scholarly journals NK Cells in the Treatment of Hematological Malignancies

2019 ◽  
Vol 8 (10) ◽  
pp. 1557 ◽  
Author(s):  
Gonzalez-Rodriguez ◽  
Villa-Álvarez ◽  
Sordo-Bahamonde ◽  
Lorenzo-Herrero ◽  
Gonzalez
Keyword(s):  
Antitumor Activity ◽  
Nk Cells ◽  
Cancer Cells ◽  
Nk Cell ◽  
Hematologic Malignancies ◽  
Therapeutic Approaches ◽  
Hematopoietic Stem ◽  
Checkpoint Proteins ◽  
Hematological Cancers ◽  
Dependent Cell

: Natural killer (NK) cells have the innate ability to kill cancer cells, however, tumor cells may acquire the capability of evading the immune response, thereby leading to malignancies. Restoring or potentiation of this natural antitumor activity of NK cells has become a relevant therapeutic approach in cancer and, particularly, in hematological cancers. The use of tumor-specific antibodies that promote antibody-dependent cell-mediated cytotoxicity (ADCC) through the ligation of CD16 receptor on NK cells has become standard for many hematologic malignancies. Hematopoietic stem cell transplantation is another key therapeutic strategy that harnesses the alloreactivity of NK cells against cancer cells. This strategy may be refined by adoptive transfer of NK cells that may be previously expanded, activated, or redirected (chimeric antigen receptor (CAR)-NK cells) against cancer cells. The antitumor activity of NK cells can also be boosted by cytokines or immunostimulatory drugs such as lenalidomide or pomalidomide. Finally, targeting immunosubversive mechanisms developed by hematological cancers and, in particular, using antibodies that block NK cell inhibitory receptors and checkpoint proteins are novel promising therapeutic approaches in these malignant diseases.

scholarly journals Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Margaret G. Lamb ◽  
Hemalatha G. Rangarajan ◽  
Brian P. Tullius ◽  
Dean A. Lee
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Cell Biology ◽  
Nk Cell ◽  
Killer Cell ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Wide Range

AbstractThe adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In the last 3 decades, NK cells have been utilized to harness the anti-tumor immune response in a wide range of malignancies, most notably with early evidence of efficacy in hematologic malignancies. NK cells are dysfunctional in patients with hematologic malignancies, and their number and function are further impaired by chemotherapy, radiation, and immunosuppressants used in initial therapy and hematopoietic stem cell transplantation. Restoring this innate immune deficit may lead to improved therapeutic outcomes. NK cell adoptive transfer has proven to be a safe in these settings, even in the setting of HLA mismatch, and a deeper understanding of NK cell biology and optimized expansion techniques have improved scalability and therapeutic efficacy. Here, we review the use of NK cell therapy in hematologic malignancies and discuss strategies to further improve the efficacy of NK cells against these diseases.

Antibody-dependent cell-mediated cytotoxicity through Natural Killer (NK) cells: unlocking NK cells for future immunotherapy

2021 ◽  
Vol 22 ◽  
Author(s):  
Ding Sheng Chin ◽  
Crystale Siew Ying Lim ◽  
Fazlina Nordin ◽  
Norsyahida Arifin ◽  
Tye Gee Jun
Keyword(s):  
Nk Cells ◽  
Cancer Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Cell Activity ◽  
Activated T Cells ◽  
Effector Cells ◽  
Adcc Assay ◽  
Dependent Cell

Background: Natural killer (NK) cells have potent effector functions that can be further improved for therapeutic purposes through antibody-dependent cell-mediated cytotoxicity (ADCC). Specific killing of virus-infected cells and cancer cells is modulated through target specific antibodies that subsequently recruit NK cells for ADCC. NK cells produce cytokines similar to activated T cells, but is less persistent as NK cells have short-lived responses. These features benefit the development of customisable and more individualised cell-based therapies. Objectives: Preclinical studies with NK cells were promising and several clinical studies are ongoing to investigate their use in antibody therapies. However, more reliable ADCC assays are required for evaluating NK cell activity to optimise therapeutic antibodies. The therapeutic potential of NK cell therapy could then be improved by harnessing ADCC. Methods: This review discuss recent studies on key components of NK cell-mediated ADCC, current clinical trials involving NK cells, ADCC assay developments and various techniques to improve ADCC. Results: Improvements can be made to NK-mediated ADCC through modifications of antibodies, effector cells and target antigens. Different aspects of antibodies were studied extensively, including modifying glycosylation patterns, novel production methods, combination regiments, bispecific antibodies, and conjugated antibodies. Modification of NK cells and tumour surface markers could improve ADCC of even treatment-resistant cancer cells. Additives such as cytokines and other immunomodulatory agents can further augment ADCC to supplement NK cell-based therapies.

Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus?

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 399-410 ◽  
Author(s):  
Mariella Della Chiesa ◽  
Michela Falco ◽  
Marina Podestà ◽  
Franco Locatelli ◽  
Lorenzo Moretta ◽  
...  
Keyword(s):  
Cord Blood ◽  
Nk Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Nk Cell ◽  
Cord Blood Transplantation ◽  
Cell Subset ◽  
Hematologic Malignancies ◽  
Cell Development ◽  
Hematopoietic Stem

Abstract Natural killer (NK) cells play a crucial role in early immunity after hematopoietic stem cell transplantation because they are the first lymphocyte subset recovering after the allograft. In this study, we analyzed the development of NK cells after intrabone umbilical cord blood (CB) transplantation in 18 adult patients with hematologic malignancies. Our data indicate that, also in this transplantation setting, NK cells are the first lymphoid population detectable in peripheral blood. However, different patterns of NK-cell development could be identified. Indeed, in a group of patients, a relevant fraction of NK cells expressed a mature phenotype characterized by the KIR+NKG2A− signature 3-6 months after transplantation. In other patients, most NK cells maintained an immature phenotype even after 12 months. A possible role for cytomegalovirus in the promotion of NK-cell development was suggested by the observation that a more rapid NK-cell maturation together with expansion of NKG2C+ NK cells was confined to patients experiencing cytomegalovirus reactivation. In a fraction of these patients, an aberrant and hyporesponsive CD56−CD16+p75/AIRM1− NK-cell subset (mostly KIR+NKG2A−) reminiscent of that described in patients with viremic HIV was detected. Our data support the concept that cytomegalovirus infection may drive NK-cell development after umbilical CB transplantation.

scholarly journals CBLB ablation with CRISPR/Cas9 enhances cytotoxicity of human placental stem cell-derived NK cells for cancer immunotherapy

2021 ◽  
Vol 9 (3) ◽  
pp. e001975
Author(s):  
Xuan Guo ◽  
Tanel Mahlakõiv ◽  
Qian Ye ◽  
Srinivas Somanchi ◽  
Shuyang He ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Negative Regulator ◽  
Hematopoietic Stem ◽  
Nsg Mice

BackgroundTumors often develop resistance to surveillance by endogenous immune cells, which include natural killer (NK) cells. Ex vivo activated and/or expanded NK cells demonstrate cytotoxicity against various tumor cells and are promising therapeutics for adoptive cancer immunotherapy. Genetic modification can further enhance NK effector cell activity or activation sensitization. Here, we evaluated the effect of the genetic deletion of ubiquitin ligase Casitas B-lineage lymphoma pro-oncogene-b (CBLB), a negative regulator of lymphocyte activity, on placental CD34+ cell-derived NK (PNK) cell cytotoxicity against tumor cells.MethodsUsing CRISPR/Cas9 technology, CBLB was knocked out in placenta-derived CD34+ hematopoietic stem cells, followed by differentiation into PNK cells. Cell expansion, phenotype and cytotoxicity against tumor cells were characterized in vitro. The antitumor efficacy of CBLB knockout (KO) PNK cells was tested in an acute myeloid leukemia (HL-60) tumor model in NOD-scid IL2R gammanull (NSG) mice. PNK cell persistence, biodistribution, proliferation, phenotype and antitumor activity were evaluated.Results94% of CBLB KO efficacy was achieved using CRISPR/Cas9 gene editing technology. CBLB KO placental CD34+ cells differentiated into PNK cells with high cell yield and >90% purity determined by CD56+ CD3− cell identity. Ablation of CBLB did not impact cell proliferation, NK cell differentiation or phenotypical characteristics of PNK cells. When compared with the unmodified PNK control, CBLB KO PNK cells exhibited higher cytotoxicity against a range of liquid and solid tumor cell lines in vitro. On infusion into busulfan-conditioned NSG mice, CBLB KO PNK cells showed in vivo proliferation and maturation as evidenced by increased expression of CD16, killer Ig-like receptors and NKG2A over 3 weeks. Additionally, CBLB KO PNK cells showed greater antitumor activity in a disseminated HL60-luciferase mouse model compared with unmodified PNK cells.ConclusionCBLB ablation increased PNK cell effector function and proliferative capacity compared with non-modified PNK cells. These data suggest that targeting CBLB may offer therapeutic advantages via enhancing antitumor activities of NK cell therapies.

