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

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. DaviesAnna Schurich, John Maher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Article number100457
JournalCell Reports Medicine
Volume2
Issue number12
Early online date21 Dec 2021
DOIs
Publication statusPublished - 21 Dec 2021

Keywords

  • cancer
  • CAR T cells
  • chimeric antigen receptor
  • chimeric co-stimulatory receptor
  • co-stimulation
  • immunotherapy
  • parallel CAR

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