Immunological Synapse Dynamics Induced by Bispecific T-cell Engagers Predict Clinical Pharmacodynamics and Tumor Evolution across Anatomical Sites

Abstract

Effector T cells form immunological synapses (IS) with recognized target cells to elicit cytolytic effects. Facilitating IS formation is the principal pharmacological action of most T cell-based cancer immunotherapies. However, the dynamics of IS formation at the cell population level, the primary driver of the pharmacodynamics of many cancer immunotherapies, remains poorly defined. With classic immunotherapy CD3/CD19 bispecific T cell engager (BiTE) as a model system, we integrate experimental and theoretical approaches to investigate the population dynamics of IS formation and their relevance to clinical pharmacodynamics and treatment resistance. Our models produce experimentally consistent predictions when defining IS formation as a series of spatiotemporally coordinated events driven by molecular and cellular interactions. The models predict tumor-killing pharmacodynamics in patients and reveal trajectories of tumor evolution across anatomical sites under BiTE immunotherapy. Our model highlight the bone marrow may serve as a sanctuary site permitting tumor evolution and antigen escape. The models also suggest the optimal dosing regimens as a function of tumor growth and patient T cell abundance that confer adequate tumor control with minimal disease evolution. This work has implications for developing more effective T cell-based cancer immunotherapies.