NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo

Vallera, Daniel A.; Ferrone, Soldano; Kodal, Behiye; Hinderlie, Peter; Bendzick, Laura; Ettestad, Brianna; Hallstrom, Caroline; Zorko, Nicholas; Rao, Arpit; Fujioka, Naomi; Ryan, Charles J.; Geller, Melissa A.; Miller, Jeffrey S.; Felices, Martin

doi:10.3390/cancers12092659

Cited by 66 publications

(62 citation statements)

References 53 publications

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“…Within the same study, in vivo studies found that TriKEs had superior antitumor activity and sustained NK cell survival for at least three weeks. The same effects were seen when ovarian, prostate and lung cancers were used, highlighting that TriKEs are effective against solid tumors [ 262 ]. Although TriKEs used in these studies contained IL-15, and IL-15 elicited severe toxicity (bowel ischemia, pneumonitis, papilledema, uveitis and grade 3 hypotension) and death in humans [ 256 ], IL-15-incorporting TriKEs showed no observable detrimental effects in mice [ 263 ].…”

Section: Nk Cells In the Context Of Immunotherapiesmentioning

confidence: 87%

Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

Lee

Silva

Palendira

et al. 2021

Cancers

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Natural killer (NK) cells are a key component of an innate immune system. They are important not only in initiating, but also in augmenting adaptive immune responses. NK cell activation is mediated by a carefully orchestrated balance between the signals from inhibitory and activating NK cell receptors. NK cells are potent producers of proinflammatory cytokines and are also able to elicit strong antitumor responses through secretion of perforin and granzyme B. Tumors can develop many mechanisms to evade NK cell antitumor responses, such as upregulating ligands for inhibitory receptors, secreting anti-inflammatory cytokines and recruiting immunosuppressive cells. Enhancing NK cell responses will likely augment the effectiveness of immunotherapies, and strategies to accomplish this are currently being evaluated in clinical trials. A comprehensive understanding of NK cell biology will likely provide additional opportunities to further leverage the antitumor effects of NK cells. In this review, we therefore sought to highlight NK cell biology, tumor evasion of NK cells and clinical trials that target NK cells.

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Section: Nk Cells In the Context Of Immunotherapiesmentioning

confidence: 87%

Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

Lee

Silva

Palendira

et al. 2021

Cancers

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“…Of note, GT Biopharma is also developing two TriKEs against solid tumors: GTB-4550 targeting PD-1, and GTB-5550 targeting B7H3 [ 174 ]. Additional TriKEs are in preclinical stage, such as 161,533 targeting CD33 [ 175 ], or a slightly different construct targeting B7-H3 and using an sdAb to bind CD16 [ 176 ]. Another related variant are trispecific “NK-cell engagers” (NKCE), which recruit NK cells by using scFv or Fab against TAA, NKp46, and CD16 [ 177 ].…”

Section: Trispecific and Other Multispecific Antibodiesmentioning

confidence: 99%

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Elshiaty

Schindler

Christopoulos

2021

IJMS

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Building upon the resounding therapeutic success of monoclonal antibodies, and supported by accelerating progress in engineering methods, the field of multispecific therapeutic antibodies is growing rapidly. Over 140 different molecules are currently in clinical testing, with excellent results in recent phase 1–3 clinical trials for several of them. Multivalent bispecific IgG-modified formats predominate today, with a clear tendency for more target antigens and further increased valency in newer constructs. The strategies to augment anticancer efficacy are currently equally divided between disruption of multiple surface antigens, and additional redirection of cytotoxic T or NK lymphocytes against the tumor. Both effects complement other modern modalities, such as tyrosine kinase inhibitors and adoptive cell therapies, with which multispecifics are increasingly applied in combination or merged, for example, in the form of antibody producing CAR-T cells and oncolytics. While mainly focused on B-cell malignancies early on, the contemporary multispecific antibody sector accommodates twice as many trials against solid compared to hematologic cancers. An exciting emerging prospect is the targeting of intracellular neoantigens using T-cell receptor (TCR) fusion proteins or TCR-mimic antibody fragments. Considering the fact that introduction of PD-(L)1 inhibitors only a few years ago has already facilitated 5-year survival rates of 30–50% for per se highly lethal neoplasms, such as metastatic melanoma and non-small-cell lung carcinoma, the upcoming enforcement of current treatments with “next-generation” immunotherapeutics, offers a justified hope for the cure of some advanced cancers in the near future.

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“…These antibodies show promise in vitro and in vivo , but most clinical research has been restricted to hematologic malignancies ( 115 ). To study the antibodies in mice, researchers have used xenogenic models such as NSG mice injected with human ovarian cancer cells and NK cells ( 116 ). Another novel NK cell stimulating antibody is a trifunctional NKCE that binds to NKp46 and CD16 on NK cells and a tumor antigen on target cells.…”

Section: Ilc Immunotherapeutics Studies In Murine Hostsmentioning

confidence: 99%

Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies

et al. 2021

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Innate lymphoid cells (ILCs) are a branch of the immune system that consists of diverse circulating and tissue-resident cells, which carry out functions including homeostasis and antitumor immunity. The development and behavior of human natural killer (NK) cells and other ILCs in the context of cancer is still incompletely understood. Since NK cells and Group 1 and 2 ILCs are known to be important for mediating antitumor immune responses, a clearer understanding of these processes is critical for improving cancer treatments and understanding tumor immunology as a whole. Unfortunately, there are some major differences in ILC differentiation and effector function pathways between humans and mice. To this end, mice bearing patient-derived xenografts or human cell line-derived tumors alongside human genes or human immune cells represent an excellent tool for studying these pathways in vivo. Recent advancements in humanized mice enable unparalleled insights into complex tumor-ILC interactions. In this review, we discuss ILC behavior in the context of cancer, the humanized mouse models that are most commonly employed in cancer research and their optimization for studying ILCs, current approaches to manipulating human ILCs for antitumor activity, and the relative utility of various mouse models for the development and assessment of these ILC-related immunotherapies.

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NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo

Cited by 66 publications

References 53 publications

Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

Targeting NK Cells to Enhance Melanoma Response to Immunotherapies

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies

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