Single-cell imaging of T cell immunotherapy responses in vivo
Chuan Yan, Qiqi Yang, Songfa Zhang, David G. Millar, Eric Alpert, Daniel Do, Alexandra Veloso, Dalton C. Brunson, Benjamin J. Drapkin, Marcello Stanzione, Irene Scarfò, John C. Moore, Sowmya Iyer, Qian Qin, Yun Wei, Karin M. McCarthy, John F. Rawls, Nick Dyson, Mark Cobbold, Marcela V. Maus, David M. Langenau
Abstract
T cell immunotherapies have revolutionized treatment for a subset of cancers. Yet, a major hurdle has been the lack of facile and predicative preclinical animal models that permit dynamic visualization of T cell immune responses at single-cell resolution in vivo. Here, optically clear immunocompromised zebrafish were engrafted with fluorescent-labeled human cancers along with chimeric antigen receptor T (CAR T) cells, bispecific T cell engagers (BiTEs), and antibody peptide epitope conjugates (APECs), allowing real-time single-cell visualization of T cell-based immunotherapies in vivo. This work uncovered important differences in the kinetics of T cell infiltration, tumor cell engagement, and killing between these immunotherapies and established early endpoint analysis to predict therapy responses. We also established EGFR-targeted immunotherapies as a powerful approach to kill rhabdomyosarcoma muscle cancers, providing strong preclinical rationale for assessing a wider array of T cell immunotherapies in this disease.