Development of Allogeneic NK Cell Adoptive Transfer Therapy in Metastatic Melanoma Patients: In Vitro Preclinical Optimization Studies
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{"title"=>"Development of Allogeneic NK Cell Adoptive Transfer Therapy in Metastatic Melanoma Patients: In Vitro Preclinical Optimization Studies", "type"=>"journal", "authors"=>[{"first_name"=>"Michal J.", "last_name"=>"Besser", "scopus_author_id"=>"35594853200"}, {"first_name"=>"Tsipi", "last_name"=>"Shoham", "scopus_author_id"=>"6507055688"}, {"first_name"=>"Orit", "last_name"=>"Harari-Steinberg", "scopus_author_id"=>"6507822144"}, {"first_name"=>"Naama", "last_name"=>"Zabari", "scopus_author_id"=>"26633362200"}, {"first_name"=>"Rona", "last_name"=>"Ortenberg", "scopus_author_id"=>"26633087300"}, {"first_name"=>"Arkadi", "last_name"=>"Yakirevitch", "scopus_author_id"=>"56191128400"}, {"first_name"=>"Arnon", "last_name"=>"Nagler", "scopus_author_id"=>"7103058110"}, {"first_name"=>"Ron", "last_name"=>"Loewenthal", "scopus_author_id"=>"7004116650"}, {"first_name"=>"Jacob", "last_name"=>"Schachter", "scopus_author_id"=>"7102481590"}, {"first_name"=>"Gal", "last_name"=>"Markel", "scopus_author_id"=>"6602505981"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84874591531", "doi"=>"10.1371/journal.pone.0057922", "issn"=>"19326203", "pui"=>"368465243", "isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "pmid"=>"23483943", "scopus"=>"2-s2.0-84874591531"}, "id"=>"d2c2a38b-20cb-3bf8-b1c4-67d3075b022d", "abstract"=>"Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.", "link"=>"http://www.mendeley.com/research/development-allogeneic-nk-cell-adoptive-transfer-therapy-metastatic-melanoma-patients-vitro-preclini", "reader_count"=>35, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Researcher"=>7, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Other"=>4, "Student > Master"=>1, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Researcher"=>7, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Other"=>4, "Student > Master"=>1, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>14, "Agricultural and Biological Sciences"=>10, "Physics and Astronomy"=>1, "Psychology"=>1, "Immunology and Microbiology"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Germany"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/976594"], "description"=>"<p>(A) HLA-C KIR-ligands: C1 and C2 represent subjects who are homozygous for HLA-C from group C1 or C2, respectively. C1 & C2 stands for subjects with one allele from C1 and one C2; (B) Number of different KIR-ligand groups identified per subject: “1” stands for only KIR ligand group C1 or C2. “2” means one of the follow combinations: C1 & A (03 or 11), C1 & Bw4, C2 & A (03 or 11) or C2 & Bw4. “3” means C1 & Bw4 & A (03 or 11) or C2 & Bw4 & A (03 or 11).</p>", "links"=>[], "tags"=>["kir-ligand", "genotyping"], "article_id"=>644056, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Frequency_of_KIR_ligand_genotyping_among_analyzed_subjects_/644056", "title"=>"Frequency of KIR-ligand genotyping among analyzed subjects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:20:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/976597"], "description"=>"<p>(A) Killing of NK cells cultured over night with 100 IU/ml of IL-2 tested in HLA-C matched and mismatched setting; (B) Individual NK cultures in matched and mismatched setting out of 3 performed. E:T ratios were 10∶1. Y axis denotes specific killing (%). Figure shows the mean of five independent experiments performed. **denotes statistical significance in <i>t-tests</i> of P = 0.01. Error bars represent SEM.</p>", "links"=>[], "tags"=>["hla-c", "mismatching", "nk-mediated"], "article_id"=>644057, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_effect_of_HLA_C_mismatching_on_NK_mediated_killing_/644057", "title"=>"The effect of HLA-C mismatching on NK-mediated killing.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:20:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/976603"], "description"=>"<p>(A) A highly significant effect of pre-incubation with anti-GD3 mAbs, but not with isotype control (IC) on the potency of NK cells cultured over night with 100 IU/ml of IL-2 against melanoma; (B) GD3-targeted ADCC can be stimulated only against GD3-positive melanoma cells and is dependent on pre-incubation of the effector cells with IL-2 overnight; (C) Combination of ADCC and HLA-C mismatching. The NK cultures and their matching status towards each melanoma culture are indicated in the figure. E:T ratios were 10∶1. Y axis denotes specific killing (%). Figure shows the mean of four independent experiments. *denotes statistical significance in <i>t-tests</i> of P<0.05 and **of P<0.01. Error bars represent SEM.