CARTmath - A Mathematical Model of CAR-T Immunotherapy in Preclinical Models

Abstract

Immunotherapy has gained great momentum with chimeric antigen receptor T cell 1 (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize 2 tumor-specific antigens increasing tumor elimination efficiency. In the last years, CAR-T cell 3 immunotherapy for hematological malignancies achieved a great response rate on patients and is a 4 very promising therapy for several other malignancies. Each new CAR design requires a preclinical 5 proof-of-concept experiment using immunodeficient mouse models. The absence of a functional 6 immune system in these mice makes them simple and suitable to be mathematically modeled. 7 In this work, we developed a three population mathematical model to describe tumor response 8 to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions 9 between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for 10 several phenomena, such as tumor-induced immunosuppression, memory pool formation, and 11 conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual 12 donor and tumor specificities were considered as uncertainties in the model parameters. Our 13 model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR 14 receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly 15 depends on some specific parameters such as the differentiation of effector to memory CAR-T 16 cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In 17 summary, our model can contribute to reduce and optimize the number of in vivo experiments 18 with in silico tests to select specific scenarios that could be tested in experimental research. Such 19 in silico laboratory was made available in a Shiny R-based platform called CARTmath. It is an 20 open-source, easy to run simulator, available at github.com/tmglncc/CARTmath or directly on 21 the webpage cartmath.lncc.br, containing this manuscript results as examples and documentation. 22 The developed model, together with the CARTmath platform, provides potential use for assessing 23 different CAR-T cell immunotherapy protocols and associated efficacy, becoming an accessory 24 towards in silico trials. 25