COMBINATION OF THE GLYCOENGINEERED TYPE II CD20 ANTIBODY OBINUTUZUMAB WITH THE NOVEL BCL-2 SELECTIVE INHIBITOR VENETOCLAX INDUCES ROBUST CELL DEATH IN NHL MODELS AND CLL PATIENT SAMPLES
(Abstract release date: 05/19/16)
EHA Library. Sampath D. 06/09/16; 132921; E1372
Disclosure(s): I am an employee of Genentech, a member of the Roche Group
Dr. Deepak Sampath
Contributions
Contributions
Abstract
Abstract: E1372
Type: Eposter Presentation
Background
Obinutuzumab (GA101) is a novel glycoengineered type II anti-CD20 monoclonal antibody that induces a high level of non-apoptotic direct cell death and, due to increased affinity for FcγRIII on effector cells, results in enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Venetoclax (ABT-199/GDC-0199) is a novel, orally bioavailable, selective BCL-2 inhibitor that induces intrinsic apoptosis in preclinical models of hematological malignancies (NHL, AML, MM) and primary CLL patient samples.
Aims
Based on their complementary mechanisms of action involving increased apoptosis (venetoclax) or direct cell death (obinutuzumab) we aimed to determine if the combination of both agents has the potential for greater efficacy in treating B lymphoid malignancies such as NHL and CLL when compared to monotherapy and co-treatment with other anti-CD20 antibodies such as rituximab.
Methods
In vitro studies primarily utilized fluorescence activated cell sorting (FACS) to measure direct cell death induction/apoptosis on NHL cell lines (WSU-DLCL2, SU-DHL4 and Z138) and primary CLL patient samples (n=27) as well as the impact of BCL-2 inhibition on ADCC induction. ADCC assays utilized peripheral blood mononuclear cells (PBMCs) isolated from healthy donors as effector (E) cells and SU-DHL4 as target (T) cells and measured by Lactate dehydrogenase (LDH) release using the LDH Cytotoxicity Detection Kit (Roche Applied Science). In vivo efficacy of venetoclax monotherapy or in combination with anti-CD20 antibodies was evaluated in WSU-DLCL2, SU-DHL4 and Z138 sub-cutaneous xenograft models. Venetoclax (100 mg/kg) was administered daily by oral gavage for 21 days and anti-CD20 antibodies (1 mg/kg) were delivered intrapertioneally once during the treatment period.
Results
Venetoclax enhanced induction of cell death when combined with obinutuzumab or rituximab in SU-DHL4, WSU-DLCL2 and Z138 cell lines. However, a greater degree of cell death was observed when venetoclax was combined with obinutuzumab versus rituxumab at lower drug concentrations. Importantly, venetoclax did not antagonize natural killer (NK)-cell mediated ADCC or B cell depletion induced by obinutuzumab or rituximab treatment. Treatment of SU-DHL4, WSU-DLCL2 and Z138 xenografts with venetoclax plus obinutuzumab resulted in complete regressions, increased overall response rates or greater tumor growth inhibition in vivo. Moreover, monotherapy with venetoclax following combination treatment with obinutuzumab resulted in sustained in vivo efficacy and increased duration of response in SU-DHL4 and WSU-DLCL2 xenograft models suggesting a potential benefit of utilizing venetoclax as maintenance therapy. In primary CLL samples (from untreated or relapsed patients), venetoclax plus anti-CD20 antibody drug combination treatment significantly increased B cell depletion (based on direct cell death/ADCC) after 7 days in culture ex vivo. Under these conditions, venetoclax in combination with obinutuzumab was more effective than the combination with rituximab or venetoclax alone. Moreover, co-culture with nurse-like cells that increases B-cell survival did not protect primary CLL cells from venetoclax demonstrating that drug efficacy is maintained in a protective tumor microenvironment such as lymph node.
