Journal Article

Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells

Arndt, Claudia, Feldmann, Anja, Ehninger, Gerhard, Ziller-Walter, Pauline, Bergmann, Ralf, Koristka, Stefanie, Bornhäuser, Martin, Bachmann, Michael P, Cartellieri, Marc, Ehninger, Armin, Kegler, Alexandra

2019

Overview

Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients’ immune system and on-target/off-side effects of proposed monoclonal antibodies, we sought to exploit αCAR-engineered T cells to efficiently eliminate CAR T cells. For comprehensive and specific recognition, a small peptide epitope (E-tag) was incorporated into the extracellular spacer region of CAR constructs. We provide first proof-of-concept for targeting this epitope by αE-tag CAR T cells, allowing an effective killing of autologous E-tagged CAR T cells both in vitro and in vivo whilst sparing cells lacking the E-tag. In addition to CAR T-cell cytotoxicity, the αE-tag-specific T cells can be empowered with cancer-fighting ability in case of relapse, hence, have versatile utility. Our proposed methodology can most probably be implemented in CAR T-cell therapies regardless of the targeted tumor antigen aiding in improving overall safety and survival control of highly potent gene-modified cells.

• Publisher: Springer Nature B.V
• Subject: Cell therapy / Cytotoxicity / Epitopes / Immune system / Lymphocytes / Lymphocytes T / Malignancy / Monoclonal antibodies / Side effects / Spacer region