UniCAR T-cells retargeted via short-lived and extended half-life target modules - a combined approach for cancer immunotherapy


UniCAR T-cells retargeted via short-lived and extended half-life target modules - a combined approach for cancer immunotherapy

Loureiro, L. R.; Feldmann, A.; Bergmann, R.; Berndt, N.; Hoffmann, A.; Mitwasi, N.; Jureczek, J.; Koristka, S.; Bachmann, M.; Arndt, C.

Chimeric antigen receptors (CARs) are highly efficient tools for T‐cell‐based cancer immunotherapy. Nonetheless, this approach is associated with mild to severe toxicities including cytokine release syndrome and on‐target/off‐tumor effects. To increase clinical safety while maintaining the efficacy of CAR T‐cell therapy, we developed a novel modular universal CAR (UniCAR) platform. UniCAR T‐cells are exclusively activated via a target module (TM) that establishes the cross‐link between UniCAR T‐cells and cancer cells. Given the small size of such molecules, they are rapidly eliminated and thus, have to be administrated via continuous infusion. Consequently, activation and possible side effects of UniCAR T‐cells can be easily controlled by TM dosing. Regulation of CAR T‐cell activity is mainly important during onset of therapy when tumor burden and the risk for severe side effects are high. Therefore, TMs with extended half‐life may improve eradication of residual tumor cells in late phase of treatment and further expedite clinical application. In this line of thought, we developed both short‐lived and longer lasting TMs directed against several tumor‐associated antigens. Short‐lived TMs are composed of a tumor‐specific binding moiety and the E5B9 peptide epitope which is recognized by UniCAR T‐cells. In order to generate extended half‐life TMs, these two components are fused to the human IgG4 Fc domain. Both short‐lived and longer lasting TMs efficiently redirect UniCAR T‐cells to cancer cells in a highly target‐specific manner, thereby promoting the secretion of pro‐inflammatory cytokines and tumor cell lysis in vitro and in vivo. As demonstrated by PET‐imaging, all TMs specifically enriched at the tumor site presenting either short or prolonged serum half‐lives. Taken together, combination of different short‐lived and extended half‐life TMs provides a highly promising and customized tool for retargeting of UniCAR T‐cells in a flexible, individualized and safe manner at different phases of tumor therapy.

  • Abstract in refereed journal
    Human Gene Therapy (2019)
  • Lecture (Conference)
    International Conference on Lymphocyte Engineering (ICLE 2019), 13.-15.09.2019, London, United Kingdom

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Permalink: https://www.hzdr.de/publications/Publ-30170
Publ.-Id: 30170