An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele

Jochéms, Caroline; Hodge, James W.; Fantini, Massimo; Fujii, Rika; Morillon, Y. Maurice; Greiner, John W.; Padget, Michelle; Tritsch, Sarah R.; Tsang, Kwong Y.; Campbell, Kerry S.; Klingemann, Hans; Boissel, Laurent; Rabizadeh, Shahrooz; Soon‐Shiong, Patrick; Schlom, Jeffrey

doi:10.18632/oncotarget.13411

Cited by 149 publications

(165 citation statements)

References 36 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…As seen in Figure 5a, no lysis of breast carcinoma tumor cells by avelumab alone is seen, but avelumab does enhance irradiated haNK-mediated tumor cell lysis. As haNK cells express PD-L1, 25 studies were also conducted to determine if irradiated haNK cells could lyse as targets viable 111 In-labeled irradiated haNK cells. As shown in Figure 5b, no haNK fratricide was observed with or without the addition of avelumab.…”

Section: Resultsmentioning

confidence: 99%

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

et al. 2017

Self Cite

View full text Add to dashboard Cite

NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety profile. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti–PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells. In the studies reported here, the ability of avelumab to enhance the lysis of a range of human carcinoma cells by irradiated haNK cells via the ADCC mechanism is demonstrated; this ADCC is shown to be inhibited by anti-CD16 blocking antibody and by concanamycin A, indicating the use of the granzyme/perforin pathway in tumor cell lysis. Studies also show that while NK cells have the ability to lyse aNK or haNK cells, the addition of NK cells to irradiated haNK cells does not inhibit haNK-mediated lysis of human tumor cells, with or without the addition of avelumab. Avelumab-mediated lysis of tumor cells by irradiated haNK cells is also shown to be similar to that of NK cells bearing the V/V Fc receptor high affinity allele. These studies thus provide the rationale for the clinical evaluation of the combined use of avelumab with that of irradiated adoptively transferred haNK cells.

show abstract

Section: Resultsmentioning

confidence: 99%

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…NK-92, which is phenotypically CD16-negative, readily mediates ADCC in the presence of a suitable IgG antibody when engineered to express FcγRIIIa (27, 97, 100). This has sparked efforts to clinically develop genetically modified NK-92 cells that harbor the high affinity V158 variant of CD16 (termed haNK) in combination with antibodies of IgG1 isotype (32, 97). Initial safety assessment of such cells in cancer patients is expected to begin soon (NCT03027128; ).…”

Section: Car-engineered Nk-92 Cells Exhibit Antibody-dependent Cell-mmentioning

confidence: 99%

Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

et al. 2017

View full text Add to dashboard Cite

Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR-engineered NK-92 cells as off-the-shelf cellular therapeutics, with special emphasis on ErbB2 (HER2)-specific NK-92 cells that are approaching clinical application.

show abstract

“…Consequently, these effector cells are unable to recognise tumour-targeted antigens by ADCC mechanisms. To overcome these cytotoxic limitations, NK-92 cells were genetically manipulated to express the high-affinity V158 variant of the Fc-gamma receptor (FcγRIIIa/CD16a, termed haNK TM ) and to produce endogenous, intracellularly retained IL-2 [95, 96]. In an ongoing phase I trial it will be evaluated whether infused haNK TM cells are safe and potent in the treatment of patients with histologically confirmed, non-resectable, and locally advanced or metastatic solid tumours (NCT03027128; https://clinicaltrials.gov; Table 1).…”

Section: Car-expressing Nk-92 Cells For Retargeting Of Solid Tumoursmentioning

confidence: 99%

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Kloeß

Kretschmer

Stahl

et al. 2019

Transfus Med Hemother

View full text Add to dashboard Cite

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.

show abstract

An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele

Cited by 149 publications

References 36 publications

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Contact Info

Product

Resources

About