Modeling and Simulation of CAR T cell Therapy in Chronic Lymphocytic Leukemia Patients

Advances in genetic engineering have made it possible to reprogram an individual’s immune cells to express receptors that recognize markers on tumor cell surfaces. The process of re-engineering T cell lymphocytes to express Chimeric Antigen Receptors (CARs) and reinfusing the CAR-modified T cells into patients to treat various cancers is being explored in clinical trials. While the majority of patients with some cancers (e.g., B cell acute lymphocytic leukemia) respond to CAR-T cell therapy, this success is not evidenced in all cancers. For example, only 26% of Chronic Lymphocytic Leukemia (CLL) patients respond to CAR T cell therapy. Understanding of the factors associated with an individual patient’s response is important for patient selection and could help develop more effective CAR T cell therapies. Here we present a mechanistic mathematical model to identify factors associated with responses to CAR T cell therapeutic interventions. The proposed model is a system of coupled ordinary differential equations designed based on known immunological principles and prevailing hypotheses on the mechanism of CAR T cell kinetics, Interleukin 6 (IL-6) secretion, and tumor killing in CAR T cell therapy. The model reports in silico disease outcomes using B cell concentration as a surrogate biomarker. Our results are consistent with the in vitro experimental observations that CAR T cell fitness in terms of its tumor cell killing capacity and proliferation plays an important role in the patient response. We demonstrate the utility of mathematical modelling in understanding the factors that play an important role in patient response to CAR T cell therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was supported in part by an appointment to the Research Participation Program at OBPV/CBER, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in this study is publicly available before the initiation of this study. Below are the links for all the datasets used in this study. Porter et al., 2015 - Table S7 and S11 - https://www.science.org/doi/10.1126/scitranslmed.aac5415#supplementary-materials Kalos et al., 2011 - Table S2 and S4 - https://www.science.org/doi/10.1126/scitranslmed.3002842#supplementary-materials Fraietta et al., 2018 - Figure 1b is digitized using WebPlotDigitizer - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320248/#!po=2.50000 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work and the model code are contained in the manuscript and supplementary material