scholarly journals Dissecting the NK Cell Population in Hematological Cancers Confirms the Presence of Tumor Cells and their Impact on NK Population Function

2020 ◽  
Author(s):  
Dang-Nghiem Vo ◽  
Michael Constantinides ◽  
Nerea Allende-Vega ◽  
Catherine Alexia ◽  
Guillaume Cartron ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Cell Population ◽  
Nk Cell ◽  
Cell Dysfunction ◽  
Cell Clearance ◽  
Hematological Cancers ◽  
Dependent Cell ◽  
Second Tumor ◽  
Population Function

Natural killer (NK) cells are part of the innate immune system, protects against pathogens and tumor cells and are the main cell effectors of monoclonal antibodies (mAbs) generating antibody-dependent cell cytotoxicity (ADCC). Hence it is relevant to understand NK physiology and status to investigate the biological effect of mAbs in the clinic. The presence of viral-sculpted NK cell populations has already been described, but the presence of cancer-sculpted NK remains unknown. Cancer induces a broad NK cell dysfunction. We investigated the NK cell population by Uniform Manifold Approximation and Projection (UMAP) embed maps in Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) patients at diagnosis and at least 30 days after treatment, which correlates with tumor cell clearance. The NK lineage largely responded to the tumor by generating antitumor NK cells and renewing the population with a subset of immature NK cells. However, we failed to identify specific “memory-like” subsets. Moreover, in patients in relapse we found essentially the same NK populations that at diagnostic, suggesting that NK cells equally respond to the first or second tumor rise. Finally, previous CMV infection largely affects tumor-associated changes in NK population, but the CMV-associated CD57+NKG2C+ NKs do not appear to play any role in tumor immunity.

Antitumor Activity of Polysaccharides Extracted from the Spore Powder of Ganoderma Lucidum (Fr.) Karst

2019 ◽  
Vol 17 (4) ◽  
pp. 394-400
Author(s):  
Wu Jiadi ◽  
Fei Dongliang ◽  
Fu Chenghao ◽  
Jiang Chunying ◽  
Zhao Yan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Nk Cells ◽  
Cancer Cells ◽  
Ganoderma Lucidum ◽  
Nk Cell ◽  
Granzyme B ◽  
Cell Numbers ◽  
Low Toxicity ◽  
4T1 Cells

Ganoderma lucidum (Fr.) Karst. has attracted much attention for its antitumor activity and low toxicity. In fact, the spores of G. lucidum may have even higher bioactivity than its fruiting body. However, there is no report on how the polysaccharides from broken spores of G. lucidum may suppress tumor growth. To make up for this gap, this article isolates a type of polysaccharide from the spore powder of G. lucidum and explores its effect on tumor growth in mice bearing 4T1 cells. The results show that the spore powder of G. lucidum could inhibit the tumor growth of 4T1-bearing mice by increasing NK cell numbers in two ways. First, the spore powder of G. lucidum suppresses Tregs to increase the percentage of NK cells, thus killing cancer cells in blood. Second, the spore powder of G. lucidum upregulates the expression of CXCR3, which recruits more NK cells from peripheral blood infiltrating in visceral organs, where NK cells secrete more granzyme B, perforin, and interferon gamma to kill cancer cells. To sum up, our research demonstrates the potential of spore powder of G. lucidum in cancer therapy.

scholarly journals Mechanisms of Resistance to NK Cell Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 893 ◽  
Author(s):  
Christian Sordo-Bahamonde ◽  
Massimo Vitale ◽  
Seila Lorenzo-Herrero ◽  
Alejandro López-Soto ◽  
Segundo Gonzalez
Keyword(s):  
Cell Therapy ◽  
Nk Cells ◽  
Cancer Cells ◽  
Cell Biology ◽  
Nk Cell ◽  
Tumor Therapy ◽  
Genetic Profile ◽  
Mechanisms Of Resistance ◽  
Hematopoietic Stem ◽  
Nk Cell Therapy

