Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells

Yun, Hyun Don; Felices, Martin; Vallera, Daniel A.; Hinderlie, Peter; Cooley, Sarah; Arock, Michel; Gotlib, Jason; Üstün, Celalettin; Miller, Jeffrey S.

doi:10.1182/bloodadvances.2018018176

Cited by 25 publications

(14 citation statements)

References 17 publications

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“…The IL-15 moiety on this TriKE may also reduce off-target toxicities caused by general IL-15 administration by activating NK cells selectively through CD16. Similarly, previously described TriKE constructs (TriKE 161533, and TriKE 1615133) (273), which incorporate an IL-15 linker and contain anti-CD16 and anti-CD33 fragments (161533 TriKE), or anti-CD16 and anti CD133 fragments (1615133 TriKE), were described for activating NK cells against neoplastic mast cells, myelodysplastic syndrome cells, and cancer stem cells (273)(274)(275), as well as providing NK cells with sustained survival and proliferation signals. The plasticity of NK cell engagers enables them to simultaneously target additional moieties, as demonstrated by Schmohl et al, who constructed a TetraKE that binds CD16 on NK cells, EpCAM on carcinoma cells, and CD133 on cancer stem cells, while containing an IL-15 linker (1615EpCAM133) (276).…”

Section: Engagers Of Nk Cells To Unleash Nk Cell Activitymentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Engagers Of Nk Cells To Unleash Nk Cell Activitymentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…Among others, CD16xCD133 bispecific killer-cell engager bears important therapeutic potential, given its ability to target the drug-resistant CD133 + cancer stem cell population [159]; another added value of these constructs is represented by their capability to redirect NK cell killing against immunosuppressive components in the TME, as in the case of the CD16xCD33 BiKE that targets MDSC [153]. Further modifications of this platform are represented by TriKEs where one tumor-antigen-specific moiety is substituted by, or implemented with (to generate a TetraKE), an activating cytokine; indeed, IL-15-containing KEs have proved to promote in vivo persistence, activation, and survival of NK cells, and also rendered NK cells more resistant to immunosuppressive factors in the TME [160][161][162][163][164][165]. Finally, the combination with inhibitors of ADAM-17, responsible for the CD16 shedding on activated NK cells [109,110,151], enhanced CD16xCD33 BiKE-dependent response against primary AML cells [166] (Table 1 and Figure 1).…”

Section: Strategies That Improve Mab Interaction With Cd16mentioning

confidence: 99%

Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Capuano

Pighi

Battella

et al. 2021

Cancers

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Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy.

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“…Due to the modest antitumor activities of unmodified NK cell infusion, various strategies have been developed in the past few years to improve NK cell recognition and activation, including overexpressing chemokines or chemokine receptors to enhance NK cell tumor infiltration ( 112 , 113 ), concurrent use of immune checkpoint inhibitors to reverse NK cell exhaustion ( 114 ), blocking the immunosuppressive TGF-β signaling from the TME ( 115 ), and promoting NK cell tumor-specific engagement through NK cell engagers (NKCEs) ( 31 , 116 – 119 ). Of note, almost all have remained in the preclinical/early clinical phase.…”

Section: Cb-derived Nk-cell Therapiesmentioning

confidence: 99%

Umbilical cord blood derived cellular therapy: advances in clinical development

Wang

Metheny

2023

Front. Oncol.

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While cord blood (CB) is primarily utilized in allogeneic hematopoietic cell transplantation (HCT), the development of novel cell therapy products from CB is a growing and developing field. Compared to adult blood, CB is characterized by a higher percentage of hematopoietic stem cells (HSCs) and progenitor cells, less mature immune cells that retain a high capacity of proliferation, and stronger immune tolerance that requires less stringent HLA-matching when used in the allogenic setting. Given that CB is an FDA regulated product and along with its unique cellular composition, CB lends itself as a readily available and safe starting material for the development of off-the-shelf cell therapies. Moreover, non-hematologic cells such as mesenchymal stem cell (MSCs) residing in CB or CB tissue also have potential in regenerative medicine and inflammatory and autoimmune conditions. In this review, we will focus on recent clinical development on CB-derived cellular therapies in the field of oncology, including T-cell therapies such as chimeric antigen receptor (CAR) T-cells, regulatory T-cells, and virus-specific T-cells; NK-cell therapies, such as NK cell engagers and CAR NK-cells; CB-HCT and various modifications; as well as applications of MSCs in HCT.

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Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells

Abstract: Key Points NK cell natural cytotoxicity and antibody-dependent cellular cytotoxicity of patients with systemic mastocytosis are normal. Trispecific killer engagers (161533 TriKE) target NK cells from normal donors and systemic mastocytosis patients to kill mast cells.

Cited by 25 publications

References 17 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

Umbilical cord blood derived cellular therapy: advances in clinical development

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