PD-1 BLOCKADE ENHANCES THE EFFICACY OF ELOTUZUMAB IN MOUSE TUMOR MODELS
(Abstract release date: 05/19/16)
EHA Library. Bezman N. 06/11/16; 135206; S450
Dr. Natalie Bezman
Contributions
Contributions
Abstract
Abstract: S450
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
Elotuzumab is a humanized monoclonal antibody (mAb) that binds specifically to human SLAMF7 (hSLAMF7) and has been approved by the US Food and Drug Administration for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received one to three prior therapies. Previous preclinical models demonstrated that elotuzumab inhibited the growth of SLAMF7-expressing human myeloma xenografts in immune-compromised mice. These models, however, lacked adaptive immune cells and therefore could not assess the mechanism of elotuzumab anti-tumor activity in the setting of a fully intact immune system.
Aims
To model elotuzumab mechanism of action, alone or in combination with PD-1 blockade, using human natural killer (NK) cells in vitro and mouse tumor models in vivo.
Methods
We evaluated elotuzumab-mediated anti-tumor activity alone or in combination with a mAb to PD-1 using mouse cell lines that stably express human SLAMF7 (A20-hSLAMF7 and EG7-hSLAMF7). The effect of treatment on the phenotype and functionality of tumor-infiltrating lymphocytes (TILs) using flow cytometry and immunohistochemistry was evaluated. In addition, the effects of elotuzumab on the phenotype of human NK cells isolated from either healthy donors or patients with MM treated with elotuzumab plus lenalidomide and dexamethasone was assessed.
Results
A murine IgG2a version of elotuzumab (elotuzumab-g2a) inhibited growth of hSLAMF7-expressing mouse tumor cells in vivo. Tumor-bearing mice treated with elotuzumab-g2a, anti-PD-1, or elotuzumab-g2a plus anti-PD-1 had significantly improved survival over those treated with control IgG2a (Figure). Anti-tumor activity mediated by elotuzumab-g2a required an Fc fragment that was able to interact with activating Fc receptors, was partially dependent on both NK cells and CD8+ cells, and synergized with anti-PD-1 treatment. TILs taken from mice treated with elotuzumab-g2a plus anti-PD-1 had increased numbers of activated tumor-specific and total CD8+ T cells. Elotuzumab-g2a and anti-PD-1 combination treatment also promoted NK cell activation and cytokine and chemokine release within the tumor. In vitro co-cultures of human NK cells, elotuzumab, and SLAMF7-expressing tumor cell lines led to NK cell degranulation, upregulation of inflammatory cytokines, and enhanced expression of activation markers. Similarly, NK cells isolated from bone marrow aspirates from patients treated with elotuzumab showed an enhanced activation state compared with NK cells isolated prior to treatment.
Conclusion
The combination of the tumor-targeted antibodies elotuzumab-g2a and anti-PD-1 showed enhanced anti-tumor efficacy in mouse tumor models. The strong control of tumor growth observed with combination treatment was due to activation of both adaptive and innate immune cells localized to the tumor microenvironment. These in vivo findings support the suggested mechanism of action of elotuzumab and PD-1 blockade and provides rationale for the clinical investigation of elotuzumab and anti-PD-1 combination therapy in patients with MM.Study support: Bristol-Myers Squibb
Session topic: New biological markers in MM
Keyword(s): Cancer immunotherapy, Multiple myeloma, Murine models, Tumor immunology
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
Elotuzumab is a humanized monoclonal antibody (mAb) that binds specifically to human SLAMF7 (hSLAMF7) and has been approved by the US Food and Drug Administration for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received one to three prior therapies. Previous preclinical models demonstrated that elotuzumab inhibited the growth of SLAMF7-expressing human myeloma xenografts in immune-compromised mice. These models, however, lacked adaptive immune cells and therefore could not assess the mechanism of elotuzumab anti-tumor activity in the setting of a fully intact immune system.
Aims
To model elotuzumab mechanism of action, alone or in combination with PD-1 blockade, using human natural killer (NK) cells in vitro and mouse tumor models in vivo.
