(648b) A Flight Simulator for Cancer Immunotherapy: Modeling CAR T-Cells in a Solid Tumor Context

Chimeric antigen receptor (CAR) T-cell therapies marry advances in cellular engineering with personalized medicine to provide patient-specific, targeted cancer treatments. Though current CAR T-cell therapies successfully target blood cell cancers, treating solid tumors has proven to be more challenging. Solid-tumor CAR designs must overcome several challenges, including tumor microenvironment barriers preventing CAR T-cell infiltration and lack of unique tumor antigens for selective targeting. Given the vast design space and influential tumor context, testing every possible design in vitro or in vivo is prohibitively time-consuming and resource intensive. Thus, there exists a need to efficiently and systematically test designs, understand underlying biological phenomena, and describe emergent behavior. In this project, we developed a flight simulator for CAR T-cell therapies: a multi-scale, multi-class agent-based model (ABM) designed to elucidate how inherent tumor features and tunable cell therapy properties affect treatment outcomes. This work builds upon a previously established ABM—a “bottom-up” computational model that utilizes first-principles to dictate probabilistic rules that guide agent behaviors and interactions within the context of a local environment. The agents include both cancerous and healthy tissue cells and CD4⁺ and CD8⁺ CAR T-cells, each equipped with metabolism and signaling modules, interacting within a vascularized and diffusive tumor microenvironment. Using this ABM as a testbed, we investigated fundamental design questions that are difficult to address experimentally by exploring tunable CAR T-cell design parameters in a simulated dish and an array of tumor settings. Our in silico experiments qualitatively mimic experimental in vitro cell behaviors, and we subsequently tested the best performing treatment settings in an in silico tissue context to predict outcomes in vivo. This work sets the foundation for future in silico experiments that use this model as a flight simulator for elucidating design rules that may ultimately guide the construction of novel CAR T-cell therapies for solid tumors.