Depletion of CAR-expressing lymphocytes using autologous anti-CAR-engrafted T cells


Depletion of CAR-expressing lymphocytes using autologous anti-CAR-engrafted T cells

Koristka, S.; Ziller-Walter, P.; Bergmann, R.; Feldmann, A.; Arndt, C.; Kegler, A.; Seifert, A.; Ehninger, G.; Bornhäuser, M.; Bachmann, M.

Adoptive transfer of chimeric antigen receptor (CAR) T cells represents one of the fastest growing areas in cancer immunotherapy. Albeit gene-modified cells have demonstrated unparalleled antitumor efficiency in B cell malignancies, highly potent CAR T cells can cause severe and partly life-threatening side effects including cytokine release syndrome, neurological toxicity and off-target effects. Hence, there is an increasing demand for developing effective approaches to selectively ablate gene-modified cells in vivo.
Previously, we described an epitope tag (E-tag) derived from the human nuclear protein La that is incorporated into the extracellular domain of CARs and accessible by an anti-La monoclonal antibody (mAb). Based on this mAb, we generated a novel CAR construct for specific binding and depletion of E-tag-expressing CAR T cells.
We demonstrate that anti-E-tag-redirected T cells selectively eliminate CAR T cells that extracellularly express the E-tag whilst CAR T cells lacking this tag are not attacked. Interestingly, T cell killing is reciprocal and occurs in dependence of an intracellular signaling domain. Our studies further indicate that T cells expressing high CAR levels are more efficiently depleted than T cells with low CAR expression. Besides, CD4+ and CD8+ target cells are equally well eliminated by both CD4+ and CD8+ effector T cells.
Overall, we provide an approach for specific and efficient depletion of overactive CAR T cells in case patients experience severe side effects. The E-tag can be incorporated into all CARs irrespective of the targeted tumor antigen and represents a promising tool to improve safety of cell-based immunotherapies.

Keywords: Chimeric antigen receptor; T lymphocytes; immunotherapy; toxicity management; epitope tag

  • Poster
    5th European Congress of Immunology, 03.-05.09.2018, Amsterdam, The Netherlands

Permalink: https://www.hzdr.de/publications/Publ-27854
Publ.-Id: 27854