Trispecific natural killer cell nanoengagers for targeted chemoimmunotherapy

Au, Kin Man; Park, Steven I; Wang, Andrew Z.

doi:10.1126/sciadv.aba8564

Cited by 75 publications

(72 citation statements)

References 47 publications

(95 reference statements)

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“…An anti-CD16 ×IL-15 × anti-CD33 TriKE is currently being tested in a phase I/II clinical trial (NCT03214666), and a second generation version has already been developed [151]. Other advancements include the development of: (i) a BIKE that additionally includes an anti-CD133 molecule to target cancer stem cells [152]; (ii) a TriKE that activates NK cells by binding NKp46 instead of presenting IL-15 [153]; and (iii) a nanoparticle-based TriKE that targets two NK cell activating receptors (CD16 and 4-1BB) and the tumor antigen EGFR, while simultaneously delivering the chemotherapeutic epirubicin [154]. Future potential modifications to TriKEs are numerous and could include blocking NK inhibitory receptors or, by using the aforementioned nanoparticles, delivering activity-boosting drugs, metabolism-fueling nutrients, such as glucose or essential amino acids, or STING agonists, which have recently been shown to enhance NK cell-mediated tumor rejection [155].…”

Section: Antibody-based Constructsmentioning

confidence: 99%

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Bachiller

Battram

Perez-Amill

et al. 2020

Cancers

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Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.

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Section: Antibody-based Constructsmentioning

confidence: 99%

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Bachiller

Battram

Perez-Amill

et al. 2020

Cancers

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“…Au et al fabricated PLGA nanoparticle-based tri-specific NK cell engagers that can target epidermal growth factor receptors on tumor cells and CD16+/4-1BB+ NK cells. This multi-specific nano-platform successfully allowed the NK cell engagement to tumor cells and NK cell activation to attack EGFR positive colorectal adenocarcinoma, triple negative breast cancer, epidermoid carcinoma, and melanoma, respectively [75]. Further, since remarkable success in CAR-T cell therapy, the engagement of immune effector NK cells to the tumor cells is one of the promising approaches in NK cell cancer immunotherapy.…”

Section: Nanoparticle-mediated Nk Cell Receptor-ligand Activation and Nano-engagersmentioning

confidence: 99%

Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles

Kim

2021

Pharmaceutics

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Among various immunotherapies, natural killer (NK) cell cancer immunotherapy using adoptive transfer of NK cells takes a unique position by targeting tumor cells that evade the host immune surveillance. As the first-line innate effector cell, it has been revealed that NK cells have distinct mechanisms to both eliminate cancer cells directly and amplify the anticancer immune system. Over the last 40 years, NK cell cancer immunotherapy has shown encouraging reports in pre-clinic and clinic settings. In total, 288 clinical trials are investigating various NK cell immunotherapies to treat hematologic and solid malignancies in 2021. However, the clinical outcomes are unsatisfying, with remained challenges. The major limitation is attributed to the immune-suppressive tumor microenvironment (TME), low activity of NK cells, inadequate homing of NK cells, and limited contact frequency of NK cells with tumor cells. Innovative strategies to promote the cytolytic activity, durable persistence, activation, and tumor-infiltration of NK cells are required to advance NK cell cancer immunotherapy. As maturing nanotechnology and nanomedicine for clinical applications, there is a greater opportunity to augment NK cell therapeutic efficacy for the treatment of cancers. Active molecules/cytokine delivery, imaging, and physicochemical properties of nanoparticles are well equipped to overcome the challenges of NK cell cancer immunotherapy. Here, we discuss recent clinical trials of NK cell cancer immunotherapy, NK cell cancer immunotherapy challenges, and advances of nanoparticle-mediated NK cell therapeutic efficacy augmentation.

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“…Recently, a nanoparticle-based trispecific NK cell engager (named nano-TriNKE) has been developed to target EGFR receptors on tumor cells and CD16 and 4-1BB on NK cells. This is in the preclinical phase but may become useful in the treatment of tumors that overexpress EGFR [ 59 ].…”

Section: Current Advances In Nk Cell Targeted Therapymentioning

confidence: 99%

Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies

St‐Pierre

Bhatia

Chandra

2021

Cancers

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Natural killer (NK) cells are lymphocytes that are integral to the body’s innate immunity, resulting in a rapid immune response to stressed or infected cells in an antigen-independent manner. The innate immune system plays an important role in the recognition of tumor-derived stress-related factors and is critical to subsequent adaptive immune responses against tumor antigens. The aim of this review is to discuss mechanisms by which tumor cells evade NK cells and to outline strategies that harness NK cells for cancer immunotherapy. We discuss strategies to relieve the exhausted state of NK cells, recent therapies focused on targeting NK-cell-specific activating and inhibitory receptors, the use of cytokines IL-2 and IL-15 to stimulate autologous or allogeneic NK cells, and ongoing trials exploring the use of genetically modified NK cells and chimeric antigen-receptor-modified NK (CAR-NK) cells.

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Trispecific natural killer cell nanoengagers for targeted chemoimmunotherapy

Cited by 75 publications

References 47 publications

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Recent Advances to Augment NK Cell Cancer Immunotherapy Using Nanoparticles

Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies

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