Conclusion
Collectively, our data demonstrate that combination of obinutuzumab with venetoclax results in greater cell death and robust anti-tumor efficacy in xenograft models representing NHL sub-types and primary CLL patient samples that is superior when compared to co-treatment with rituximab. The preclinical data presented supports clinical investigation of obinutuzumab and venetoclax combination therapy, which is currently in phase Ib clinical trials for relapsed/refractory CLL (clinical trial.gov identifier NCT01685892), and warrants further investigation in other B-cell malignancies such as NHL.
Session topic: E-poster
Keyword(s): Apoptosis, BCL2, B-CLL, CD20
Type: Eposter Presentation
Background
Obinutuzumab (GA101) is a novel glycoengineered type II anti-CD20 monoclonal antibody that induces a high level of non-apoptotic direct cell death and, due to increased affinity for FcγRIII on effector cells, results in enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Venetoclax (ABT-199/GDC-0199) is a novel, orally bioavailable, selective BCL-2 inhibitor that induces intrinsic apoptosis in preclinical models of hematological malignancies (NHL, AML, MM) and primary CLL patient samples.
Aims
Based on their complementary mechanisms of action involving increased apoptosis (venetoclax) or direct cell death (obinutuzumab) we aimed to determine if the combination of both agents has the potential for greater efficacy in treating B lymphoid malignancies such as NHL and CLL when compared to monotherapy and co-treatment with other anti-CD20 antibodies such as rituximab.
Methods
In vitro studies primarily utilized fluorescence activated cell sorting (FACS) to measure direct cell death induction/apoptosis on NHL cell lines (WSU-DLCL2, SU-DHL4 and Z138) and primary CLL patient samples (n=27) as well as the impact of BCL-2 inhibition on ADCC induction. ADCC assays utilized peripheral blood mononuclear cells (PBMCs) isolated from healthy donors as effector (E) cells and SU-DHL4 as target (T) cells and measured by Lactate dehydrogenase (LDH) release using the LDH Cytotoxicity Detection Kit (Roche Applied Science). In vivo efficacy of venetoclax monotherapy or in combination with anti-CD20 antibodies was evaluated in WSU-DLCL2, SU-DHL4 and Z138 sub-cutaneous xenograft models. Venetoclax (100 mg/kg) was administered daily by oral gavage for 21 days and anti-CD20 antibodies (1 mg/kg) were delivered intrapertioneally once during the treatment period.
Results
Venetoclax enhanced induction of cell death when combined with obinutuzumab or rituximab in SU-DHL4, WSU-DLCL2 and Z138 cell lines. However, a greater degree of cell death was observed when venetoclax was combined with obinutuzumab versus rituxumab at lower drug concentrations. Importantly, venetoclax did not antagonize natural killer (NK)-cell mediated ADCC or B cell depletion induced by obinutuzumab or rituximab treatment. Treatment of SU-DHL4, WSU-DLCL2 and Z138 xenografts with venetoclax plus obinutuzumab resulted in complete regressions, increased overall response rates or greater tumor growth inhibition in vivo. Moreover, monotherapy with venetoclax following combination treatment with obinutuzumab resulted in sustained in vivo efficacy and increased duration of response in SU-DHL4 and WSU-DLCL2 xenograft models suggesting a potential benefit of utilizing venetoclax as maintenance therapy. In primary CLL samples (from untreated or relapsed patients), venetoclax plus anti-CD20 antibody drug combination treatment significantly increased B cell depletion (based on direct cell death/ADCC) after 7 days in culture ex vivo. Under these conditions, venetoclax in combination with obinutuzumab was more effective than the combination with rituximab or venetoclax alone. Moreover, co-culture with nurse-like cells that increases B-cell survival did not protect primary CLL cells from venetoclax demonstrating that drug efficacy is maintained in a protective tumor microenvironment such as lymph node.
Conclusion
Collectively, our data demonstrate that combination of obinutuzumab with venetoclax results in greater cell death and robust anti-tumor efficacy in xenograft models representing NHL sub-types and primary CLL patient samples that is superior when compared to co-treatment with rituximab. The preclinical data presented supports clinical investigation of obinutuzumab and venetoclax combination therapy, which is currently in phase Ib clinical trials for relapsed/refractory CLL (clinical trial.gov identifier NCT01685892), and warrants further investigation in other B-cell malignancies such as NHL.