Methods
We evaluated elotuzumab-mediated anti-tumor activity alone or in combination with a mAb to PD-1 using mouse cell lines that stably express human SLAMF7 (A20-hSLAMF7 and EG7-hSLAMF7). The effect of treatment on the phenotype and functionality of tumor-infiltrating lymphocytes (TILs) using flow cytometry and immunohistochemistry was evaluated. In addition, the effects of elotuzumab on the phenotype of human NK cells isolated from either healthy donors or patients with MM treated with elotuzumab plus lenalidomide and dexamethasone was assessed.
Results
A murine IgG2a version of elotuzumab (elotuzumab-g2a) inhibited growth of hSLAMF7-expressing mouse tumor cells in vivo. Tumor-bearing mice treated with elotuzumab-g2a, anti-PD-1, or elotuzumab-g2a plus anti-PD-1 had significantly improved survival over those treated with control IgG2a (Figure). Anti-tumor activity mediated by elotuzumab-g2a required an Fc fragment that was able to interact with activating Fc receptors, was partially dependent on both NK cells and CD8+ cells, and synergized with anti-PD-1 treatment. TILs taken from mice treated with elotuzumab-g2a plus anti-PD-1 had increased numbers of activated tumor-specific and total CD8+ T cells. Elotuzumab-g2a and anti-PD-1 combination treatment also promoted NK cell activation and cytokine and chemokine release within the tumor. In vitro co-cultures of human NK cells, elotuzumab, and SLAMF7-expressing tumor cell lines led to NK cell degranulation, upregulation of inflammatory cytokines, and enhanced expression of activation markers. Similarly, NK cells isolated from bone marrow aspirates from patients treated with elotuzumab showed an enhanced activation state compared with NK cells isolated prior to treatment.
Conclusion
The combination of the tumor-targeted antibodies elotuzumab-g2a and anti-PD-1 showed enhanced anti-tumor efficacy in mouse tumor models. The strong control of tumor growth observed with combination treatment was due to activation of both adaptive and innate immune cells localized to the tumor microenvironment. These in vivo findings support the suggested mechanism of action of elotuzumab and PD-1 blockade and provides rationale for the clinical investigation of elotuzumab and anti-PD-1 combination therapy in patients with MM.Study support: Bristol-Myers Squibb
Session topic: New biological markers in MM
Keyword(s): Cancer immunotherapy, Multiple myeloma, Murine models, Tumor immunology
Abstract: S450
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
Elotuzumab is a humanized monoclonal antibody (mAb) that binds specifically to human SLAMF7 (hSLAMF7) and has been approved by the US Food and Drug Administration for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received one to three prior therapies. Previous preclinical models demonstrated that elotuzumab inhibited the growth of SLAMF7-expressing human myeloma xenografts in immune-compromised mice. These models, however, lacked adaptive immune cells and therefore could not assess the mechanism of elotuzumab anti-tumor activity in the setting of a fully intact immune system.
Aims
To model elotuzumab mechanism of action, alone or in combination with PD-1 blockade, using human natural killer (NK) cells in vitro and mouse tumor models in vivo.
Methods
We evaluated elotuzumab-mediated anti-tumor activity alone or in combination with a mAb to PD-1 using mouse cell lines that stably express human SLAMF7 (A20-hSLAMF7 and EG7-hSLAMF7). The effect of treatment on the phenotype and functionality of tumor-infiltrating lymphocytes (TILs) using flow cytometry and immunohistochemistry was evaluated. In addition, the effects of elotuzumab on the phenotype of human NK cells isolated from either healthy donors or patients with MM treated with elotuzumab plus lenalidomide and dexamethasone was assessed.
Results
A murine IgG2a version of elotuzumab (elotuzumab-g2a) inhibited growth of hSLAMF7-expressing mouse tumor cells in vivo. Tumor-bearing mice treated with elotuzumab-g2a, anti-PD-1, or elotuzumab-g2a plus anti-PD-1 had significantly improved survival over those treated with control IgG2a (Figure). Anti-tumor activity mediated by elotuzumab-g2a required an Fc fragment that was able to interact with activating Fc receptors, was partially dependent on both NK cells and CD8+ cells, and synergized with anti-PD-1 treatment. TILs taken from mice treated with elotuzumab-g2a plus anti-PD-1 had increased numbers of activated tumor-specific and total CD8+ T cells. Elotuzumab-g2a and anti-PD-1 combination treatment also promoted NK cell activation and cytokine and chemokine release within the tumor. In vitro co-cultures of human NK cells, elotuzumab, and SLAMF7-expressing tumor cell lines led to NK cell degranulation, upregulation of inflammatory cytokines, and enhanced expression of activation markers. Similarly, NK cells isolated from bone marrow aspirates from patients treated with elotuzumab showed an enhanced activation state compared with NK cells isolated prior to treatment.
