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Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma.

Herting F, Friess T, Bader S, Muth G, Hölzlwimmer G, Rieder N, Umana P, Klein C - Leuk. Lymphoma (2014)

Bottom Line: Owing to strong single-agent efficacy in these models, suboptimal doses of obinutuzumab were applied to demonstrate a combination effect.Obinutuzumab plus bendamustine achieved superior tumor growth inhibition versus rituximab plus bendamustine and showed a statistically significant effect versus the respective single treatments.Obinutuzumab monotherapy was at least as effective as rituximab plus chemotherapy in vivo, and obinutuzumab plus chemotherapy was superior to the respective monotherapies.

View Article: PubMed Central - PubMed

Affiliation: Discovery Oncology, Pharma Research and Early Development (pRED), Roche Diagnostics GmbH , Penzberg , Germany.

ABSTRACT
Obinutuzumab (GA101) is a novel glycoengineered type II CD20 antibody in development for non-Hodgkin lymphoma. We compared the anti-tumor activity of obinutuzumab and rituximab in preclinical studies using subcutaneous Z138 and WSU-DLCL2 xenograft mouse models. Obinutuzumab and rituximab were assessed alone and in combination with bendamustine, fludarabine, chlorambucil, doxorubicin and cyclophosphamide/vincristine. Owing to strong single-agent efficacy in these models, suboptimal doses of obinutuzumab were applied to demonstrate a combination effect. Obinutuzumab plus bendamustine achieved superior tumor growth inhibition versus rituximab plus bendamustine and showed a statistically significant effect versus the respective single treatments. Combinations of obinutuzumab with fludarabine, chlorambucil or cyclophosphamide/vincristine demonstrated significantly superior activity to rituximab-based treatment. Obinutuzumab monotherapy was at least as effective as rituximab plus chemotherapy in vivo, and obinutuzumab plus chemotherapy was superior to the respective monotherapies. These data support further clinical investigation of obinutuzumab plus chemotherapy.

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Tumor panels from Z138 tumor-bearing mice showing mantle cell NHL of Z138 human cell line: (A) (× 400 hematoxylin and eosin [H&E]) shows “starry sky” pattern as a result of apoptosis and phagocytosis; (B) (× 100 H&E) highlights infiltrative growth into surrounding subcutaneous tissue (muscle and fat), lacking distinct encapsulation (left; #101), respectively, with formation of a thin tumor-surrounding capsule of tumors of vehicle-treated mice (right, #102); (C) (× 200 CD20) shows strong membrane-bound CD20 expression in almost all MCL cells; (D) (× 100 H&E) demonstrates improved demarcation with increased capsule thickness after treatment with obinutuzumab (GA101) and bendamustine (left, #501) or after treatment with rituximab and bendamustine (right, #602). Note the small rim in the periphery of the tumor with increased vacuolated/degenerative and apoptotic tumor cells.
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Figure 6: Tumor panels from Z138 tumor-bearing mice showing mantle cell NHL of Z138 human cell line: (A) (× 400 hematoxylin and eosin [H&E]) shows “starry sky” pattern as a result of apoptosis and phagocytosis; (B) (× 100 H&E) highlights infiltrative growth into surrounding subcutaneous tissue (muscle and fat), lacking distinct encapsulation (left; #101), respectively, with formation of a thin tumor-surrounding capsule of tumors of vehicle-treated mice (right, #102); (C) (× 200 CD20) shows strong membrane-bound CD20 expression in almost all MCL cells; (D) (× 100 H&E) demonstrates improved demarcation with increased capsule thickness after treatment with obinutuzumab (GA101) and bendamustine (left, #501) or after treatment with rituximab and bendamustine (right, #602). Note the small rim in the periphery of the tumor with increased vacuolated/degenerative and apoptotic tumor cells.

Mentions: Tumors analyzed from Z138 xenografts showed evidence of cellular and nuclear polymorphism, an extreme rate of proliferation (mean of ≥ 10 mitotic figures per FOV) and a severe rate of apoptosis (mean of 6–9 apoptotic cells per FOV). A representative panel from human mantle cell Z138 tumor-bearing animals is shown in Figure 6. Compared with controls, tumors from mice treated with obinutuzumab (GA101) or rituximab alone showed improved tumor demarcation, with increased thickness of the surrounding fibrous capsule. Additionally, an increase in degenerative and apoptotic tumor cells in the tumor periphery was observed in H&E-stained sections. These morphological changes were enhanced after the addition of bendamustine to obinutuzumab (GA101) or rituximab (Figure 6). No differences in histopathological parameters were observed between the bendamustine monotherapy and vehicle treatment groups. CD20 immunohistochemical staining was strong and membrane-bound in almost all (> 95%) tumor cells; there were no marked differences in CD20 expression between the different treatment groups or compared with vehicle-treated tumors.


Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma.