Session topic: E-poster
Keyword(s): Apoptosis, BCL2, B-CLL, CD20
Abstract: E1372
Type: Eposter Presentation
Background
Obinutuzumab (GA101) is a novel glycoengineered type II anti-CD20 monoclonal antibody that induces a high level of non-apoptotic direct cell death and, due to increased affinity for FcγRIII on effector cells, results in enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Venetoclax (ABT-199/GDC-0199) is a novel, orally bioavailable, selective BCL-2 inhibitor that induces intrinsic apoptosis in preclinical models of hematological malignancies (NHL, AML, MM) and primary CLL patient samples.
Aims
Based on their complementary mechanisms of action involving increased apoptosis (venetoclax) or direct cell death (obinutuzumab) we aimed to determine if the combination of both agents has the potential for greater efficacy in treating B lymphoid malignancies such as NHL and CLL when compared to monotherapy and co-treatment with other anti-CD20 antibodies such as rituximab.
Methods
In vitro studies primarily utilized fluorescence activated cell sorting (FACS) to measure direct cell death induction/apoptosis on NHL cell lines (WSU-DLCL2, SU-DHL4 and Z138) and primary CLL patient samples (n=27) as well as the impact of BCL-2 inhibition on ADCC induction. ADCC assays utilized peripheral blood mononuclear cells (PBMCs) isolated from healthy donors as effector (E) cells and SU-DHL4 as target (T) cells and measured by Lactate dehydrogenase (LDH) release using the LDH Cytotoxicity Detection Kit (Roche Applied Science). In vivo efficacy of venetoclax monotherapy or in combination with anti-CD20 antibodies was evaluated in WSU-DLCL2, SU-DHL4 and Z138 sub-cutaneous xenograft models. Venetoclax (100 mg/kg) was administered daily by oral gavage for 21 days and anti-CD20 antibodies (1 mg/kg) were delivered intrapertioneally once during the treatment period.
Results
Venetoclax enhanced induction of cell death when combined with obinutuzumab or rituximab in SU-DHL4, WSU-DLCL2 and Z138 cell lines. However, a greater degree of cell death was observed when venetoclax was combined with obinutuzumab versus rituxumab at lower drug concentrations. Importantly, venetoclax did not antagonize natural killer (NK)-cell mediated ADCC or B cell depletion induced by obinutuzumab or rituximab treatment. Treatment of SU-DHL4, WSU-DLCL2 and Z138 xenografts with venetoclax plus obinutuzumab resulted in complete regressions, increased overall response rates or greater tumor growth inhibition in vivo. Moreover, monotherapy with venetoclax following combination treatment with obinutuzumab resulted in sustained in vivo efficacy and increased duration of response in SU-DHL4 and WSU-DLCL2 xenograft models suggesting a potential benefit of utilizing venetoclax as maintenance therapy. In primary CLL samples (from untreated or relapsed patients), venetoclax plus anti-CD20 antibody drug combination treatment significantly increased B cell depletion (based on direct cell death/ADCC) after 7 days in culture ex vivo. Under these conditions, venetoclax in combination with obinutuzumab was more effective than the combination with rituximab or venetoclax alone. Moreover, co-culture with nurse-like cells that increases B-cell survival did not protect primary CLL cells from venetoclax demonstrating that drug efficacy is maintained in a protective tumor microenvironment such as lymph node.
Conclusion
Collectively, our data demonstrate that combination of obinutuzumab with venetoclax results in greater cell death and robust anti-tumor efficacy in xenograft models representing NHL sub-types and primary CLL patient samples that is superior when compared to co-treatment with rituximab. The preclinical data presented supports clinical investigation of obinutuzumab and venetoclax combination therapy, which is currently in phase Ib clinical trials for relapsed/refractory CLL (clinical trial.gov identifier NCT01685892), and warrants further investigation in other B-cell malignancies such as NHL.
