Blocking CD30 on T Cells by a Dual Specific CAR for CD30 and Colon Cancer Antigens Improves the CAR T Cell Response against CD30 ? Tumors

摘要

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.