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  • Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.

Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.

Cell reports. Medicine (2022-01-15)
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
ABSTRACT

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. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs.

MATERIALS
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Product Description

Roche
Phytohemagglutinin-L (PHA-L), from Phaseolus vulgaris