Eintrag weiter verarbeiten
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma
Gespeichert in:
| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , |
| In: | Clinical Cancer Research, 22, 2016, 21, S. 5211-5222 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Carlsten, Mattias Korde, Neha Kotecha, Ritesh Reger, Robert Bor, Simona Kazandjian, Dickran Landgren, Ola Childs, Richard W. Carlsten, Mattias Korde, Neha Kotecha, Ritesh Reger, Robert Bor, Simona Kazandjian, Dickran Landgren, Ola Childs, Richard W. |
|---|---|
| author |
Carlsten, Mattias Korde, Neha Kotecha, Ritesh Reger, Robert Bor, Simona Kazandjian, Dickran Landgren, Ola Childs, Richard W. |
| spellingShingle |
Carlsten, Mattias Korde, Neha Kotecha, Ritesh Reger, Robert Bor, Simona Kazandjian, Dickran Landgren, Ola Childs, Richard W. Clinical Cancer Research Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma Cancer Research Oncology |
| author_sort |
carlsten, mattias |
| spelling |
Carlsten, Mattias Korde, Neha Kotecha, Ritesh Reger, Robert Bor, Simona Kazandjian, Dickran Landgren, Ola Childs, Richard W. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-16-1108 <jats:title>Abstract</jats:title> <jats:p>Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.</jats:p> <jats:p>Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.</jats:p> <jats:p>Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.</jats:p> <jats:p>Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211–22. ©2016 AACR.</jats:p> <jats:p>See related commentary by Felices and Miller, p. 5161</jats:p> Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma Clinical Cancer Research |
| doi_str_mv |
10.1158/1078-0432.ccr-16-1108 |
| facet_avail |
Online Free |
| finc_class_facet |
Medizin |
| format |
ElectronicArticle |
| fullrecord |
blob:ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE1OC8xMDc4LTA0MzIuY2NyLTE2LTExMDg |
| id |
ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE1OC8xMDc4LTA0MzIuY2NyLTE2LTExMDg |
| institution |
DE-D275 DE-Bn3 DE-Brt1 DE-Zwi2 DE-D161 DE-Gla1 DE-Zi4 DE-15 DE-Pl11 DE-Rs1 DE-105 DE-14 DE-Ch1 DE-L229 |
| imprint |
American Association for Cancer Research (AACR), 2016 |
| imprint_str_mv |
American Association for Cancer Research (AACR), 2016 |
| issn |
1078-0432 1557-3265 |
| issn_str_mv |
1078-0432 1557-3265 |
| language |
English |
| mega_collection |
American Association for Cancer Research (AACR) (CrossRef) |
| match_str |
carlsten2016checkpointinhibitionofkir2dwiththemonoclonalantibodyiph2101inducescontractionandhyporesponsivenessofnkcellsinpatientswithmyeloma |
| publishDateSort |
2016 |
| publisher |
American Association for Cancer Research (AACR) |
| recordtype |
ai |
| record_format |
ai |
| series |
Clinical Cancer Research |
| source_id |
49 |
| title |
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_unstemmed |
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_full |
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_fullStr |
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_full_unstemmed |
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_short |
Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_sort |
checkpoint inhibition of kir2d with the monoclonal antibody iph2101 induces contraction and hyporesponsiveness of nk cells in patients with myeloma |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-16-1108 |
| publishDate |
2016 |
| physical |
5211-5222 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.</jats:p>
<jats:p>Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.</jats:p>
<jats:p>Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.</jats:p>
<jats:p>Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211–22. ©2016 AACR.</jats:p>
<jats:p>See related commentary by Felices and Miller, p. 5161</jats:p> |
| container_issue |
21 |
| container_start_page |
5211 |
| container_title |
Clinical Cancer Research |
| container_volume |
22 |
| format_de105 |
Article, E-Article |
| format_de14 |
Article, E-Article |
| format_de15 |
Article, E-Article |
| format_de520 |
Article, E-Article |
| format_de540 |
Article, E-Article |
| format_dech1 |
Article, E-Article |
| format_ded117 |
Article, E-Article |
| format_degla1 |
E-Article |
| format_del152 |
Buch |
| format_del189 |
Article, E-Article |
| format_dezi4 |
Article |
| format_dezwi2 |
Article, E-Article |
| format_finc |
Article, E-Article |
| format_nrw |
Article, E-Article |
| _version_ |
1792348158167089154 |
| geogr_code |
not assigned |
| last_indexed |
2024-03-01T18:06:40.696Z |
| geogr_code_person |
not assigned |
| openURL |
url_ver=Z39.88-2004&ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fvufind.svn.sourceforge.net%3Agenerator&rft.title=Checkpoint+Inhibition+of+KIR2D+with+the+Monoclonal+Antibody+IPH2101+Induces+Contraction+and+Hyporesponsiveness+of+NK+Cells+in+Patients+with+Myeloma&rft.date=2016-11-01&genre=article&issn=1557-3265&volume=22&issue=21&spage=5211&epage=5222&pages=5211-5222&jtitle=Clinical+Cancer+Research&atitle=Checkpoint+Inhibition+of+KIR2D+with+the+Monoclonal+Antibody+IPH2101+Induces+Contraction+and+Hyporesponsiveness+of+NK+Cells+in+Patients+with+Myeloma&aulast=Childs&aufirst=Richard+W.&rft_id=info%3Adoi%2F10.1158%2F1078-0432.ccr-16-1108&rft.language%5B0%5D=eng |