</p>", "links"=>[], "tags"=>["immunology", "oncology"], "article_id"=>644060, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ADCC_killing_effect_against_melanoma_/644060", "title"=>"ADCC killing effect against melanoma.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:21:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/976606"], "description"=>"<p>CD3-depleted cells were expanded in AIM-V or X-VIVO 10 medium with 500 IU/ml IL-2 for two weeks or three weeks. 5000 rad irradiated feeder cells were added once on the day of culture initiation (“1× feeder”) or a second time 7 days after culture initiation (“2× feeder”). Ratio of irradiated feeder cells to CD3-depleted cells was always 10∶1. NK cell subset was defined by flow cytometry analysis as the CD56+ CD3- population in gated live cells. (A) Fold expansion of NK cells after 14 days of expansion; (B) NK cell frequency (%) after 14 days; (C) Fold expansion of NK cells after 21 days; (<b>D</b>) NK cell frequency (%) after 21 days.</p>", "links"=>[], "tags"=>["ex-vivo", "irradiated", "feeder"], "article_id"=>644062, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Optimizing_ex_vivo_expansion_Addition_of_irradiated_feeder_cells_/644062", "title"=>"Optimizing ex-vivo expansion; Addition of irradiated feeder cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:21:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/976609"], "description"=>"<p>CD3-depleted cells were expanded in AIM-V or X-VIVO 10 medium with 500 IU/ml IL-2 and one or two rounds of irradiated feeder cells in the presence (“with”) or absence (w/o) of the anti-CD3 antibody OKT3 (30 ng/ml). On the day of initiation OKT3 was added directly to the ready culture comprised of irradiated feeder cells and CD3-depleted cells (10∶1) (“OKT3 directly”) or irradiated feeder were pre-incubated with OKT3 and washed before mixing them with the CD3-depleted cells (“OKT3 pre-incubated”). NK and T cell frequency was defined by flow cytometry analysis in gated live cells. (A) Fold expansion of NK cells after 14 days of expansion; (B) NK cell frequency (%) after 14 days; (C) Fold expansion of NK cells after 21 days; (D) NK cell frequency (%) after 21 days, (E) CD3 T-cell frequency (%) after 21 days; (F) Fold expansion of NK cells after 14 days; (G) Fold expansion of NK cells after 21 days; (H) CD3 T-cell frequency (%) after 21 days.</p>", "links"=>[], "tags"=>["ex-vivo"], "article_id"=>644064, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Optimizing_ex_vivo_expansion_Addition_of_OKT_3_/644064", "title"=>"Optimizing ex-vivo expansion; Addition of OKT-3.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:22:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/976612"], "description"=>"<p>CD3-depleted cells were cultured under 12 different condition sets as delineated under “A” to “L”. 500 IU/ml IL-2 was present in the culture medium during the entire expansion process. Feeder “1×” refers to supplementing irradiated feeder cells only once at culture initiation and “2×” refers to a second addition of irradiated feeder cells after one week. The ratio of irradiated feeder cells to CD3-depleted cells was always 10∶1. OKT3 “+p” indicates that the first round irradiated feeder cells were pre-incubated (“p”) with OKT3, washed from unbound antibody and then added to the CD3-depleted cells; whereas OKT3 “+” alone indicates that OKT3 was directly added to the ready cell culture comprised of CD3- depleted and irradiated feeder cells. (A) and (C) plots show calculated results of fold increase in NK cell numbers following 2 weeks (A) and 3 weeks (C). (B) and (D) plots show NK cell frequency in percentage out of total cells at each analyzed group presented in A and C respectively. NK cell subset was defined by flow cytometry analysis as the CD56+ CD3- population in gated live cells. Each dot represents the result of an independent experiments performed with CD3-depleted cells from different healthy donors.</p>", "links"=>[], "tags"=>["ex-vivo"], "article_id"=>644066, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Optimizing_ex_vivo_expansion_and_activation_/644066", "title"=>"Optimizing ex-vivo expansion and activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:22:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/976616"], "description"=>"<p>Cultured NK cells were analyzed at different time points: ”d1” following culturing with only IL-2 for overnight, “d14” and “d21” indicate 14 and 21 days in culture respectively. The letters “K”, “H” and “L” indicate culture condition set as delineated in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057922#pone-0057922-g004\" target=\"_blank\">Figure 4</a>. (A–B) shows the results of comparing selected culturing conditions: (A) killing