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

• Published in: Molecular therapy 2019-10, Vol.27 (10), p.1825-1835
• Main Authors: Hombach, Andreas A., Rappl, Gunter, Abken, Hinrich
• Format: Article
• Language: English
• Subjects: adoptive cell therapy; Antigens; Cancer; CAR; CAR T cell therapy; Carcinoembryonic antigen; CD30; CD30 antigen; CEA; Cell activation; chimeric antigen receptor; Chimeric antigen receptors; Colon cancer; Colorectal cancer; Cytokines; Cytotoxicity; Experiments; Interleukin 2; Ligands; Lymphocytes; Lymphocytes T; Lymphoma; Original; Solid tumors; T cell receptors; Tumors
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.06.007

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. [Display omitted] Hombach et al. found that simultaneous targeting of CD30 on T cells and a tumor-associated antigen (TAA) on solid cancer cells by a bispecific CAR with an integrated anti-CD30-binding domain improved the activation and anti-tumor activity of redirected CAR T cells against solid cancer cells.