Herting F, Friess T, Bader S, Muth G, Hölzlwimmer G, Rieder N, Umana P, Klein C - Leuk. Lymphoma (2014)

Tumor panels from Z138 tumor-bearing mice showing mantle cell NHL of Z138 human cell line: (A) (× 400 hematoxylin and eosin [H&E]) shows “starry sky” pattern as a result of apoptosis and phagocytosis; (B) (× 100 H&E) highlights infiltrative growth into surrounding subcutaneous tissue (muscle and fat), lacking distinct encapsulation (left; #101), respectively, with formation of a thin tumor-surrounding capsule of tumors of vehicle-treated mice (right, #102); (C) (× 200 CD20) shows strong membrane-bound CD20 expression in almost all MCL cells; (D) (× 100 H&E) demonstrates improved demarcation with increased capsule thickness after treatment with obinutuzumab (GA101) and bendamustine (left, #501) or after treatment with rituximab and bendamustine (right, #602). Note the small rim in the periphery of the tumor with increased vacuolated/degenerative and apoptotic tumor cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196549&req=5

Figure 6: Tumor panels from Z138 tumor-bearing mice showing mantle cell NHL of Z138 human cell line: (A) (× 400 hematoxylin and eosin [H&E]) shows “starry sky” pattern as a result of apoptosis and phagocytosis; (B) (× 100 H&E) highlights infiltrative growth into surrounding subcutaneous tissue (muscle and fat), lacking distinct encapsulation (left; #101), respectively, with formation of a thin tumor-surrounding capsule of tumors of vehicle-treated mice (right, #102); (C) (× 200 CD20) shows strong membrane-bound CD20 expression in almost all MCL cells; (D) (× 100 H&E) demonstrates improved demarcation with increased capsule thickness after treatment with obinutuzumab (GA101) and bendamustine (left, #501) or after treatment with rituximab and bendamustine (right, #602). Note the small rim in the periphery of the tumor with increased vacuolated/degenerative and apoptotic tumor cells.
Mentions: Tumors analyzed from Z138 xenografts showed evidence of cellular and nuclear polymorphism, an extreme rate of proliferation (mean of ≥ 10 mitotic figures per FOV) and a severe rate of apoptosis (mean of 6–9 apoptotic cells per FOV). A representative panel from human mantle cell Z138 tumor-bearing animals is shown in Figure 6. Compared with controls, tumors from mice treated with obinutuzumab (GA101) or rituximab alone showed improved tumor demarcation, with increased thickness of the surrounding fibrous capsule. Additionally, an increase in degenerative and apoptotic tumor cells in the tumor periphery was observed in H&E-stained sections. These morphological changes were enhanced after the addition of bendamustine to obinutuzumab (GA101) or rituximab (Figure 6). No differences in histopathological parameters were observed between the bendamustine monotherapy and vehicle treatment groups. CD20 immunohistochemical staining was strong and membrane-bound in almost all (> 95%) tumor cells; there were no marked differences in CD20 expression between the different treatment groups or compared with vehicle-treated tumors.

Bottom Line: Owing to strong single-agent efficacy in these models, suboptimal doses of obinutuzumab were applied to demonstrate a combination effect.Obinutuzumab plus bendamustine achieved superior tumor growth inhibition versus rituximab plus bendamustine and showed a statistically significant effect versus the respective single treatments.Obinutuzumab monotherapy was at least as effective as rituximab plus chemotherapy in vivo, and obinutuzumab plus chemotherapy was superior to the respective monotherapies.

View Article: PubMed Central - PubMed

Affiliation: Discovery Oncology, Pharma Research and Early Development (pRED), Roche Diagnostics GmbH , Penzberg , Germany.

ABSTRACT
Obinutuzumab (GA101) is a novel glycoengineered type II CD20 antibody in development for non-Hodgkin lymphoma. We compared the anti-tumor activity of obinutuzumab and rituximab in preclinical studies using subcutaneous Z138 and WSU-DLCL2 xenograft mouse models. Obinutuzumab and rituximab were assessed alone and in combination with bendamustine, fludarabine, chlorambucil, doxorubicin and cyclophosphamide/vincristine. Owing to strong single-agent efficacy in these models, suboptimal doses of obinutuzumab were applied to demonstrate a combination effect. Obinutuzumab plus bendamustine achieved superior tumor growth inhibition versus rituximab plus bendamustine and showed a statistically significant effect versus the respective single treatments. Combinations of obinutuzumab with fludarabine, chlorambucil or cyclophosphamide/vincristine demonstrated significantly superior activity to rituximab-based treatment. Obinutuzumab monotherapy was at least as effective as rituximab plus chemotherapy in vivo, and obinutuzumab plus chemotherapy was superior to the respective monotherapies. These data support further clinical investigation of obinutuzumab plus chemotherapy.

Show MeSH
Related in: MedlinePlus