activity of representative NK cultures in HLA-C matched and mismatched settings. The mean results of three independent experiments is shown; (B) expression of the indicated NK lysis receptors by the various NK cultures; (C) killing activity of representative NK cultures against MHC class I negative lymphoma cells (721.221) and melanoma cells (1106mel). The mean results of three independent experiments is shown; (D–E) shows the results of comparing different time points along culture in the optimal culturing condition H: (D) expression of the indicated NK lysis receptors by the various NK cultures; (E) killing activity in HLA-C mismatched setting in the presence of IgG1 isotype control antibodies or the indicated blocking antibodies. E:T ratios were 10∶1. MFI means Median Fluorescence Intensity. Figure shows the mean of three independent experiments. *denotes statistical significance in <i>t-tests</i> of P<0.05. Error bars represent SEM.</p>", "links"=>[], "tags"=>["potency", "melanoma", "cultures", "nk", "lysis", "receptor"], "article_id"=>644068, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NK_cell_potency_against_primary_melanoma_cultures_in_relation_to_NK_lysis_receptor_surface_expression_following_ex_vivo_expansion_protocols_/644068", "title"=>"NK cell potency against primary melanoma cultures in relation to NK lysis receptor surface expression following <i>ex-vivo</i> expansion protocols.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:23:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/976622"], "description"=>"<p>The indicated NK cultures were tested against HLA-C mismatched melanoma cells in the presence of anti-GD3 or isotype control (IC) antibodies. Y axis denotes specific killing (%). Figure shows the mean results of three independent experiments. *denotes statistical significance in <i>t-tests</i> of P = 0.01. Error bars represent SEM.</p>", "links"=>[], "tags"=>["ex-vivo", "nk", "adcc", "stimulation", "hla-c", "mismatching", "melanoma"], "article_id"=>644072, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combining_ex_vivo_NK_cell_activation_ADCC_stimulation_and_HLA_C_mismatching_against_melanoma_cells_/644072", "title"=>"Combining ex-vivo NK cell activation, ADCC stimulation and HLA-C mismatching against melanoma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-03-05 09:24:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/976628", "https://ndownloader.figshare.com/files/976635"], "description"=>"<div><p>Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible <i>ex vivo</i> expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.</p> </div>", "links"=>[], "tags"=>["allogeneic", "nk", "adoptive", "metastatic", "melanoma", "vitro", "preclinical", "optimization", "studies"], "article_id"=>644074, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.s001", "https://dx.doi.org/10.1371/journal.pone.0057922.s002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Development_of_Allogeneic_NK_Cell_Adoptive_Transfer_Therapy_in_Metastatic_Melanoma_Patients_In_Vitro_Preclinical_Optimization_Studies__/644074", "title"=>"Development of Allogeneic NK Cell Adoptive Transfer Therapy in Metastatic Melanoma Patients: In Vitro Preclinical Optimization Studies", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-03-05 09:24:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1006017"], "description"=>"<p>The table shows the identity of each of the two alleles of HLA-A, HLA-B and HLA-C for two melanoma patients (Mel008 and Mel10) and seven healthy NK donors (depicted as “HD” followed by a serial number). The table indicates whether one of the HLA-A alleles or HLA-B alleles is a KIR-ligand (highlighted in gray). Similarly, the table indicates whether each HLA-C is of C1 or C2 subgroup, effectively classifying all patients to homozygotes of C1 or C2, or C1–C2 heterozygotes (highlighted in gray). The table is arranged to demonstrate melanoma-NK pairs that are either HLA-C matched or mismatched.</p>", "links"=>[], "tags"=>["matched", "mismatched", "nk", "donors", "melanoma"], "article_id"=>666635, "categories"=>["Cancer", "Immunology"], "users"=>["Michal J. Besser", "Tsipi Shoham", "Orit Harari-Steinberg", "Naama Zabari", "Rona Ortenberg", "Arkadi Yakirevitch", "Arnon Nagler", "Ron Loewenthal", "Jacob Schachter", "Gal Markel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0057922.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HLA_C_matched_and_mismatched_NK_donors_and_melanoma_patients_/666635", "title"=>"HLA-C matched and mismatched NK donors and melanoma patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-03-04 01:50:35"}

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Relative Metric

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