Virtual clinical trials via a QSP immuno-oncology model to simulate the response to a conditionally activated PD-L1 targeting antibody in NSCLC.

Recently, immunotherapies for antitumoral response have adopted conditionally activated molecules with the objective of reducing systemic toxicity. Amongst these are conditionally activated antibodies, such as PROBODY® activatable therapeutics (Pb-Tx), engineered to be proteolytically activated by proteases found locally in the tumor microenvironment (TME). These PROBODY® therapeutics molecules have shown potential as PD-L1 checkpoint inhibitors in several cancer types, including both effectiveness and locality of action of the molecule as shown by several clinical trials and imaging studies. Here, we perform an exploratory study using our recently published quantitative systems pharmacology model, previously validated for triple-negative breast cancer (TNBC), to computationally predict the effectiveness and targeting specificity of a PROBODY® therapeutics drug compared to the non-modified antibody. We begin with the analysis of anti-PD-L1 immunotherapy in non-small cell lung cancer (NSCLC). As a first contribution, we have improved previous virtual patient selection methods using the omics data provided by the iAtlas database portal compared to methods previously published in literature. Furthermore, our results suggest that masking an antibody maintains its efficacy while improving the localization of active therapeutic in the TME. Additionally, we generalize the model by evaluating the dependence of the response to the tumor mutational burden, independently of cancer type, as well as to other key biomarkers, such as CD8/Treg Tcell and M1/M2 macrophage ratio. While our results are obtained from simulations on NSCLC, our findings are generalizable to other cancer types and suggest that an effective and highly selective conditionally activated PROBODY® therapeutics molecule is a feasible option.

Eliciting the antitumor immune response with a conditionally activated PD-L1 targeting antibody analyzed with a quantitative systems pharmacology model.

Conditionally activated molecules, such as Probody therapeutics (PbTx), have recently been investigated to improve antitumoral response while reducing systemic toxicity. PbTx are engineered to be proteolytically activated by proteases that are preferentially active locally in the tumor microenvironment (TME). Here, we perform an exploratory study using our recently published quantitative systems pharmacology model, previously validated for other drugs, to evaluate the effectiveness and targeting specificity of an anti-PD-L1 PbTx compared to the non-modified antibody. We have informed the model using the PbTx dynamics and pharmacokinetics published in the literature for anti-PD-L1 in patients with triple-negative breast cancer (TNBC). Our results suggest masking of the antibody slightly decreases its efficacy, while increasing the localization of active therapeutic component in the TME. We also perform a parameter optimization for the PbTx design and drug dosing regimens to maximize the response rate. Although our results are specific to the case of TNBC, our findings are generalizable to any conditionally activated PbTx molecule in solid tumors and suggest that design of a highly effective and selective PbTx is feasible.

Projecting the Pandemic Trajectory through Modeling the Transmission Dynamics of COVID-19.

The course of the COVID-19 pandemic has given rise to many disease trends at various population scales, ranging from local to global. Understanding these trends and the epidemiological phenomena that lead to the changing dynamics associated with disease progression is critical for public health officials and the global community to rein in further spread of this and other virulent diseases. Classic epidemiological modeling based on dynamical systems are powerful tools used for modeling and understanding diseases, but often necessitate modifications to the classic compartmental models to reflect empirical observations. In this paper, we present a collection of extensions to the classic SIRS model to support public health decisions associated with viral pandemics. Specifically, we present models that reflect different levels of disease severity among infected individuals, capture the effect of vaccination on different population groups, capture the effect of different vaccines with different levels of effectiveness, and model the impact of a vaccine with varying number of doses. Further, our mathematical models support the investigation of a pandemic's trend under the emergence of new variants and the associated reduction in vaccine effectiveness. Our models are supported through numerical simulations, which we use to illustrate phenomena that have been observed in the COVID-19 pandemic. Our findings also confirm observations that the mild infectious group accounts for the majority of infected individuals, and that prompt immunization results in weaker pandemic waves across all levels of infection as well as a lower number of disease-caused deaths. Finally, using our models, we demonstrate that, when dealing with a single variant and having access to a highly effective vaccine, a three-dose vaccine has a strong ability to reduce the infectious population. However, when a new variant with higher transmissibility and lower vaccine efficiency emerges, it becomes the dominant circulating variant, as was observed in the recent emergence of the Omicron variant.

Drug-Resistant Cancer Treatment Strategies Based on the Dynamics of Clonal Evolution and PKPD Modeling of Drug Combinations.

A method for determining a dosage strategy is proposed to combat drug resistance in tumor progression. The method is based on a dynamic model for the clonal evolution of cancerous cells and considers the Pharmacokinetic/Pharmacodynamic (PKPD) modeling of combination therapy. The proposed mathematical representation models the dynamic and kinetic effects of multiple drugs on the number of cells while considering potential mutations and assuming that no cross-resistance arises. An optimization problem is then proposed to minimize the total number of cancerous cells in a finite treatment period given a limited number of treatments. The dosage schedule, including the amount of each drug to be administered and the timing, is found by solving the optimization problem. This treatment schedule is constrained to achieve a target minimum effectiveness, while also ensuring that the concentration of the drugs, individually and totally, does not exceed a prescribed toxicity threshold. The proposed optimization problem is represented as a Complementary Geometric Programming (CGP) problem. The results show that the solution of the optimization problem for combination therapy is the dosing schedule that leads to tumor eradication at the end of the treatment period. The results also investigate the tumor dynamics for all mutation types when undergoing treatment, showing that single drug therapies can fail to combat the emergence of resistance, while optimized combination therapies can reduce the amount of all mutation types during the course of treatment, thereby combating resistance.

Dosage strategies for delaying resistance emergence in heterogeneous tumors.

Drug resistance in cancer treatments is a frequent problem that, when it arises, leads to failure in therapeutic efforts. Tumor heterogeneity is the primary reason for resistance emergence and a precise treatment design that takes heterogeneity into account is required to postpone the rise of resistant subpopulations in the tumor environment. In this paper, we present a mathematical framework involving clonal evolution modeling of drug-sensitive and drug-resistant clones. Using our framework, we examine delaying the rise of resistance in heterogeneous tumors during control phase of therapy in a containment treatment approach. We apply pharmacokinetic/pharmacodynamic (PKPD) modeling and show that dosage strategies can be designed to control the resistant subpopulation. Our results show that the drug dosage and schedule determine the relative dynamics of sensitive and resistant clones. We present an optimal control problem that finds the dosing strategy that maximizes the delay in resistance emergence for a given period of containment treatment.

Drug Combinations: Mathematical Modeling and Networking Methods.

Treatments consisting of mixtures of pharmacological agents have been shown to have superior effects to treatments involving single compounds. Given the vast amount of possible combinations involving multiple drugs and the restrictions in time and resources required to test all such combinations in vitro, mathematical methods are essential to model the interactive behavior of the drug mixture and the target, ultimately allowing one to better predict the outcome of the combination. In this review, we investigate various mathematical methods that model combination therapies. This survey includes the methods that focus on predicting the outcome of drug combinations with respect to synergism and antagonism, as well as the methods that explore the dynamics of combination therapy and its role in combating drug resistance. This comprehensive investigation of the mathematical methods includes models that employ pharmacodynamics equations, those that rely on signaling and how the underlying chemical networks are affected by the topological structure of the target proteins, and models that are based on stochastic models for evolutionary dynamics. Additionally, this article reviews computational methods including mathematical algorithms, machine learning, and search algorithms that can identify promising combinations of drug compounds. A description of existing data and software resources is provided that can support investigations in drug combination therapies. Finally, the article concludes with a summary of future directions for investigation by the research community.