Development of novel target modules for retargeting of UniCAR T cells to GD2 positive tumor cells

Mitwasi, Nicola; Feldmann, Anja; Bergmann, Ralf; Berndt, Nicole; Arndt, Claudia; Koristka, Stefanie; Kegler, Alexandra; Jureczek, Justyna; Hoffmann, Anja; Ehninger, Armin; Cartellieri, Marc; Albert, Susann; Rössig, Claudia; Ehninger, Gerhard; Pietzsch, Jens; Steinbach, Jörg; Bachmann, Michael

doi:10.18632/oncotarget.21017

Cited by 46 publications

(75 citation statements)

References 58 publications

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“…UniCAR T cells are only active in the presence of a TM. Accordingly, once the respective TM is eliminated, the UniCAR cells are automatically switched off 36,38 . In addition, high flexibility with respect to the target antigen is achieved by allowing redirection of the same modified T cells to various targets through the simultaneous or sequential use of different TMs.…”

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confidence: 99%

“UniCAR”-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

Mitwasi

Feldmann

Arndt

et al. 2020

Sci Rep

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Antigen-specific redirection of immune effector cells with chimeric antigen receptors (CARs) demonstrated high therapeutic potential for targeting cancers of different origins. Beside CART cells, natural killer (NK) cells represent promising alternative effectors that can be combined with CAR technology. Unlike T cells, primary NK cells and the NK cell line NK-92 can be applied as allogeneic off-the-shelf products with a reduced risk of toxicities. We previously established a modular universal CAR (UniCAR) platform which consists of UniCAR-expressing immune cells that cannot recognize target antigens directly but are redirected by a tumour-specific target module (TM). The TM contains an antigen-binding moiety fused to a peptide epitope which is recognized by the UniCAR molecule, thereby allowing an on/off switch of CAR activity, and facilitating flexible targeting of various tumour antigens depending on the presence and specificity of the TM. Here, we provide proof of concept that it is feasible to generate a universal off-the-shelf cellular therapeutic based on UniCAR NK-92 cells targeted to tumours expressing the disialoganglioside GD2 by GD2-specific TMs that are either based on an antibody-derived single-chain fragment variable (scFv) or an IgG4 backbone. Redirected UniCAR NK-92 cells induced specific killing of GD2-expressing cells in vitro and in vivo, associated with enhanced production of interferon-γ. Analysis of radiolabelled proteins demonstrated that the IgG4-based format increased the in vivo half-life of the TM markedly in comparison to the scFv-based molecule. In summary, UniCAR NK-92 cells represent a universal off-the-shelf platform that is highly effective and flexible, allowing the use of different TM formats for specific tumour targeting.

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confidence: 99%

“UniCAR”-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

Mitwasi

Feldmann

Arndt

et al. 2020

Sci Rep

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“…For a fast steering of the UniCAR system, the TM needs to be rapidly eliminated. As it was shown by previous PET analyses, TMs based on scFvs or nanobodies fullfill this prerequisite, eg, previous studies . Such TMs have usually short elimination half‐lives of about 15 to 45 minutes.…”

Section: Modular Targeting Strategiesmentioning

confidence: 59%

“…Replacing TMs with short half‐life by TMs with extended half‐life could facilitate the treatment and may be applied when most of the tumor burden is destroyed, and thus, the risk of CRS and TLS will be low. For both types of TMs, we have shown proof of concept in vitro and in experimental mice for retargeting of UniCARs and PET imaging including for CD19, CD123, CD33, PSCA, PSMA, GD2, EGFR, MUC1, STn, and others (Bachmann, unpublished). Interestingly, TMs are not limited to ab derivates.…”

Section: Modular Targeting Strategiesmentioning

confidence: 90%

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Theranostic CAR T cell targeting: A brief review

Arndt

Bachmann

Bergmann

et al. 2019

Labelled Comp Radiopharmac

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More than hundred years ago, Paul Ehrlich postulated that our immune system should be able to recognize tumor cells. Just recently, the development of check point inhibitors, bispecific antibodies, and T cells genetically modified to express chimeric antigen receptors (CARs) underlines the true power of our immune system. T cells genetically modified with CARs can lead to complete remission of malignant hematologic diseases. However, they can also cause life‐threatening side effects. In case of cytokine release syndrome, tumor lysis syndrome, or deadly side effects on the central nervous system, an emergency shut down of CAR T cells is needed. Targeting of tumor‐associated antigens that are also expressed on vital tissues require a possibility to repeatedly switch the activity of CAR T cells on and off on demand and to follow the treatment by imaging. Theranostic, modular CARs such as the UniCAR system may help to overcome these problems.

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“…Over the past years, we have described and established a universal modular Ab-based CAR platform technology (UniCAR) (see also Fig. 1A) (22,27,30,35,(37)(38)(39)(40)(41). As schematically summarized in Fig.…”

Section: Identification and Characterization Of Car Constructs Suitabmentioning

confidence: 99%

Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells

Albert

Koristka

Gerbaulet

et al. 2019

The Journal of Immunology

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Long-term survival of adoptively transferred chimeric Ag receptor (CAR) T cells is often limited. Transplantation of hematopoietic stem cells (HSCs) transduced to express CARs could help to overcome this problem as CAR-armed HSCs can continuously deliver CAR+ multicell lineages (e.g., T cells, NK cells). In dependence on the CAR construct, a variable extent of tonic signaling in CAR T cells was reported; thus, effects of CAR-mediated tonic signaling on the hematopoiesis of CAR-armed HSCs is unclear. To assess the effects of tonic signaling, two CAR constructs were established and analyzed 1) a signaling CAR inducing a solid Ag-independent tonic signaling termed CAR-28/ζ and 2) a nonstimulating control CAR construct lacking intracellular signaling domains termed CAR-Stop. Bone marrow cells from immunocompetent mice were isolated, purified for HSC-containing Lin−cKit+ cells or the Lin−cKit+ Sca-1+ subpopulation (Lin−Sca-1+cKit+), and transduced with both CAR constructs. Subsequently, modified bone marrow cells were transferred into irradiated mice, in which they successfully engrafted and differentiated into hematopoietic progenitors. HSCs expressing the CAR-Stop sustained normal hematopoiesis. In contrast, expression of the CAR-28/ζ led to elimination of mature CAR+ T and B cells, suggesting that the CAR-mediated tonic signaling mimics autorecognition via the newly recombined immune receptors in the developing lymphocytes.

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Development of novel target modules for retargeting of UniCAR T cells to GD2 positive tumor cells

Cited by 46 publications

References 58 publications

“UniCAR”-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

“UniCAR”-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

Theranostic CAR T cell targeting: A brief review

Tonic Signaling and Its Effects on Lymphopoiesis of CAR-Armed Hematopoietic Stem and Progenitor Cells

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