the initial recruitment of lymphocytes to tumor vessels is limited by cell retention in normal tissue, which results in a low flux of these cells into the tumor vasculature. We grew MCaIV (mouse mammary carcinoma) tumors in the leg of SCID mice and injected 111In-oxine-labeled, primed T lymphocytes directed against the tumor intravenously. The systemic distribution of cells in normal organs was similar between mice injected with primed and control lymphocyte populations, except for a delayed clearance of primed lymphocytes from the lungs. Kinetics of lymphocyte localization to the tumor were identical between the primed and control lymphocyte populations. Splenectomy before the injection of primed lymphocytes increased delivery of cells to the lungs and liver after 1 hour with no significant improvement in tumor localization. Within 24 to 168 hours after injection, localization of cells in the liver of splenectomized mice was higher than in the control group. However, no significant difference in tumor localization was observed between groups. A physiologically based compartmental model of lymphocyte distribution predicted the compartmental sequestration and identified model parameters critical for experimental planning and therapeutic optimization.

Conventional and high-speed intravital multiphoton laser scanning microscopy of microvasculature, lymphatics, and leukocyte-endothelial interactions.

The ability to determine various functions of genes in an intact host will be an important advance in the postgenomic era. Intravital imaging of gene regulation and the physiological effect of the gene products can play a powerful role in this pursuit. Intravital epifluorescence microscopy has provided powerful insight into gene expression, tissue pH, tissue pO2, angiogenesis, blood vessel permeability, leukocyte-endothelial (L-E) interaction, molecular diffusion, convection and binding, and barriers to the delivery of molecular and cellular medicine. Multiphoton laser scanning microscopy (MPLSM) has recently been applied in vivo to overcome three drawbacks associated with traditional epifluorescence microscopy: (i) limited depth of imaging due to scattering of excitation and emission light; (ii) projection of three-dimensional structures onto a two-dimensional plane; and (iii) phototoxicity. Here, we use MPLSM for the first time to obtain high-resolution images of deep tissue lymphatic vessels and show an increased accuracy in quantifying lymphatic size. We also demonstrate the use of MPLSM to perform accurate calculations of the volume density of angiogenic vessels and discuss how this technique may be used to assess the potential of antiangiogenic treatments. Finally, high-speed MPLSM, applied for the first time in vivo, is used to compare L-E interactions in normal tissue and a rhabdomyosarcoma tumor. Our work demonstrates the potential of MPLSM to noninvasively monitor physiology and pathophysiology both at the tissue and cellular level. Future applications will include the use of MPLSM in combination with fluorescent reporters to give novel insight into the regulation and function of genes.