Immunological and Translational Aspects of NK Cell-Based Antitumor Immunotherapies

Shevtsov, Maxim; Multhoff, Gabriele

doi:10.3389/fimmu.2016.00492

Cited by 47 publications

(43 citation statements)

References 107 publications

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“…Therefore, the previous estimates are a reasonable proxy for the amount of time NK cells will be active after allogenic engraftment. In agreement, the persistence of ex vivo haploidentical IL-2activated and -expanded NK cells ranges between 7 and 10 days in patients with AML, NHL, and ovarian cancer (7).…”

Section: Nk Cells In Clinics: the Problemssupporting

confidence: 64%

“…This is significantly longer than T cell doubling time during the initial expansion phase, which are 8 and 11 h for CD8 + and CD4 + T cells, respectively (9). Moreover, after allogeneic engraftment most clinical results failed to show significant expansion of donor NK cells (6,7,(10)(11)(12)(13). Perhaps the high renew and short lifespan account for these poor in vivo expansions because NK cells have already strongly expanded during their maturation and they are prone to "effector-like" phenotype, at least in the blood population.…”

Section: Nk Cells In Clinics: the Problemsmentioning

confidence: 99%

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Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

et al. 2020

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The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

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Section: Nk Cells In Clinics: the Problemssupporting

confidence: 64%

Section: Nk Cells In Clinics: the Problemsmentioning

confidence: 99%

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

et al. 2020

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“…Оказалось, что различие между определени-ем с помощью тест-системы CD3/CD16/CD56 и с помощью CD3/CD16 является статистически значимым (p < 0,05). Было показано, что основ- , на долю кото-рых приходится до 10% [13,20,25,27].…”

Section: результатыunclassified

Heterogeneity of Nk and NKT Lymphocyte Populations in Healthy Donors

Tabakov¹,

Заботина²,

Борунова³

et al. 2017

Med. immunol.

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Резюме. Натуральные киллеры (NK) и NKT-лимфоциты являются важными составляющими врожденного иммунитета и играют роль первой линии защиты от онкологических заболеваний. Данные популяции отличаются высокой гетерогенностью и разделяются на несколько субпопуля-ций, отличающихся по степени экспрессии маркеров CD56 и CD16 и функциональной активно-стью. Исследование гетерогенности данных популяций лимфоцитов у здоровых доноров актуаль-но, так как является основой для изучения нарушений баланса между различными субпопуляциями у онкологических больных. Изменения соотношения выше представленных субпопуляций могут обладать прогностическим и клиническим значением при опухолевых заболеваниях. Было проведе-но исследование лимфоцитов периферической крови 50 здоровых доноров. При анализе популяции NK-лимфоцитов было выявлено 18,0±11,3% антиген-положительных клеток, колебания значений составило от 7,6 до 29,2%, в то время как количество клеток с фенотипами CD3 dim CD16 dim , не содержащая внутриклеточный перфорин (2,0%). Популяция NKT-клеток с фенотипом СD3 + CD16/СD56 + вы-является в 7,1% (25% -3,45; 75% -8,75) антиген-положительных клеток в диапазоне от 2,5 до 11,9% и не подчиняется законам нормального распределения. При анализе с помощью комбинации МКА CD3/CD56/CD16 количество CD3 + CD56 + клеток составило 4,33% (25% -2,25; 75% -7,3), а коли-чество CD3 + CD16 + -3,087% (25% -0,9; 75% -6,2). Оказалось, что различия между определением с помощью тест-системы CD3/CD16/CD56 и с помощью CD3/CD16 является статистически значи- Россия, Москва, Каширское шоссе, 23. Тел.: 8 (962) 956-25-97.

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“…4,5 IgG antibodies bound to a target antigen on tumor cells engage with FcgRs expressed on the surface of various immune cells and trigger intracellular signaling in immune effector cells to induce antibody-dependent cell-mediated cytotoxicity (ADCC) by releasing cytotoxic reagents such as perforin or granzyme. 6 In antitumor immunotherapy using therapeutic monoclonal antibodies such as trastuzumab (Herceptin Ò ) and cetuximab (Erbitux Ò ), numerous research and clinical results indicate that ADCC is one of the most critical tumor cell-killing mechanisms. 7 In addition to the ADCC effector function, antibodies recruit phagocytic cells such as macrophages to induce antibody-dependent cell-mediated phagocytosis (ADCP).…”

Section: Introductionmentioning

confidence: 99%

“…The antibody-tumor cell immune complexes associate with FcgRIIIa (CD16) on NK cells and induce the activation of effector cells to release cytotoxic granules that contain perforins or granzymes. 6 Therefore, the significance of high FcgRIIIa binding and antitumor effects mediated by ADCC has been well established, and ADCC activity is critical for the success of antitumor therapies using monoclonal antibodies. 7,22,23 Here, we report the generation of engineered aglycosylated Fc variants for FcgRIIIa binding and effector function.…”

Section: Introductionmentioning

confidence: 99%

Engineered aglycosylated full-length IgG Fc variants exhibiting improved FcγRIIIa binding and tumor cell clearance

Kwon²,

Lee

et al. 2017

mAbs

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FcγRIIIa, which is predominantly expressed on the surface of natural killer cells, plays a key role in antibody-dependent cell-mediated cytotoxicity (ADCC), a major effector function of therapeutic IgG antibodies that results in the death of aberrant cells. Despite the potential uses of aglycosylated IgG antibodies, which can be easily produced in bacteria and do not have complicated glycan heterogeneity issues, they show negligible binding to FcγRIIIa and abolish the activation of immune leukocytes for tumor cell clearance, in sharp contrast to most glycosylated IgG antibodies used in the clinical setting. For directed evolution of aglycosylated Fc variants that bind to FcγRIIIa and, in turn, exert potent ADCC effector function, we randomized the aglycosylated Fc region of full-length IgG expressed on the inner membrane of Escherichia coli. Multiple rounds of high-throughput screening using flow cytometry facilitated the isolation of aglycosylated IgG Fc variants that exhibited higher binding affinity to FcγRIIIa-158V and FcγRIIIa-158F compared with clinical-grade trastuzumab (Herceptin®). The resulting aglycosylated trastuzumab IgG antibody Fc variants could elicit strong peripheral blood mononuclear cell-mediated ADCC without glycosylation in the Fc region.

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Immunological and Translational Aspects of NK Cell-Based Antitumor Immunotherapies

Cited by 47 publications

References 107 publications

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

Heterogeneity of Nk and NKT Lymphocyte Populations in Healthy Donors

Engineered aglycosylated full-length IgG Fc variants exhibiting improved FcγRIIIa binding and tumor cell clearance

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