Feldmann and Hoffmann et al. developed a novel switchable humanized artificial receptor platform comprising either of two peptides as extracellular domains, termed RevCARs, which are redirected against tumor by RevTMs (bispecific antibodies recognizing peptide and target antigen). RevCAR T cells + RevTMs killed prostate cell lines (LNCAP and PC3) in vitro, increased cytokine release upon activation, and reduced tumor size in vivo. Dual-RevCARs with bicistronic expression of separate activation (CD4) and co-stimulatory (CD28) signals for AND gate targeting demonstrated increased tumor lysis and cytokine release in the presence of both RevTMs.
Contributed by Shishir Pant
ABSTRACT: Chimeric antigen receptor (CAR) T cells show remarkable therapeutic effects in some hematological malignancies. However, CAR T cells can also cause life-threatening side effects. In order to minimize off- target and on-target/off-tumor reactions, improve safety, enable controllability, provide high flexibility, and increase tumor specificity, we established a novel humanized artificial receptor platform termed RevCARs. RevCAR genes encode for small surface receptors lacking any antigen-binding moiety. Steering of RevCAR T cells occurs via bispecific targeting molecules (TMs). The small size of RevCAR-encoding genes allows the construction of polycistronic vectors. Here, we demonstrate that RevCAR T cells effi- ciently kill tumor cells, can be steered by TMs, flexibly redirected against multiple targets, and used for combinatorial targeting following the “OR” and “AND” gate logic.