Hombach, Andreas and Barden, Markus and Hannappel, Lisa and Chmielewski, Markus and Rappl, Gunter and 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. MOLECULAR THERAPY, 30 (2). pp. 593-605. ISSN 1525-0016, 1525-0024
Full text not available from this repository. (Request a copy)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: | Article |
|---|---|
| Uncontrolled Keywords: | INDUCED KILLER-CELLS; HLA-E EXPRESSION; PHASE-I TRIAL; CD28 COSTIMULATION; ANTITUMOR-ACTIVITY; CHIMERIC RECEPTOR; RETROVIRAL VECTOR; FUSION PROTEIN; SPACER DOMAIN; GENE-THERAPY |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 05:19 |
| Last Modified: | 30 Jan 2024 05:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57146 |
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