Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Poznanski, Sophie M.; Ritchie, Tyrah M.; Fan, Isabella Y.; El-Sayes, Abdullah; Portillo, Ana L.; Ben-Avi, Ronny; Rojas, Eduardo A. Peña; Chew, Marianne V.; Shargall, Yaron; Ashkar, Ali A.

doi:10.1136/jitc-2020-001933

Cited by 25 publications

(26 citation statements)

References 27 publications

(33 reference statements)

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“…While in our study the enhancement of NK cell anti-tumor functions through the CAR is modest, our group has previously shown that K562-mb-IL21 expansion converts human NK cells to a unique and highly activated CD56 superbright NK cell subset (Poznanski et al, 2018). Indeed, we have shown that these expanded NK cells already exert highly potent cytotoxic function against a variety of primary tumor cells and cancer cell lines independent of tumor antigen expression (Nham et al, 2018;Poznanski et al, 2021b;Shenouda et al, 2017). This work demonstrates that CAR-expression can specifically redirect and further increase the activation potential of highly activated expanded NK cells toward tumor cells.…”

Section: Ll Open Access Isciencementioning

confidence: 56%

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors

et al. 2021

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Despite the remarkable success of chimeric antigen receptor (CAR)-T cells against hematologic malignancies, severe off-tumor effects have constrained their use against solid tumors. Recently, CAR-engineered natural killer (NK) cells have emerged as an effective and safe alternative. Here, we demonstrate that HER2 CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances their anti-tumor functions against various HER2-expressing cancer cells, regardless of MHC class I expression. Moreover, HER2 CAR-NK cells exert higher cytotoxicity than donor-matched HER2 CAR-T cells against tumor targets. Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression. Further, HER2 CAR-NK cells maintain high cytotoxic function in the presence of immunosuppressive factors enriched in solid tumors. These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors.

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Section: Ll Open Access Isciencementioning

confidence: 56%

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors

et al. 2021

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“…Intriguingly, some patients will benefit from combinations, e.g., co-targeting metabolic changes and PD-L1 [37] or CTLA-4 [38] rather than from monotherapy. Poznanski et al cultured the expanded NK cells using IL-21-expressing feeder cells which have metabolic adaptations and can harbour features to better sustain function in the TME [39]. Simultaneously, it was reported that efficient immunotherapies could be developed when metabolism of chimeric antigen receptor NK cells was engineered [40].…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer mesenchymal stem cells inhibit natural killer cell function by up-regulating FBP1

Han¹,

Guo²,

Huang³

et al. 2021

cejoi

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Introduction:The dysfunction of natural killer (nK) cells has been widely reported in malignancies, including in solid tumours. gastric cancer mesenchymal stem cells (gCMSCs) are one of the vital elements of stromal cells in the tumour environment (TME) which possess immunosuppressive activity. This study aimed to determine whether gCMSCs are involved in the inhibition of nK cell immune function and explore its underlying mechanism. Material and methods: CD107a and perforin expression of gCMSCs conditioned medium (gCMSCs-CM)-primed nK cells were detected by flow cytometry. To determine nK cell cytotoxicity, the CytoTox96 non-Radioactive Cytotoxicity assay kit was used. glucose uptake and lactate production assay were performed to evaluate the metabolism state of nK cells treated with gCMSCs-CM. The expression of FBP1 in nK cells was analysed by immunoblotting.Results: gCMSCs inhibited the degranulation capacity, perforin production and cytotoxicity of nK cells. gCMSCs-CM restrained nK cell glucose uptake and lactate production, thus weakening their glycolytic metabolism. FBP1 expression of nK cells was upregulated in the presence of gCMSCs-CM. using FBP1 inhibitor could reverse the dysfunctional state of nK cells.Conclusions: This study indicated that gCMSCs could exert immunosuppressive effects on nK cells by up-regulating FBP1 expression, opening up new avenues for nK cell-based gC immunotherapy.

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“…105 NK cells expanded from induced-pluripotent stem cells (iPSCs) increased PDL1 expression of tumor cell lines, sensitized non-responding tumors from patients with lung cancer to PD1-targeted immunotherapy and killed PDL1patient tumors (Figure 2). 102 In contrast, native NK cells, that are susceptible to immunosuppression in the TME, had no effect on tumor PDL1 expression. Accordingly, only combined treatment of expanded NK cells and PD1directed inhibitors resulted in synergistic tumor cell kill of initially non-responding patient tumors.…”

Section: Immune Checkpoints and Nk Cellsmentioning

confidence: 94%

“… 101 Lung cancer remains the leading cause of cancer death worldwide despite the responses found for immune checkpoint inhibitors (ICIs), including programmed death receptor-1 (PD1) or PD ligand 1 (PDL1)-blockade therapy. 102 These ICIs has achieved marked tumor regression in some patients with advanced PD1/PDL1-positive lung cancer; however, lasting responses were limited to a 15% subpopulation of patients. 103 IFN-γ, released by cytotoxic NK and T cells, is a critical enhancer of PDL1 expression on tumors and a predictor of response to immunotherapies.…”

Section: Introductionmentioning

confidence: 99%

The Impact of NK Cell-Based Therapeutics for the Treatment of Lung Cancer for Biologics: Targets and Therapy

Hamilton¹,

Plangger²

2021

BTT

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Lung cancer has a dismal prognosis and novel targeted therapies leave still room for major improvements and better outcomes. Immunotherapy targeting immune checkpoint (IC) proteins, either as single agents or in combination with chemotherapy, is active but responders constitute only approximately 10-15% of non-small cell lung cancer (NSCLC) patients. Other effector immune cells such as CAR-T cells or NK cells may help to overcome the limitations of the IC inhibitor therapies for lung cancer. NK cells can kill tumor cells without previous priming and are present in the circulatory system and lymphoid organs. Tissue-residing NK cells differ from peripheral effector cells and, in case of the lung, comprise CD56bright CD16-negative populations showing high cytokine release but low cytotoxicity in contrast to the circulating CD56dim CD16-positive NK cells exhibiting high cytotoxic efficacy. This local attenuation of NK cell killing potency seems due to a specific stage of NK differentiation, immunosuppressive factors as well as presence of myeloidderived suppressor cells (MDSCs) and regulatory T cells (TREGs). Improved NK cell-based immunotherapies involve IL-2-stimulated effector cells, NK cells expanded with the help of cytokines, permanent NK cell lines, induced pluripotent stem cell-derived NK cells and NK cells armed with chimeric antigen receptors. Compared to CAR T cell therapy, NK cells administration is devoid of graft-versus-host disease (GvHD) and cytokine-release syndrome. Although NK cells are clearly active against lung cancer cells, the low-cytotoxicity differentiation state in lung tumors, the presence of immunosuppressive leucocyte populations, limited infiltration and adverse conditions of the microenvironment need to be overcome. This goal may be achieved in the future using large numbers of activated and armed NK cells as provided by novel methods in NK cell isolation, expansion and stimulation of cytotoxic activity, including combinations with monoclonal antibodies in antibody-dependent cytotoxicity (ADCC). This review discusses the basic characteristics of NK cells and the potential of NK cell preparations in cancer therapy.

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Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy

Cited by 25 publications

References 27 publications

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors

Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors

Gastric cancer mesenchymal stem cells inhibit natural killer cell function by up-regulating FBP1

The Impact of NK Cell-Based Therapeutics for the Treatment of Lung Cancer for Biologics: Targets and Therapy

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