Session topic: E-poster
Keyword(s): Apoptosis, BCL2, B-CLL, CD20
Type: Eposter Presentation
Background
Obinutuzumab (GA101) is a novel glycoengineered type II anti-CD20 monoclonal antibody that induces a high level of non-apoptotic direct cell death and, due to increased affinity for FcγRIII on effector cells, results in enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Venetoclax (ABT-199/GDC-0199) is a novel, orally bioavailable, selective BCL-2 inhibitor that induces intrinsic apoptosis in preclinical models of hematological malignancies (NHL, AML, MM) and primary CLL patient samples.
Aims
Based on their complementary mechanisms of action involving increased apoptosis (venetoclax) or direct cell death (obinutuzumab) we aimed to determine if the combination of both agents has the potential for greater efficacy in treating B lymphoid malignancies such as NHL and CLL when compared to monotherapy and co-treatment with other anti-CD20 antibodies such as rituximab.
Methods
In vitro studies primarily utilized fluorescence activated cell sorting (FACS) to measure direct cell death induction/apoptosis on NHL cell lines (WSU-DLCL2, SU-DHL4 and Z138) and primary CLL patient samples (n=27) as well as the impact of BCL-2 inhibition on ADCC induction. ADCC assays utilized peripheral blood mononuclear cells (PBMCs) isolated from healthy donors as effector (E) cells and SU-DHL4 as target (T) cells and measured by Lactate dehydrogenase (LDH) release using the LDH Cytotoxicity Detection Kit (Roche Applied Science). In vivo efficacy of venetoclax monotherapy or in combination with anti-CD20 antibodies was evaluated in WSU-DLCL2, SU-DHL4 and Z138 sub-cutaneous xenograft models. Venetoclax (100 mg/kg) was administered daily by oral gavage for 21 days and anti-CD20 antibodies (1 mg/kg) were delivered intrapertioneally once during the treatment period.
Results
Venetoclax enhanced induction of cell death when combined with obinutuzumab or rituximab in SU-DHL4, WSU-DLCL2 and Z138 cell lines. However, a greater degree of cell death was observed when venetoclax was combined with obinutuzumab versus rituxumab at lower drug concentrations. Importantly, venetoclax did not antagonize natural killer (NK)-cell mediated ADCC or B cell depletion induced by obinutuzumab or rituximab treatment. Treatment of SU-DHL4, WSU-DLCL2 and Z138 xenografts with venetoclax plus obinutuzumab resulted in complete regressions, increased overall response rates or greater tumor growth inhibition in vivo. Moreover, monotherapy with venetoclax following combination treatment with obinutuzumab resulted in sustained in vivo efficacy and increased duration of response in SU-DHL4 and WSU-DLCL2 xenograft models suggesting a potential benefit of utilizing venetoclax as maintenance therapy. In primary CLL samples (from untreated or relapsed patients), venetoclax plus anti-CD20 antibody drug combination treatment significantly increased B cell depletion (based on direct cell death/ADCC) after 7 days in culture ex vivo. Under these conditions, venetoclax in combination with obinutuzumab was more effective than the combination with rituximab or venetoclax alone. Moreover, co-culture with nurse-like cells that increases B-cell survival did not protect primary CLL cells from venetoclax demonstrating that drug efficacy is maintained in a protective tumor microenvironment such as lymph node.
Conclusion
Collectively, our data demonstrate that combination of obinutuzumab with venetoclax results in greater cell death and robust anti-tumor efficacy in xenograft models representing NHL sub-types and primary CLL patient samples that is superior when compared to co-treatment with rituximab. The preclinical data presented supports clinical investigation of obinutuzumab and venetoclax combination therapy, which is currently in phase Ib clinical trials for relapsed/refractory CLL (clinical trial.gov identifier NCT01685892), and warrants further investigation in other B-cell malignancies such as NHL.
Session topic: E-poster
Keyword(s): Apoptosis, BCL2, B-CLL, CD20
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