Tamara Muliaditan, Leena Halim, Lynsey M Whilding, Benjamin Draper, Daniela Y Achkova, Fahima Kausar, Maya Glover, Natasha Bechman, Appitha Arulappu, Jenifer Sanchez, Katie R Flaherty, Jana Obajdin, Kristiana Grigoriadis, Pierre Antoine, Daniel Larcombe-Young, Caroline M Hull, Richard Buus, Peter Gordon, Anita Grigoriadis, David M Davies, Anna Schurich, John Maher
Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors...
December 21, 2021: Cell reports medicine