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.

scholarly journals Dissecting the NK Cell Population in Hematological Cancers Confirms the Presence of Tumor Cells and Their Impact on NK Population Function

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 727
Author(s):  
Dang-Nghiem Vo ◽  
Michael Constantinides ◽  
Nerea Allende-Vega ◽  
Catherine Alexia ◽  
Guillaume Cartron ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Cell Population ◽  
Nk Cell ◽  
Specific Activity ◽  
Specific Memory ◽  
Cell Clearance ◽  
Hematological Cancers ◽  
Dependent Cell ◽  
Second Tumor

The lymphocyte lineage natural killer (NK) cell is part of the innate immune system and protects against pathogens and tumor cells. NK cells are the main cell effectors of the monoclonal antibodies (mAbs) that mediates antibody-dependent cell cytotoxicity (ADCC). Hence, it is relevant to understand NK physiology and status to investigate the biological effect of mAbs in the clinic. NK cells are heterogeneous with multiple subsets that may have specific activity against different attacks. The presence of viral-sculpted NK cell populations has already been described, but the presence of cancer-sculpted NK cells remains unknown. Cancer induces a broad NK cell dysfunction, which has not been linked to a specific population. Here, we investigated the NK cell population by Uniform Manifold Approximation and Projection (UMAP) embed maps in Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) patients at diagnosis and at least 30 days after treatment, which correlates with tumor cell clearance. We found that the NK lineage largely responded to the tumor by generating antitumor NK cells and renewing the population with a subset of immature NK cells. However, we failed to identify a specific “memory-like” subset with the NK cell markers used. Moreover, in patients in relapse, we found essentially the same NK populations as those found at diagnosis, suggesting that NK cells equally respond to the first or second tumor rise. Finally, we observed that previous cytomegalovirus (CMV) infection largely affects the tumor-associated changes in NK population, but the CMV-associated CD57+NKG2C+ NK cell population does not appear to play any role in tumor immunity.

scholarly journals Phase I Trial of Prophylactic Donor-Derived IL-2-Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2673
Author(s):  
Raynier Devillier ◽  
Boris Calmels ◽  
Sophie Guia ◽  
Mohammed Taha ◽  
Cyril Fauriat ◽  
...  
Keyword(s):  
Phase I ◽  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Functional Characterization ◽  
Immunosuppressive Treatment ◽  
Hematologic Malignancies ◽  
Cell Phenotype ◽  
Hematopoietic Stem

Background: NK cell-based immunotherapy to prevent relapse after allogeneic transplantation is an appealing strategy because NK cells can provide strong antitumor effect without inducing graft-versus-host disease (GVHD). Thus, we designed a phase-I clinical trial evaluating the safety of a prophylactic donor-derived ex vivo IL-2 activated NK cell (IL-2 NK) infusion after allo-HSCT for patients with hematologic malignancies. Methods: Donor NK cells were purified and cultured ex vivo with IL-2 before infusion, at three dose levels. To identify the maximum tolerated dose was the main objective. In addition, we performed phenotypical and functional characterization of the NK cell therapy product, and longitudinal immune monitoring of NK cell phenotype in patients. Results: Compared to unstimulated NK cells, IL-2 NK cells expressed higher levels of activating receptors and exhibited increased degranulation and cytokine production in vitro. We treated 16 patients without observing any dose-limiting toxicity. At the last follow up, 11 out of 16 treated patients were alive in complete remission of hematologic malignancies without GVHD features and immunosuppressive treatment. Conclusions: Prophylactic donor-derived IL-2 NK cells after allo-HSCT is safe with low incidence of GVHD. Promising survivals and IL-2 NK cell activated phenotype may support a potential clinical efficacy of this strategy.

scholarly journals Platelet-Mediated Protection of Cancer Cells From Immune Surveillance – Possible Implications for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurent Schmied ◽  
Petter Höglund ◽  
Stephan Meinke
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Tumor Metastasis ◽  
Nk Cell ◽  
High Exposure ◽  
Hematological Cancers ◽  
The Impact

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.

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