Generation of BiKEs and TriKEs to Improve NK Cell-Mediated Targeting of Tumor Cells

Felices, Martin; Lenvik, Todd; Davis, Zachary; Miller, Jeffrey S.; Vallera, Daniel A.

doi:10.1007/978-1-4939-3684-7_28

Cited by 139 publications

(137 citation statements)

References 92 publications

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“…There are a number of strategies to improve NK cell function in the tumor microenvironment that are being tested for other indications that might be useful in ovarian cancer. For instance, utilization of therapeutic antibodies or bi- and trispecific immune killer engagers have the potential to drive antigen-specific tumor lysis (35). However, utilization of these therapeutic reagents might be limited in the peritoneal cavity of ovarian cancer patients by low CD16 expression on NK cells, needed to drive ADCC.…”

Section: Discussionmentioning

confidence: 99%

IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer

Felices

Chu

Kodal

et al. 2017

Gynecologic Oncology

106

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Objective Natural killer (NK) cells represent a powerful immunotherapeutic target as they lyse tumors directly, do not require differentiation, and can elicit potent inflammatory responses. The objective of these studies was to use an IL-15 super-agonist complex, ALT-803 (Altor BioScience Corporation), to enhance the function of both normal and ovarian cancer patient derived NK cells by increasing cytotoxicity and cytokine production. Methods NK cell function from normal donor peripheral blood mononuclear cells (PBMCs) and ovarian cancer patient ascites was assessed using flow cytometry and chromium release assays +/− ALT-803 stimulation. To evaluate the ability of ALT-803 to enhance NK cell function in vivo against ovarian cancer, we used a MA148-luc ovarian cancer NOD scid gamma (NSG) xenogeneic mouse model with transferred human NK cells. Results ALT-803 potently enhanced functionality of NK cells against all ovarian cancer cell lines with significant increases seen in CD107a, IFNγ and TNFα expression depending on target cell line. Function was also rescued in NK cells derived from ovarian cancer patient ascites. Finally, only animals treated with intraperitoneal ALT-803 displayed an NK dependent significant decrease in tumor. Conclusions ALT-803 enhances NK cell cytotoxicity against ovarian cancer in vitro and in vivo and is able to rescue functionality of NK cells derived from ovarian cancer patient ascites. These findings suggest that ALT-803 has the potential to enhance NK-cell-based immunotherapeutic approaches for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer

Felices

Chu

Kodal

et al. 2017

Gynecologic Oncology

106

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“…Recent studies have shown that NK cells and their function can be augmented using antibody‐dependent cell‐mediated cytotoxicity (ADCC), through monoclonal antibody therapies or novel single‐chain variable fragment (scFv) recombinant reagents called bispecific and trispecific killer engagers (BiKEs and TriKEs). BiKEs simultaneously target both TAs and the CD16 activating receptor expressed on mature NK cells . Upon signalling, CD16 triggers the release of lytic granules and cytokines such as interferon gamma (IFN‐γ) and TNF‐α at the tumour site .…”

Section: Immunotherapy Approaches For Canine Sarcomasmentioning

confidence: 99%

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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Sarcomas represent a group of genomically chaotic, highly heterogenous tumours of mesenchymal origin with variable mutational load. Conventional therapy with surgery and radiation therapy is effective for managing small, low‐grade sarcomas and remains the standard therapeutic approach. For advanced, high‐grade, recurrent, or metastatic sarcomas, systemic chemotherapy provides minimal benefit, therefore, there is a drive to develop novel approaches. The discovery of “Coley's toxins” in the 19th century, and their use to stimulate the immune system supported the application of unconventional therapies for the treatment of sarcomas. While promising, this initial work was abandoned and treatment paradigm and disease course of sarcomas was largely unchanged for several decades. Exciting new therapies are currently changing treatment algorithms for advanced carcinomas and melanomas, and similar approaches are being applied to advance the field of sarcoma research. Recent discoveries in subtype‐specific cancer biology and the identification of distinct molecular targets have led to the development of promising targeted strategies with remarkable potential to change the landscape of sarcoma therapy in dogs. The purpose of this review article is to describe the current standard of care and limitations as well as emerging approaches for sarcoma therapy that span many of the most active paradigms in oncologic research, including immunotherapies, checkpoint inhibitors, and drugs capable of cellular metabolic reprogramming.

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“…To further optimize NK-cell mediated ADCC, bi-and trispecific killer engagers (BiKEs and TriKEs) have been designed which bind CD16 at higher affinity than a natural Fc binder to create a specific immune synapse between NK cells and tumor cells[69]. BiKEs bind to NK cells through a single chain variable fragment (scFv) spaced with an inert linker and combined in a single sequence to a scFv directed against one or more desired tumor antigens (e.g.…”

Section: 3 Potential Strategies To Simultaneously Enhance Nk and γδmentioning

confidence: 99%

NK Cells and γδT Cells for Relapse Protection after Allogeneic Hematopoietic Cell Transplantation (HCT)

2017

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Purpose of review The outcome of allogeneic stem cell transplantation (allo-HCT) is still compromised by relapse and complications. NK cells and γδT cells, effectors which both function through MHC-unrestricted mechanisms, can target transformed and infected cells without inducing Graft-versus-Host Disease (GVHD). Allo-HCT platforms based on CD34+ selection or αβ-TCR depletion result in low grades of GVHD, early immune reconstitution (IR) of NK and γδT cells and minimal usage of GVHD prophylaxis. In this review we will discuss strategies to retain and expand the quantity, diversity and functionality of these reconstituting innate cell types. Recent findings Bisphosphonates, IL-15 cytokine administration, specific antibodies, checkpoint inhibitors and (CMV based) vaccination are currently being evaluated to enhance IR. All these approaches have shown to potentially enhance both NK and γδT cell immuno-repertoires. Summary Rapidly accumulating data linking innate biology to proposed clinical immune interventions, will give unique opportunities to unravel shared pathways which determine the Graft-versus-Tumor effects of NK and γδT cells.

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Generation of BiKEs and TriKEs to Improve NK Cell-Mediated Targeting of Tumor Cells

Cited by 139 publications

References 92 publications

IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer

IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

NK Cells and γδT Cells for Relapse Protection after Allogeneic Hematopoietic Cell Transplantation (HCT)

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