CAR-Expressing Natural Killer Cells for Cancer Retargeting

Kloeß, Stephan; Kretschmer, Anna; Stahl, Lilly; Stephan, Frank; Koehl, Ulrike

doi:10.1159/000495771

Cited by 69 publications

(57 citation statements)

References 96 publications

(121 reference statements)

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“…The advantageous provided by NK cells in general and by NK-92 cell line, in particular, have made them an attractive option for clinical translation. Currently, several trials employing CAR NK-92 are ongoing, which will provide a valuable insight into the translational value of these cells in the treatment of cancer 49,50 . In this study, NK-92 were modified with universal CAR (UniCAR) molecules in order to create a switchable and highly flexible therapeutic platform 36 .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…A variety of CAR-T or CAR-NK cell-based adoptive immunotherapy has been developed for hematopoietic cancers or solid tumors therapy [117,118]. Successful application of T cell immunotherapy for late-stage breast cancer has been published very recently [119].…”

Section: Chimeric Antigen Receptor (Car) Cell-based Egfrs Targeting Tmentioning

confidence: 99%

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

Maennling

Tur

Niebert

et al. 2019

Cancers

158

109

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The epidermal growth factor receptor (EGFR) family contains four transmembrane tyrosine kinases (EGFR1/ErbB1, Her2/ErbB2, Her3/ErbB3 and Her4/ErbB4) and 13 secreted polypeptide ligands. EGFRs are overexpressed in many solid tumors, including breast, pancreas, head-and-neck, prostate, ovarian, renal, colon, and non-small-cell lung cancer. Such overexpression produces strong stimulation of downstream signaling pathways, which induce cell growth, cell differentiation, cell cycle progression, angiogenesis, cell motility and blocking of apoptosis.The high expression and/or functional activation of EGFRs correlates with the pathogenesis and progression of several cancers, which make them attractive targets for both diagnosis and therapy. Several approaches have been developed to target these receptors and/or the EGFR modulated effects in cancer cells. Most approaches include the development of anti-EGFRs antibodies and/or small-molecule EGFR inhibitors. This review presents the state-of-the-art and future prospects of targeting EGFRs to treat breast cancer.

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“…Additionally, a large variety of strategies to improve efficacy of CAR T cells in solid malignancies are under pre-clinical investigation [89][90][91][92][93][94]. Yet, the direct translation of the CAR T cell approach to solid malignancies is often impeded by the lack of a suitable cancer specific antigen resulting in either disappointing efficacy or substantial off target toxicity in early clinical trials [95].…”

Section: Adoptive T Cell Therapy In Other Hematological and Solid Malmentioning

confidence: 99%

Advances in cancer immunotherapy 2019 – latest trends

Krüger

Ilmer

Kobold

et al. 2019

J Exp Clin Cancer Res

477

303

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Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

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CAR-Expressing Natural Killer Cells for Cancer Retargeting

Cited by 69 publications

References 96 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

Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials

Advances in cancer immunotherapy 2019 – latest trends

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