Universal CAR technology for redirection of human T cells to leukemic and solid tumor cells


Universal CAR technology for redirection of human T cells to leukemic and solid tumor cells

Feldmann, A.; Bergmann, R.; Albert, S.; Arndt, C.; Aliperta, R.; Koristka, S.; Ehninger, A.; Cartellieri, M.; Ehninger, G.; Steinbach, J.; Bachmann, M.

In recent years, adoptively transferred autologous human T cells that are genetically modified with chimeric antigen receptors (CARs) have been very successfully used for treatment of different hematological malignancies. However, immunotherapy of solid tumors seems to be more challenging. Especially for this application it is of great interest to enhance the very promising CAR technology.
Conventional CARs consist of (I) an extracellular single-chain fragment variable (scFv) redirected to a tumor-associated antigen (TAA), (II) a transmembrane region and (III) intracellular activating motifs. Although these CAR-armed T cells showed impressive therapeutic effects in leukemia patients, some limitations have appeared. Most importantly, CAR-armed T cells can cause life-threatening side effects as a consequence of immoderate on-target, on-tumor reactions or aggressive on-target, off-tumor attack against healthy tissues. Furthermore, under the pressure of a monospecific CAR therapy the targeted antigen can be reduced on tumor cells. To overcome these problems we have recently described a novel modular universal CAR (UniCAR) platform that consists of two separate arms: (I) the universal effector arm and (II) the individual targeting arm. T cells that are genetically modified with UniCARs are redirected to the short peptide epitope E5B9 that is physiologically not presented on the surface of living cells. E5B9 is coupled to the anti-TAA scFv of the target module (TM). Consequently, UniCAR T cells can be cross-linked to tumor cells via the TM which results in antigen-specific tumor cell killing.
We recently described a series of monospecific and bispecific TMs against TAAs including PSCA, PSMA, CD33, CD123, and EGFR (1-3). Here we summarize both in vitro and in experimental mice that all these TMs can efficiently redirect UniCAR T cells against tumor cells in a strictly target-dependent and target-specific manner. Killing occurred at pM TM concentrations. The killing efficacy of UniCAR T cells was comparable to conventional CAR T cells. Redirected UniCAR T cells released pro-inflammatory cytokines as measured by ELISA and/or flow cytometry-based multiplex assays including for example TNF, IL-2 and IFN-γ but not IL-6. In agreement with the UniCAR concept, TMs were released from UniCAR TM complexes in a concentration-dependent manner as measured by dynamic PET analysis.
In summary, we demonstrate that the reactivity of UniCAR-armed T cells can be switched on and off in the presence or absence of a variety of TMs against a series of different TAAs and thus supporting its high flexibility. Moreover, UniCAR activity can be regulated in a dose-dependent manner and thus improve the safety of the CAR technology.

1_A. Feldmann, C. Arndt, R. Bergmann, S. Loff, M. Cartellieri, D. Bachmann, R. Aliperta, M. Hetzenecker, F. Ludwig, S. Albert, P. Ziller-Walter, A. Kegler, S. Koristka, S. Gärtner, M. Schmitz, A. Ehninger, G. Ehninger, J. Pietzsch, J. Steinbach and M. Bachmann. Retargeting of T lymphocytes to PSCA- or PSMA positive prostate cancer cells using the novel modular chimeric antigen receptor platform technology “UniCAR”. Oncotarget 2017, in press.

2_S. Albert, C. Arndt, A. Feldmann, R. Bergmann, D. Bachmann, S. Koristka, F. Ludwig, P. Ziller-Walter, A. Kegler, S. Gärtner, M. Schmitz, A. Ehninger, M. Cartellieri, G. Ehninger, H.-J. Pietzsch, J. Pietzsch, J. Steinbach and M. Bachmann. A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform. OncoImmunology 2017, in press.

3_M. Cartellieri, A. Feldmann, S. Koristka, C. Arndt, S. Loff, A. Ehninger, M. von Bonin, EP Bejestani, G Ehninger and MP Bachmann. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 2016 Aug 12;6(8):e458. doi: 10.1038/bcj.2016.61.

  • Lecture (Conference)
    Cellular Therapy 2017, 9th International Symposium Erlangen, 16.-17.03.2017, Erlangen, Deutschland

Permalink: https://www.hzdr.de/publications/Publ-25247
Publ.-Id: 25247