Universität zu Köln

Hombach, Andreas ORCID: 0000-0001-9328-8442, Barden, Markus, Hannappel, Lisa, Chmielewski, Markus, Rappl, Gunter, Sachinidis, Agapios and Abken, Hinrich (2022). IL12 integrated into the CAR exodomain converts CD8(+) T cells to poly-functional NK-like cells with superior killing of antigen-loss tumors. Mol. Ther., 30 (2). S. 593 - 606. CAMBRIDGE: CELL PRESS. ISSN 1525-0024

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Abstract

Chimeric antigen receptor (CAR)-redirected T cell therapy often fails to control tumors in the long term due to selecting cancer cells that downregulated or lost CAR targeted antigen. To reprogram the functional capacities specifically of engineered CAR T cells, we inserted IL12 into the extracellular moiety of a CD28-zeta CAR; both the CAR endodomain and IL12 were functionally active, as indicated by antigen-redirected effector functions and STAT4 phosphorylation, respectively. The IL12-CAR reprogrammed CD8(+) T cells toward a so far not recognized natural killer (NK) cell-like signature and a CD94(+)CD56(+) CD62L(high) phenotype closely similar, but not identical, to NK and cytokine induced killer (CIK) cells. In contrast to conventional CAR T cells, IL12-CAR T cells acquired antigen-independent, human leukocyte antigen E (HLA-E) restricted cytotoxic capacities eliminating antigen-negative cancer cells in addition to eliminating cancer cells with CAR cognate antigen. Simultaneous signaling through both the CAR endodomain and IL12 were required for inducing maximal NK-like cytotoxicity; adding IL12 to conventional CAR T cells was not sufficient. Antigen-negative tumors were attacked by IL12-CAR T cells, but not by conventional CART cells. Overall, we present a prototype of a new family of CARs that augments tumor recognition and elimination through expanded functional capacities by an appropriate cytokine integrated into the CAR exodomain.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hombach, Andreas UNSPECIFIED orcid.org/0000-0001-9328-8442 UNSPECIFIED Barden, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Hannappel, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Rappl, Gunter UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-673479
DOI:	10.1016/j.ymthe.2021.10.011
Journal or Publication Title:	Mol. Ther.
Volume:	30
Number:	2
Page Range:	S. 593 - 606
Date:	2022
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1525-0024
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INDUCED KILLER-CELLS; HLA-E EXPRESSION; PHASE-I TRIAL; CD28 COSTIMULATION; ANTITUMOR-ACTIVITY; CHIMERIC RECEPTOR; RETROVIRAL VECTOR; FUSION PROTEIN; SPACER DOMAIN; GENE-THERAPY Multiple languages Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67347