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CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack.

Abstract：

:Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3ζ performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naïve T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3ζ and CD28-CD3ζ CARs. In contrast to CD3ζ, CD28-CD3ζ CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3ζ CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions.

journal_name

Gene Ther

journal_title

Gene therapy

authors

Chmielewski M,Hombach AA,Abken H

doi

10.1038/gt.2010.127

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

62-72

issue

1

eissn

0969-7128

issn

1476-5462

pii

gt2010127

journal_volume

18

pub_type

杂志文章

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