Three-Compartment Model of CAR T-cell Immunotherapy

Abstract

Immunotherapy has gained great momentum with CAR T (chimeric antigen receptor) cellular therapy, in which the patient's T lymphocytes are genetically manipulated to recognize tumor-specific antigens to increase elimination efficiency. Although recently approved by FDA to treat B cell malignancies, issues such as dose, administration protocol, toxicity, resistance to immunotherapy, among others, remain open and are the subject of intense research nowadays. Improved CAR T cell immunotherapy requires a better understanding of the interplay between CAR T cell doses and tumor burden. We developed a threecompartment mathematical model to describe tumor response to CAR T cell immunotherapy in immunodeficient mouse models (NSG and SCID/beige) based on two published articles from literature. We modeled different receptors as CART 19BBz or CART 123, and different tumor targets as HDML-2 and RAJI. We considered interactions between tumor cells, effector T cells, and T cell differentiation into memory T cells; tumor-induced immunosuppressive effects, conversion of memory T cells into effector T cells in the presence of tumor cells, and individual specificities considered as uncertainties in the parameters of the model. The model was able to represent the two considered immunotherapy scenarios. For the HDML-2 scenario, the tumor is eliminated after the immunotherapy with the CAR T cells even in case of a challenge due to the memory T cells long-term immune protection. For the Raji tumor, expressing indoleamine 2,3-dioxygenase (IDO) activity, the model represented tumor dynamics even when IDO inhibitors are introduced. Using in silico studies considering different dosing quantities and tumor burden, we showed that the proposed model can represent the three possible outcomes: tumor elimination, equilibrium, and escape. We found that therapy effectiveness may also depend on small variations in the parameters' values, regarded as intrinsic individual specificities, as T cell proliferation capacity, as well as immunosuppressive tumor microenvironment factors. These issues may significantly reduce the chance of tumor elimination. In this way, the developed model provides potential use for assessing different CAR T cell protocols and associated efficacy without further in vivo experiments.

Best Practices and Considerations for Clinical Pharmacology and Pharmacometric Aspects for Optimal Development of CAR‐T and TCR‐T Cell Therapies: An Industry Perspective

“…Similarly, a three-compartment mathematical CAR-T model was developed to understand the immunotherapy effect of CAR-Ts on tumor suppression and to characterize the long-term immunological memory in cancer. [88][89][90] The authors leveraged the model to evaluate the impact of different doses, dose fractionation, and tumor burden on tumor responses, including elimination, equilibrium (dormancy), and escape. Similar mechanistic modeling approaches have been used to understand the impact of the CAR-T, leukemic, and Bcell dynamics on the treatment outcomes including, responses, side-effects, relapses, and associated critical factors in patients with B-cell ALL 91,92 or to characterize the BCMA targeting CAR-Ts and tumor dynamics in multiple myeloma indication.…”

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.…”

Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept

“…Mathematical models can disentangle complex systems, such as those arising in mutually interacting immunity, tumour growth, and immunotherapy and have been used extensively for that purpose in the last few years (see e.g., the reviews [21][22][23][24][25][26][27]). Some recent mathematical modelling studies have been carried out to study different aspects of CAR-T cell therapies [28][29][30][31][32][33][34][35]. In this paper we study, in silico, using a mathematical model, the response of a solid tumour to a dual CAR-T product targetting both CD19 and a tumour-associated antigen.…”