A Model-Based Investigation of Cytokine Dynamics in Immunotherapies

Abstract

With the advent of effective immunotherapies to battle cancers and diseases, an obstacle in recovery has become the potential side effects, specifically cytokine release syndrome (CRS). As there is little quantitative understanding of risks for developing CRS and the degree of its severity, this work explored a model-based approach to produce a library of in silico patients through sensitivity analysis of cytokine interaction parameters and a Monte Carlo sampling. The objective of producing the in silico patients was to correlate a known grading system of cytokine release syndrome severity and thus design a new formula for grading CRS. Using our CRS grading system as the foundation, this work produced not only a formula which related the in silico patient data to the different grades, but we effectively demonstrated a selective approach to reduce the grade of CRS with sequential cytokine inhibition targets. We achieved the reduction of grades by applying the insight from the sensitivity analysis, beginning with the most sensitive targets. Cytokines IL-1, IL-8, TNF-α, INF-γ, IL-6, IL-2, IL-4, IL-10, and IL-12 were in turn the best targets for inhibition to alleviate CRS. Using this approach, patient cytokine time profiles in real-time can be related to the CRS grading system and if the grade is severe enough, action can be taken earlier during the treatment to prevent potentially life-threatening symptoms. What’s more, the identified inhibition sequence of the 9 cytokines provides guidance for clinical intervention of CRS.

A Systematic Review of the Efforts and Hindrances of Modeling and Simulation of CAR T-cell Therapy

“…These models generate or validate hypotheses from experimental data, predict different possible outcomes through in silico simulations and are among the most prominent methods used to study several aspects of diseases, such as the interplay of complex immune responses and drugs/biologics (6,7). Different modeling approaches can be considered to explore issues in drug development, including but not limited to disease progression (8)(9)(10)(11)(12), immune response to immunotherapy (13)(14)(15)(16)(17), and others (18)(19)(20)(21)(22). FDA's recent Model-Informed Drug Development Pilot Program facilitates the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources.…”

“…An increased understanding could help to better predict risk and improve mitigation strategies so the associated serious complications can be prevented. Two such studies were conducted by Teachey et al (21) and Hopkins et al (14), in which these authors identified the cytokines associated with CRS and the cytokine inhibitor targets to alleviate it. Teachey et al measured cytokines and clinical biomarkers in 51 patients, including 39 children (5-23 years) and 12 adults (25-72 years) with r/r ALL treated with tisa-cel, and identified that the peak levels of 24 cytokines in the first month after CAR T-cell infusion were associated with sCRS (21).…”

“…The findings in this study provide a step forward in predicting severity of CRS and the general cytokine dynamics, even though patient-level cytokine kinetic data was not made available to readers. Hopkins et al (14), on the other hand, used a set of ODEs to better understand the inhibitor/inductor mechanisms of nine cytokines important in CRS and to propose optimized CRS treatment strategies. The authors advanced a model of cytokine dynamics during CRS, published earlier by Yiu et al (47), and analyzed the model parameter sensitivities.…”

“…This comparison may help bring new insights into the biology of CRS development and help manage the risk. Another ODE-based model developed by Hopkins et al (14) helps in understanding inhibitor mechanisms of the cytokines, which in turn helps in optimizing CRS treatment strategies.…”

Computational Analysis of Cytokine Release Following Bispecific T-Cell Engager Therapy: Applications of a Logic-Based Model

“…In the model of Hardiansyah et al (23), IL-6, IL-10, and IFN-g are produced by CAR-T-cells as a function of their abundance and a phenomenological function of IL-10 inhibits IFN-g production. Hopkins et al, instead, focused on 9 cytokines and their cross-regulation with a model developed from clinical data related to the anti-CD28 monoclonal antibody TGN1412 (24). The CRS was fitted to a phenomenological function, and a sensitivity analysis was used to assess the most effective cytokine inhibition protocol.…”