Universität zu Köln

Hombach, Andreas A. and Abken, Hinrich (2011). Costimulation by chimeric antigen receptors revisited: the T cell antitumor response benefits from combined CD28-OX40 signalling. Int. J. Cancer, 129 (12). S. 2935 - 2945. HOBOKEN: WILEY. ISSN 1097-0215

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Abstract

The therapeutic success of adoptive therapy with chimeric antigen receptor (CAR) engineered T cells depends on the appropriate costimulation of CD3 zeta to induce full T cell activation. Costimulatory endodomains of the CD28 family are therefore fused with CD3 zeta in a dual signalling CAR. Serious adverse events in two most recent trials; however, highlight the need to analyse in more detail the impact of each costimulatory endodomain on individual effector functions of redirected T cells. We therefore performed a thoroughly controlled side-by-side comparison of the most frequently used endodomains with respect to their impact on CD4(+) and CD8(+) T cell effector functions. CD28 reinforced T cell proliferation and is mandatory to induce IL-2. In the absence of added IL-2, CD28 and OX40 (CD137) but not 4-1BB (CD134) enhanced specific cytolysis. While CD28, 4-1BB and OX40 similarly improved pro-inflammatory cytokine secretion, OX40 most efficiently prevented activation induced cell death of CD62L(-) effector memory T cells. CD28 was superior to initiate the T cell response, OX40 and 4-1BB sustained the response in long term with OX40 being most effective. We consequently combined the beneficial functions in a 3rd generation CD28-OX40 CAR which substantially improved the antitumor response without loosing specificity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hombach, Andreas A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-483353
DOI:	10.1002/ijc.25960
Journal or Publication Title:	Int. J. Cancer
Volume:	129
Number:	12
Page Range:	S. 2935 - 2945
Date:	2011
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADOPTIVE IMMUNOTHERAPY; CD28 COSTIMULATION; CLONAL EXPANSION; ADVERSE EVENT; TARGET-CELLS; TUMOR-CELLS; PHASE-I; ACTIVATION; CANCER; CYTOTOXICITY Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48335