Journal
MOLECULAR THERAPY
Volume 27, Issue 10, Pages 1825-1835Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2019.06.007
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Funding
- German Federal Ministry of Education and Research through the CD20CAR Time project within the funding program Innovations for Individualized Medicine [Fkz 01EK1507A-C]
- Else KronerFresenius-Stiftung
- Deutsche Krebshilfe
- Fortune Program of the Medical Faculty of the University of Cologne
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Chimeric antigen receptor (CAR)-engineered T cells are efficacious in controlling advanced leukemia and lymphoma, however, they fail in the treatment of solid cancer, which is thought to be due to insufficient T cell activation. We revealed that the immune response of CAR T cells with specificity for carcinoembryonic antigen (CEA) was more efficacious against CEA(+) cancer cells when simultaneously incubated with an anti-CD30 immunotoxin or anti-CD30 CAR T cells, although the targeted cancer cells lack CD30. The same effect was achieved when the anti-CD30 single-chain variable fragment (scFv) was integrated into the extracellular domain of the anti-CEA CAR. Improvement in T cell activation was due to interfering with the T cell CD30-CD30L interaction by the antagonistic anti-CD30 scFv HRS3; an agonistic anti-CD30 scFv or targeting the high-affinity interleukin-2 (IL-2) receptor was not effective. T cells with the anti-CD30/CEA CAR showed superior immunity against established CEA(+) CD30(-) tumors in a mouse model. The concept is broadly applicable since anti-CD30/TAG72 CAR T cells also showed improved elimination of TAG72(+) CD30(-) cancer cells. Taken together, targeting CD30 on CAR T cells by the HRS3 scFv within the anti-tumor CAR improves the redirected immune response against solid tumors.
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