Designing multivalent proteins based on natural killer cell receptors and their ligands as immunotherapy for cancer

Smits, Nicole C.; Coupet, Tiffany A.; Godbersen, Claire; Sentman, Charles L.

doi:10.1080/14712598.2016.1195364

Cited by 5 publications

(5 citation statements)

References 82 publications

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“…Additional components can be added to manipulate the immune synapse between NK cells and their targets. Some have suggested that engaging NKG2D through fusion proteins (Smits et al 2016, von Strandmann et al 2006) may be more advantageous. In addition, scFvs that block NK cell-specific or broad checkpoints like KIRs, TIGIT, NKG2A, or PD1 may be optimal.…”

Section: Bispecific and Trispecific Killer Cell Engagersmentioning

confidence: 99%

Natural Killer Cells in Cancer Immunotherapy

Miller

Lanier

2019

Annu. Rev. Cancer Biol.

121

111

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Natural killer (NK) cells have evolved to complement T and B cells in host defense against pathogens and cancer. They recognize infected cells and tumors using a sophisticated array of activating, costimulatory, and inhibitory receptors that are expressed on NK cell subsets to create extensive functional diversity. NK cells can be targeted to kill with exquisite antigen specificity by antibody-dependent cellular cytotoxicity. NK and T cells share many of the costimulatory and inhibitory receptors that are currently under evaluation in the clinic for cancer immunotherapy. As with T cells, genetic engineering is being employed to modify NK cells to specifically target them to tumors and to enhance their effector functions. As the selective pressures exerted by immunotherapies to augment CD8+T cell responses may result in loss of MHC class I, NK cells may provide an important fail-safe to eliminate these tumors by their capacity to eliminate tumors that are “missing self.”

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Section: Bispecific and Trispecific Killer Cell Engagersmentioning

confidence: 99%

Natural Killer Cells in Cancer Immunotherapy

Miller

Lanier

2019

Annu. Rev. Cancer Biol.

121

111

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“…by targeting NKG2D-L with chimeric antigen receptor T (CAR-T) cells (NKR-2) (NCT03018405), (CYAD-02) (NCT04167696). Other promising constructs which utilize the extracellular domain of NKG2D to target NKG2DL expressed on various tumors are NKG2DL-targeted Bispecific T-cell Engagers (NKG2D-BiTE) (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas

Hagelstein

Lutz²,

Schmidt³

et al. 2021

Front. Immunol.

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Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.

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“…NKG2D and its ligands are recognized as modulators of tumor immunity and as such of interest to cancer immunotherapy [43] , [44] , [45] , [46] . Among current approaches are the development of multivalent immunoligands containing MICA or ULBP2 for stimulation of T cell and NK cell NKG2D [47] , [48] , [49] and pharmacological enhancement of NKG2D ligand expression [50] .…”

Section: Discussionmentioning

confidence: 99%

Control of Tumor Initiation by NKG2D Naturally Expressed on Ovarian Cancer Cells

et al. 2017

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Cancer cells may co-opt the NKG2D lymphocyte receptor to complement the presence of its ligands for autonomous stimulation of oncogenic signaling. Previous studies raise the possibility that cancer cell NKG2D may induce high malignancy traits, but its full oncogenic impact is unknown. Using epithelial ovarian cancer as model setting, we show here that ex vivo NKG2D+ cancer cells have stem-like capacities, and provide formal in vivo evidence linking NKG2D stimulation with the development and maintenance of these functional states. NKG2D+ ovarian cancer cell populations harbor substantially greater capacities for self-renewing in vitro sphere formation and in vivo tumor initiation in immunodeficient (NOD scid gamma) mice than NKG2D− controls. Sphere formation and tumor initiation are impaired by NKG2D silencing or ligand blockade using antibodies or a newly designed pan ligand-masking NKG2D multimer. In further support of pathophysiological significance, a prospective study of 47 high-grade serous ovarian cancer cases revealed that the odds of disease recurrence were significantly greater and median progression-free survival rates higher among patients with above and below median NKG2D+ cancer cell frequencies, respectively. Collectively, our results define cancer cell NKG2D as an important regulator of tumor initiation in ovarian cancer and presumably other malignancies and thus challenge current efforts in immunotherapy aimed at enhancing NKG2D function.

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Designing multivalent proteins based on natural killer cell receptors and their ligands as immunotherapy for cancer

Cited by 5 publications

References 82 publications

Natural Killer Cells in Cancer Immunotherapy

Natural Killer Cells in Cancer Immunotherapy

Bispecific NKG2D-CD3 and NKG2D-CD16 Fusion Proteins as Novel Treatment Option in Advanced Soft Tissue Sarcomas

Control of Tumor Initiation by NKG2D Naturally Expressed on Ovarian Cancer Cells

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