Conclusion
The combination of the tumor-targeted antibodies elotuzumab-g2a and anti-PD-1 showed enhanced anti-tumor efficacy in mouse tumor models. The strong control of tumor growth observed with combination treatment was due to activation of both adaptive and innate immune cells localized to the tumor microenvironment. These in vivo findings support the suggested mechanism of action of elotuzumab and PD-1 blockade and provides rationale for the clinical investigation of elotuzumab and anti-PD-1 combination therapy in patients with MM.Study support: Bristol-Myers Squibb
Session topic: New biological markers in MM
Keyword(s): Cancer immunotherapy, Multiple myeloma, Murine models, Tumor immunology
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:15 - 12:30
Location: Auditorium 2
Background
Elotuzumab is a humanized monoclonal antibody (mAb) that binds specifically to human SLAMF7 (hSLAMF7) and has been approved by the US Food and Drug Administration for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received one to three prior therapies. Previous preclinical models demonstrated that elotuzumab inhibited the growth of SLAMF7-expressing human myeloma xenografts in immune-compromised mice. These models, however, lacked adaptive immune cells and therefore could not assess the mechanism of elotuzumab anti-tumor activity in the setting of a fully intact immune system.
Aims
To model elotuzumab mechanism of action, alone or in combination with PD-1 blockade, using human natural killer (NK) cells in vitro and mouse tumor models in vivo.
Methods
We evaluated elotuzumab-mediated anti-tumor activity alone or in combination with a mAb to PD-1 using mouse cell lines that stably express human SLAMF7 (A20-hSLAMF7 and EG7-hSLAMF7). The effect of treatment on the phenotype and functionality of tumor-infiltrating lymphocytes (TILs) using flow cytometry and immunohistochemistry was evaluated. In addition, the effects of elotuzumab on the phenotype of human NK cells isolated from either healthy donors or patients with MM treated with elotuzumab plus lenalidomide and dexamethasone was assessed.
Results
A murine IgG2a version of elotuzumab (elotuzumab-g2a) inhibited growth of hSLAMF7-expressing mouse tumor cells in vivo. Tumor-bearing mice treated with elotuzumab-g2a, anti-PD-1, or elotuzumab-g2a plus anti-PD-1 had significantly improved survival over those treated with control IgG2a (Figure). Anti-tumor activity mediated by elotuzumab-g2a required an Fc fragment that was able to interact with activating Fc receptors, was partially dependent on both NK cells and CD8+ cells, and synergized with anti-PD-1 treatment. TILs taken from mice treated with elotuzumab-g2a plus anti-PD-1 had increased numbers of activated tumor-specific and total CD8+ T cells. Elotuzumab-g2a and anti-PD-1 combination treatment also promoted NK cell activation and cytokine and chemokine release within the tumor. In vitro co-cultures of human NK cells, elotuzumab, and SLAMF7-expressing tumor cell lines led to NK cell degranulation, upregulation of inflammatory cytokines, and enhanced expression of activation markers. Similarly, NK cells isolated from bone marrow aspirates from patients treated with elotuzumab showed an enhanced activation state compared with NK cells isolated prior to treatment.
Conclusion
The combination of the tumor-targeted antibodies elotuzumab-g2a and anti-PD-1 showed enhanced anti-tumor efficacy in mouse tumor models. The strong control of tumor growth observed with combination treatment was due to activation of both adaptive and innate immune cells localized to the tumor microenvironment. These in vivo findings support the suggested mechanism of action of elotuzumab and PD-1 blockade and provides rationale for the clinical investigation of elotuzumab and anti-PD-1 combination therapy in patients with MM.Study support: Bristol-Myers Squibb
Session topic: New biological markers in MM
Keyword(s): Cancer immunotherapy, Multiple myeloma, Murine models, Tumor immunology
{{ help_message }}
{{filter}}