Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster Display session

333 - Pooling signaling and costimulatory domains in a flexible CARpool design

Date

14 Dec 2018

Session

Poster Display session

Presenters

Lorraine Springuel

Citation

Annals of Oncology (2018) 29 (suppl_10): x11-x16. 10.1093/annonc/mdy485

Authors

L. Springuel, J. Bolsée, A. Velghe, S. Agaugué, D. Gilham

Author affiliations

  • Research & Development, Celyad SA, 1435 - Mon-Saint-Guibert/BE
More

Resources

Abstract 333

Background

Chimeric Antigen Receptors (CARs) consist of a target binding moiety fused to an extracellular spacer, a transmembrane region and an intracellular signaling tail comprising a tandem alignment of co-stimulatory and activatory domains. This linear configuration displays rigid spatial orientation and ratio of co-stimulation to activation domains. We have developed a novel mix and match approach (CARpool) where the costimulatory signal is provided in trans on accessory proteins that associate with the antigen binding chain via transmembrane interactions.

Methods

Several CD3ζ-containing CAR chains were designed using the transmembrane and cytoplasmic domains of NKG2D or NKp44, associating with DAP10 and DAP12 respectively. Each CAR contained a B7H6-targeting scFv and was co-expressed with corresponding accessory protein using a 2A site. Primary human T cells engineered with the diverse constructs were screened for CAR expression, phenotype and in vitro function.

Results

NKG2D-based CAR complexes were moderately expressed at the cell surface but bound B7H6 and led to potent cells. Modification of the position of the charged residue within the transmembrane domain of the CAR is being used to modulate the surface expression and thus their potency. NKp44-based CAR complexes were more frequently expressed on primary T cells and bound B7H6, though functionality appears to be dependent on the nature of the extracellular spacer.

Conclusions

These studies provide proof-of-concept for a novel CAR design where it is possible to incorporate or interchange costimulatory domain(s) in a stoichiometrically controlled way. Recapitulating physiological TCR activation by providing co-stimulation in trans within the CARpool may result in optimal downstream signaling, thereby enhancing anti-tumoral activity.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Celyad SA.

Funding

Celyad SA.

Disclosure

L. Springuel, J. Bolsée, A. Velghe, S. Agaugué, D. Gilham: Employee of Celyad SA.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.