Applying Mathematical Models to Study the Role of the Immune System in Chronic Myelogenous Leukemia

Although tyrosine kinase inhibitors (TKIs) such as imatinib have transformed chronic myelogenous leukemia (CML) into a chronic condition, these therapies are not curative in the majority of cases. Most patients must continue TKI therapy indefinitely, a requirement that is both expensive and that compromises a patient's quality of life. While TKIs are known to reduce leukemic cells' proliferative capacity and to induce apoptosis, their effects on leukemic stem cells, the immune system, and the microenvironment are not fully understood. A more complete understanding of their global therapeutic effects would help us to identify any limitations of TKI monotherapy and to address these issues through novel combination therapies. Mathematical models are a complementary tool to experimental and clinical data that can provide valuable insights into the underlying mechanisms of TKI therapy. Previous modeling efforts have focused on CML patients who show biphasic and triphasic exponential declines in BCR-ABL ratio during therapy. However, our patient data indicates that many patients treated with TKIs show fluctuations in BCR-ABL ratio yet are able to achieve durable remissions. To investigate these fluctuations, we construct a mathematical model that integrates CML with a patient's autologous immune response to the disease. In our model, we define an immune window, which is an intermediate range of leukemic concentrations that lead to an effective immune response against CML. While small leukemic concentrations provide insufficient stimulus, large leukemic concentrations actively suppress a patient's immune system, thus limiting it's ability to respond. Our patient data and modeling results suggest that at diagnosis, a patient's high leukemic concentration is able to suppress their immune system. TKI therapy drives the leukemic population into the immune window, allowing the patient's immune cells to expand and eventually mount an efficient response against the residual CML. This response drives the leukemic population below the immune window, causing the immune population to contract and allowing the leukemia to partially recover. The leukemia eventually reenters the immune window, thus stimulating a sequence of weaker immune responses as the two populations approach equilibrium. We hypothesize that a patient's autologous immune response to CML may explain the fluctuations in BCR-ABL ratio that are regularly seen during TKI therapy. These fluctuations may serve as a signature of a patient's individual immune response to CML. By applying our modeling framework to patient data, we are able to construct an immune profile that can then be used to propose patient-specific combination therapies aimed at further reducing a patient's leukemic burden. Our characterization of a patient's anti-leukemia immune response may be especially valuable in the study of drug resistance, treatment cessation, and combination therapy.

Energy Management of a Battery-Ultracapacitor Hybrid Energy Storage System in Electric Vehicles

Electric vehicle (EV) batteries tend to have accelerated degradation due to high peak power and harsh charging/discharging cycles during acceleration and deceleration periods, particularly in urban driving conditions. An oversized energy storage system (ESS) can meet the high power demands; however, it suffers from increased size, volume and cost. In order to reduce the overall ESS size and extend battery cycle life, a battery-ultracapacitor (UC) hybrid energy storage system (HESS) has been considered as an alternative solution. In this work, we investigate the optimized configuration, design, and energy management of a battery-UC HESS. One of the major challenges in a HESS is to design an energy management controller for real-time implementation that can yield good power split performance. We present the methodologies and solutions to this problem in a battery-UC HESS with a DC-DC converter interfacing with the UC and the battery. In particular, a multi-objective optimization problem is formulated to optimize the power split in order to prolong the battery lifetime and to reduce the HESS power losses. This optimization problem is numerically solved for standard drive cycle datasets using Dynamic Programming (DP). Trained using the DP optimal results, an effective real-time implementation of the optimal power split is realized based on Neural Network (NN). This proposed online energy management controller is applied to a midsize EV model with a 360V/34kWh battery pack and a 270V/203Wh UC pack. The proposed online energy management controller effectively splits the load demand with high power efficiency and also effectively reduces the battery peak current. More importantly, a 38V-385Wh battery and a 16V-2.06Wh UC HESS hardware prototype and a real-time experiment platform has been developed. The real-time experiment results have successfully validated the real-time implementation feasibility and effectiveness of the real-time controller design for the battery-UC HESS. A battery State-of-Health (SoH) estimation model is developed as a performance metric to evaluate the battery cycle life extension effect. It is estimated that the proposed online energy management controller can extend the battery cycle life by over 60%.