Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

Oei, Vincent Yi Sheng; Siernicka, Marta; Graczyk-Jarzynka, Agnieszka; Hoel, Hanna Julie; Yang, Weiwen; Palacios, Daniel; Almåsbak, Hilde; Bajor, Małgorzata; Clement, Dennis; Brandt, L.; Önfelt, Björn; Goodridge, Jodie P.; Winiarska, Magdalena; Zagożdżon, Radosław; Olweus, Johanna; Kyte, Jon-Amund; Malmberg, Karl‐Johan

doi:10.1158/2326-6066.cir-17-0207

Cited by 74 publications

(61 citation statements)

References 49 publications

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“…Primary human CAR-NK cells have a high potential for use as both autologous or allogeneic cytotoxic CAR effector cells in immunotherapeutic approaches [8]. However, compared to vulnerable/sensitive lymphomas with stable overexpression of B-cell antigens, most antigens used for solid tumour therapy show alternating surface expression levels with heterogeneity even within the tumour or between primary and metastatic lesions [64, reviewed in 65-67].…”

Section: Effectiveness Of Car-engineered Primary Nk Cells Against Solmentioning

confidence: 99%

“…Currently, this leads to first immunotherapeutic approaches to cure both lymphomas of B cell origin and acute lymphoid leukaemia (ALL). This includes human NK cells of different origins, such as the NK cell line NK-92, primary cord blood (CB)-derived as well as peripheral blood (PB) NK cells, which have recently entered clinical implementation testing the effectiveness in different phase I/II studies (Table 1) [4, 8-10]. Other than primary NK cells collected from CB or PB, the transformed cell line NK-92 originated from undifferentiated NK-cell precursors [11-13].…”

Section: Introductionmentioning

confidence: 99%

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CAR-Expressing Natural Killer Cells for Cancer Retargeting

Kloeß

Kretschmer

Stahl

et al. 2019

Transfus Med Hemother

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Since the approval in 2017 and the outstanding success of Kymriah® and Yescarta®, the number of clinical trials investigating the safety and efficacy of chimeric antigen receptor-modified autologous T cells has been constantly rising. Currently, more than 200 clinical trials are listed on clinicaltrial.gov. In contrast to CAR-T cells, natural killer (NK) cells can be used from allogeneic donors as an “off the shelf product” and provide alternative candidates for cancer retargeting. This review summarises preclinical results of CAR-engineered NK cells using both primary human NK cells and the cell line NK-92, and provides an overview about the first clinical CAR-NK cell studies targeting haematological malignancies and solid tumours, respectively.

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Section: Effectiveness Of Car-engineered Primary Nk Cells Against Solmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Kloeß

Kretschmer

Stahl

et al. 2019

Transfus Med Hemother

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“…Remarkable benefits might be achieved by engineering the CAR protein into memory-like NK cells or a specific NK cell subset. In fact, CD19-specific CAR-engineered NKG2C + CD57 + adaptive NK cells showed an enhanced ability to kill CD19 + tumor cells compared with that of other NK subsets (75). Different combinations of multiple strategies could play an increasingly prominent role in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, activating signaling mediated by CAR is able to overcome the uneducated NK cell hyporesponsiveness, thereby mediating target cell killing. Indeed, CAR-mediated activation is able to overcome the dominant inhibition associated with NKG2A-mediated signaling, thereby enhancing NK cells' antitumor responses (75,76).…”

Section: Car-modified Nk Cells In Tumor Immunotherapymentioning

confidence: 99%

Targeting Natural Killer Cells for Tumor Immunotherapy

Zhang

Shi

2020

Front. Immunol.

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Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous-or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.

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“…Amino acid sequences from CD28 or CD8α are commonly used, as well as CH2 and CH3 domains from IgG1, 2, or 4. While both CH2 and CH3 domains can also be utilized to detect CAR expression on the cell's surface, binding between CH2 domains and Fcγ receptors has been observed and can lead to off-target activation [8,11].…”

Section: Ectodomainsmentioning

confidence: 99%

You Have Got a Fast CAR: Chimeric Antigen Receptor NK Cells in Cancer Therapy

Pfefferle

Huntington

2020

Cancers

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The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating them across a wide range of malignancies. However, along with the exciting potential of CAR-T therapy comes the real possibility of serious side effects. While the FDA has approved commercialized CAR-T cell therapy, challenges associated with manufacturing, costs, and related toxicities have resulted in increased attention being paid to implementing CAR technology in innate cytotoxic natural killer (NK) cells. Here, we review the current landscape of the CAR-NK field, from successful clinical implementation to outstanding challenges which remain to be addressed to deliver the full potential of this therapy to more patients.

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Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

Cited by 74 publications

References 49 publications

CAR-Expressing Natural Killer Cells for Cancer Retargeting

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Targeting Natural Killer Cells for Tumor Immunotherapy

You Have Got a Fast CAR: Chimeric Antigen Receptor NK Cells in Cancer Therapy

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