Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Bachanová, Veronika; Sarhan, Dhifaf; DeFor, Todd E.; Cooley, Sarah; Panoskaltsis‐Mortari, Angela; Blazar, Bruce R.; Curtsinger, Julie; Burns, Linda J.; Weisdorf, Daniel J.; Miller, Jeffrey S.

doi:10.1007/s00262-017-2100-1

Cited by 77 publications

(62 citation statements)

References 38 publications

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“…18,42 In several trials testing efficacy of haploidentical NK cells in patients with advanced relapsed or refractory tumors, responses were observed only in a small subgroup of patients and were hampered by co-expansion of Tregs which were thought to be of patient origin. 43-46 Our results suggest that expansion of Tregs may arise in the tumor microenvironment upon PD-L1 expression, and can even occur by expansion from the very small amount of T cells transferred as part of an adoptive NK cell product. To mitigate such in situ Treg generation, PD-L1 blockade may prevent Tregs induction and improve overall efficacy of adoptive NK cell therapy.…”

Section: Discussionmentioning

confidence: 82%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Discussionmentioning

confidence: 82%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…[reviewed in Paul and Lal (37)]. The infusion of HLA mismatched NK cells has led to promising clinical results, confirming a direct anti-neoplastic effect (38,39). Hence, the respective impacts of T-cell and NK-cell reactivity in HLA mismatched transplants and other cell therapy approaches are still unknown but may account for the effects on GVT and GVHD observed in haplo-identical and cord blood transplants.…”

Section: Target Antigens In Hematological Cancers Histocompatibility mentioning

confidence: 99%

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

et al. 2020

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Over the last decades, T-cell immunotherapy has revealed itself as a powerful, and often curative, strategy to treat blood cancers. In hematopoietic cell transplantation, most of the so-called graft-vs.-leukemia (GVL) effect hinges on the recognition of histocompatibility antigens that reflect immunologically relevant genetic variants between donors and recipients. Whether other variants acquired during the neoplastic transformation, or the aberrant expression of gene products can yield antigenic targets of similar relevance as the minor histocompatibility antigens is actively being pursued. Modern genomics and proteomics have enabled the high throughput identification of candidate antigens for immunotherapy in both autologous and allogeneic settings. As such, these major histocompatibility complex-associated tumor-specific (TSA) and tumor-associated antigens (TAA) can allow for the targeting of multiple blood neoplasms, which is a limitation for other immunotherapeutic approaches, such as chimeric antigen receptor (CAR)-modified T cells. We review the current strategies taken to translate these discoveries into T-cell therapies and propose how these could be introduced in clinical practice. Specifically, we discuss the criteria that are used to select the antigens with the greatest therapeutic value and we review the various T-cell manufacturing approaches in place to either expand antigen-specific T cells from the native repertoire or genetically engineer T cells with minor histocompatibility antigen or TSA/TAA-specific recombinant T-cell receptors. Finally, we elaborate on the current and future incorporation of these therapeutic T-cell products into the treatment of hematological malignancies.

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“…After NK cell transplantation, leukaemia‐associated transcripts disappeared in elderly patients. Most recently, it was shown that haploidentical NK cells induce remissions in non‐Hodgkin's lymphoma patients (Bachanova et al, ). These studies point to the utility of allogeneic NK‐cell transplants in the antitumour response in a variety of cancers.…”

Section: Adoptive Nk‐cell Therapymentioning

confidence: 99%

Current strategies exploiting NK‐cell therapy to treat haematologic malignancies

Johnson

Miller

2018

Int J Immunogenetics

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Natural killer (NK) cells recognize targets that have been changed via malignant transformation or infection. Previously, NK cells were thought to be short-lived, but we now know that NK cells can be long-lived and remember past exposures in response to CMV. NK cells use a plethora of activating and inhibitory receptors to recognize these changes and attack targets, but tumour cells often evade NK cells. Therefore, major efforts are being made to hone in on NK cell antitumour properties in immunotherapy. In the clinical setting, haploidentical NK cells can be adoptively transferred to help treat cancer. To expand NK cells in vivo and enhance tumour targeting, IL-15 is being tested in combination with a glycogen synthase kinase (GSK) 3 inhibitor (CHIR99021), an inhibitor that has been shown to expand mature, highly functional NK cells capable of killing multiple tumour targets. One major limitation to NK cell therapy is lack of specificity. To address this concern, bispecific or trispecific engagers that target NK cells to the tumour and an ADAM17 inhibitor that prevents CD16 shedding after NK cell activation are being tested. Additionally, monoclonal antibodies are being designed to redirect the inhibitory signals that limit NK cell functionality. Further understanding of the biology of NK cells will inform strategies to exploit NK cells for therapeutic purposes.

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Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Cited by 77 publications

References 38 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies

Current strategies exploiting NK‐cell therapy to treat haematologic malignancies

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