| SOLR | |
| _version_ | 1792348158167089154 |
| author | Carlsten, Mattias, Korde, Neha, Kotecha, Ritesh, Reger, Robert, Bor, Simona, Kazandjian, Dickran, Landgren, Ola, Childs, Richard W. |
| author_facet | Carlsten, Mattias, Korde, Neha, Kotecha, Ritesh, Reger, Robert, Bor, Simona, Kazandjian, Dickran, Landgren, Ola, Childs, Richard W., Carlsten, Mattias, Korde, Neha, Kotecha, Ritesh, Reger, Robert, Bor, Simona, Kazandjian, Dickran, Landgren, Ola, Childs, Richard W. |
| author_sort | carlsten, mattias |
| container_issue | 21 |
| container_start_page | 5211 |
| container_title | Clinical Cancer Research |
| container_volume | 22 |
| description | <jats:title>Abstract</jats:title> <jats:p>Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.</jats:p> <jats:p>Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.</jats:p> <jats:p>Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.</jats:p> <jats:p>Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211–22. ©2016 AACR.</jats:p> <jats:p>See related commentary by Felices and Miller, p. 5161</jats:p> |
| doi_str_mv | 10.1158/1078-0432.ccr-16-1108 |
| facet_avail | Online, Free |
| finc_class_facet | Medizin |
| format | ElectronicArticle |
| format_de105 | Article, E-Article |
| format_de14 | Article, E-Article |
| format_de15 | Article, E-Article |
| format_de520 | Article, E-Article |
| format_de540 | Article, E-Article |
| format_dech1 | Article, E-Article |
| format_ded117 | Article, E-Article |
| format_degla1 | E-Article |
| format_del152 | Buch |
| format_del189 | Article, E-Article |
| format_dezi4 | Article |
| format_dezwi2 | Article, E-Article |
| format_finc | Article, E-Article |
| format_nrw | Article, E-Article |
| geogr_code | not assigned |
| geogr_code_person | not assigned |
| id | ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE1OC8xMDc4LTA0MzIuY2NyLTE2LTExMDg |
| imprint | American Association for Cancer Research (AACR), 2016 |
| imprint_str_mv | American Association for Cancer Research (AACR), 2016 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
| issn | 1078-0432, 1557-3265 |
| issn_str_mv | 1078-0432, 1557-3265 |
| language | English |
| last_indexed | 2024-03-01T18:06:40.696Z |
| match_str | carlsten2016checkpointinhibitionofkir2dwiththemonoclonalantibodyiph2101inducescontractionandhyporesponsivenessofnkcellsinpatientswithmyeloma |
| mega_collection | American Association for Cancer Research (AACR) (CrossRef) |
| physical | 5211-5222 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | ai |
| recordtype | ai |
| series | Clinical Cancer Research |
| source_id | 49 |
| spelling | Carlsten, Mattias Korde, Neha Kotecha, Ritesh Reger, Robert Bor, Simona Kazandjian, Dickran Landgren, Ola Childs, Richard W. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-16-1108 <jats:title>Abstract</jats:title> <jats:p>Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. On the basis of data showing KIR-ligand mismatched natural killer (NK) cells reduce the risk of leukemia and multiple myeloma relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK cells, our single-arm phase II clinical trial in patients with smoldering multiple myeloma was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind the lack of clinical efficacy.</jats:p> <jats:p>Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and 24 hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK cell phenotype and function was analyzed using high-resolution flow cytometry.</jats:p> <jats:p>Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK cell responsiveness and KIR2D expression on the NK cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK cells by trogocytosis, with reductions in NK cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the antimyeloma cytotoxicity of remaining KIR2Ddull patient NK cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK cells.</jats:p> <jats:p>Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK cell tumor killing via checkpoint inhibition. Clin Cancer Res; 22(21); 5211–22. ©2016 AACR.</jats:p> <jats:p>See related commentary by Felices and Miller, p. 5161</jats:p> Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma Clinical Cancer Research |
| spellingShingle | Carlsten, Mattias, Korde, Neha, Kotecha, Ritesh, Reger, Robert, Bor, Simona, Kazandjian, Dickran, Landgren, Ola, Childs, Richard W., Clinical Cancer Research, Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma, Cancer Research, Oncology |
| title | Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_full | Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_fullStr | Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_full_unstemmed | Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_short | Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| title_sort | checkpoint inhibition of kir2d with the monoclonal antibody iph2101 induces contraction and hyporesponsiveness of nk cells in patients with myeloma |
| title_unstemmed | Checkpoint Inhibition of KIR2D with the Monoclonal Antibody IPH2101 Induces Contraction and Hyporesponsiveness of NK Cells in Patients with Myeloma |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-16-1108 |