Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

Navin, Ishwar; Lam, Michael T.; Parihar, Robin

doi:10.3390/cancers12123871

Cited by 24 publications

(21 citation statements)

References 175 publications

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“…However, the therapeutic effects of NK cells in treatment of solid malignancies have not been as effective as that for hematologic malignancies. Because of the relatively isolated physiological location and the specific immunosuppressive microenvironment of solid tumors, NK cells have difficulty in infiltrating into tumors, and moreover, their ability to proliferate and persist are disrupted once inside the tumor [ 7 , 8 ]. The resolution of these two obstacles would highly improve the therapeutic efficacy of NK cells against solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Anti-Tumor Activity of Expanded PBMC-Derived NK Cells by Feeder-Free Protocol in Ovarian Cancer

Chen

et al. 2021

Cancers

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Natural killer (NK) cells have shown great therapeutic potential against a wide range of cancers due to their pan-specific target recognition. Numerous reports indicate that NK cell immunotherapy is an effective therapeutic approach for treating hematological malignancies, but shows limited effects against solid tumors. In this study, several models of ovarian cancer (OC) were used to test the anti-cancer effects of NK cells derived from human peripheral blood mononuclear cells and expanded using a feeder cell-free expansion system (eNKs). The results show that eNKs exhibit potent inhibitory activity on tumor growth in different ovarian cancer xenograft mice (i.e., solid tumors, abdominal metastatic tumors, and ascites), importantly, in a dose-dependent manner. Moreover, adoptive transfer of eNKs resulted in significant reduction in ascites formation in OC peritoneal tumor models, and especially in reducing intraperitoneal ascites. We found that eNKs could migrate to the tumor site, retain their activity, and proliferate to maintain high cell counts in cutaneous xenograft mice. In addition, when increased the infusion with a high dose of 12 × 107 cells/mouse, Graft-versus-host disease could be induced by eNK. These data show that eNK cell immunotherapy could be a promising treatment strategy for ovarian cancers, including solid tumors and ascites.

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Section: Introductionmentioning

confidence: 99%

Anti-Tumor Activity of Expanded PBMC-Derived NK Cells by Feeder-Free Protocol in Ovarian Cancer

Chen

et al. 2021

Cancers

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“…However, the landscape is quite different for solid tumors mostly because NK cells must face the formidable task of overcoming the immunosuppressive TME to avoid becoming exhausted and dysfunctional ( 31 , 32 ). Also, even if NK cell can overcome this hostile environment, their weak capacity to infiltrate solid tumors is another of the reasons that explain the low success of NK cell-based therapies to treat solid tumors ( 28 , 29 ). Thus, adoptive transfer of NK cells might require the combination with additional strategies to bolster an effective anti-tumor NK cell function.…”

Section: Nk Cells At the Forefront In Immuno-oncologymentioning

confidence: 99%

“…Given the formidable challenge of overcoming the immunosuppressive TME to leverage NK cell-based immunotherapies for solid tumors ( 28 , 29 ), it becomes necessary to elucidate the regulatory circuits that shut down NK cell effector functions in this particular niche. NK cells can function as drivers of tumor inflammation, which leads to tumor immune cell infiltration and promotes the conversion of “cold” tumors into “hot” tumors, subsequently conferring better responsiveness to ICI ( 10 ).…”

Section: The Problem Of the Tme And Tam As Tumor Protective Shieldmentioning

confidence: 99%

“…Notably, a big success represents the use of CAR-NK cells directed against CD19, as they induce tumor regression without the development of major toxic effects in the majority of patients with relapsed or refractory CD19-positive leukemias or lymphomas ( 24 ). However, treatment of solid tumors with CAR-T or CAR-NK cells has not yielded the expected results, mainly because they must face the immunosuppressive TME ( 29 ). Some CAR-T cells engineered to express NKG2D with increased effector functions against cell lines in vitro and against xenografted human or syngeneic mouse tumor cell lines in vivo have been developed ( 227 – 238 ).…”

Section: The Opportunity For the Nkg2d-nkg2dl Axis In Immuno-oncologymentioning

confidence: 99%

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Leveraging NKG2D Ligands in Immuno-Oncology

2021

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Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

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“…Several limitations reduce the efficacy of CAR NK therapy in solid tumors. The heterogeneity of antigen expression, barriers limiting the trafficking of CAR NK cells to the solid tumor site, excretion of the matrix metalloproteinases that disrupt the ADCC-mediated tumor killing, hypoxia and metabolic-deficiencies of the TME, and the immunosuppressive TME secondary to secretion of inhibitory cytokines by M2 macroaphages, regulatory T cells, and MDSCs, are examples of CAR NK therapy limitations in solid malignancies [ 17 , 114 ]. Here, we discuss recent approaches to improve the CAR NK therapy outcome, especially in solid malignancies, and further approaches to increase the safety and efficacy of CAR-modified NK therapy.…”

Section: Challenges and Future Approachesmentioning

confidence: 99%

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects

Elahi

Heidary

Hadiloo

et al. 2021

Stem Cell Rev and Rep

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Graphical abstract Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative “off-the-shelf” carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.

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Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

Cited by 24 publications

References 175 publications

Anti-Tumor Activity of Expanded PBMC-Derived NK Cells by Feeder-Free Protocol in Ovarian Cancer

Anti-Tumor Activity of Expanded PBMC-Derived NK Cells by Feeder-Free Protocol in Ovarian Cancer

Leveraging NKG2D Ligands in Immuno-Oncology

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects

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