NK Cells in the Treatment of Hematological Malignancies

González-Rodríguez, Ana Pilar; Villa-Álvarez, Mónica; Sordo‐Bahamonde, Christian; Lorenzo‐Herrero, Seila; González, Segundo

doi:10.3390/jcm8101557

Cited by 44 publications

(50 citation statements)

References 165 publications

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“…Rituximab and Obinutuzumab are clinically utilized mAbs targeting CD-20, which is expressed on the surface of mature B-cells and on the surface of most malignant B-cells (215). Evidence for the involvement of ADCC in the mechanism of Rituximab stems from the correlation between FcγR polymorphism and clinical responses in some hematologic malignancies, in addition to lack of therapeutic effects in FcγR deficient mice (216)(217)(218). Therefore, in order to improve effector function mediated by mAbs targeting CD-20, Obinutuzumab was glycomodified to reduce Fc fucosylation (219).…”

Section: Nct02240706 Nct02632721mentioning

confidence: 99%

“…Therefore, in order to improve effector function mediated by mAbs targeting CD-20, Obinutuzumab was glycomodified to reduce Fc fucosylation (219). Indeed, Obinutuzumab demonstrated superior ADCC in xenograft models and in-vitro efficacy assays compared to Rituximab (218). Furthermore, the glyco-engineered Obinutuzumab appears to be less affected by the inhibitory effects of KIR/HLA ligation compared to Rituximab (220).…”

Section: Nct02240706 Nct02632721mentioning

confidence: 99%

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Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Nct02240706 Nct02632721mentioning

confidence: 99%

Section: Nct02240706 Nct02632721mentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…Despite most of the current cancer immunotherapies being focused on T cells, NK cells are being increasingly considered to be a key target of immunotherapy (as recently reviewed in [17,18]) ( Table 1). For example, their ADCC function can contribute to the cytotoxic effects of different mAbs used in the therapy of many cancers, especially, but not limited to, those of hematological origin [18][19][20][21]. Rituximab (a mAb specific to the B cell marker CD20), trastuzumab (anti-ErbB2/HER2 mAb) and cetuximab (an anti-EGFR mAb) have proved marked efficacies in the treatment of various solid and hematological tumors [22].…”

Section: Nk Cell-based Therapiesmentioning

confidence: 99%

“…Particularly, bispecific and trispecific killer cell engagers (BiKEs and TRiKEs) that stimulate NK cells against one or more tumor antigens are promising agents that are in preclinical and initial clinical studies [25][26][27]. Similarly, novel mAbs that block NK cell-expressed checkpoint proteins and inhibitory receptors-including PD-1/PD-L1, NKG2A-HLA-E, Tim-3, LAG-3, TIGIT and CD96-are under preclinical and clinical evaluation [8,18,[28][29][30][31][32][33]. The therapeutic effect of hematopoietic stem cell transplantation (HSCT) mainly relies on the allogenic immune response against the cancer cells exerted by the donor's T and NK cells [34].…”

Section: Nk Cell-based Therapiesmentioning

confidence: 99%

Mechanisms of Resistance to NK Cell Immunotherapy

Sordo‐Bahamonde

Vitale

Lorenzo‐Herrero

et al. 2020

Cancers

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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

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“…Recently, NK cells have been the focus of CAR-expressing cell research because they can be used in an allogeneic setting without causing graft-versus-host disease. Clinical trials involving immunotherapies using several types of CAR NK cells have been initiated (e.g., NCT03415100, NCT03056339, and NCT03692767) [82]. In addition, tumor-specific TCR-transduced T cells (TCR-T) for hematological malignancies have been developed and tested in clinical trials.…”

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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NK Cells in the Treatment of Hematological Malignancies

Cited by 44 publications

References 165 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Mechanisms of Resistance to NK Cell Immunotherapy

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

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