Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma
| Autor: | Sarai Solano, Jose Luis Perez-Gracia, Carlos Alfaro, Sandra Hervas-Stubbs, Arantza Azpilikueta, Maria C. Ochoa, Juan Dubrot, Anjana Gupta, Ignacio Melero, Ainhoa Arina, Brandon McCluskey, Asis Palazon, Oihana Murillo, Babatunde O. Oyajobi |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
medicine.drug_class Multiple Myeloma/drug therapy Antibodies Monoclonal/therapeutic use Biology Monoclonal antibody Article Mice Tumor Necrosis Factor Receptor Superfamily Member 9 Immune system Adjuvants Immunologic Antigen Antigens CD medicine Animals Humans CTLA-4 Antigen Plasmacytoma/drug therapy CD40 Antigens Multiple myeloma Mice Inbred BALB C CD40 CD137 Antibodies Monoclonal medicine.disease Adjuvants Immunologic/therapeutic use Survival Analysis Antigens CD137/immunology Tumor Burden Disease Models Animal Oncology Immunology biology.protein Plasmacytoma Female Antibody Multiple Myeloma |
| Popis: | Purpose: Eradication of post-treatment residual myeloma cells is needed to prevent relapses, and immunostimulatory monoclonal antibodies (mAb) such as anti-CD137, CTLA-4, CD40, etc., which enhance the immune response against malignancies, represent a means of achieving this purpose. This study explores anti-CD137 mAbs for multiple myeloma treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers.Experimental Design: The antitumor effect of anti-CD137 mAb on mouse plasmacytomas derived from HOPC and NS0 cell lines was studied and compared with that of anti-CTLA-4, anti-CD40, and anti-ICAM-2 mAbs. The antitumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human multiple myeloma. Depletions of specific cell populations and gene-targeted mice were used to unravel the requirements for tumor rejection.Results: Agonistic mAb against CD137 and blocking anti-CTLA-4 mAb showed activity against i.p. HOPC tumors, resulting in extended survival of mice that also became immune to rechallenge. Anti-CD137 mAbs induced complete eradications of established s.c. NS0-derived tumors that were dependent on IFN-γ, natural killer cells, and CD8+ T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-γ production. Antitumor efficacy of anti-CD137 mAb was preserved in CD28-deficient mice despite the fact that CD28 signaling increases the expression of CD137 on CD8+ T cells. Importantly, anti-CD137 mAb treatment significantly decreased systemic tumor burden in the disseminated 5TGM1 model.Conclusions: The immune-mediated antitumor activity of anti-CD137 mAb in mouse models holds promise for myeloma treatment in humans. |
| Databáze: | OpenAIRE |
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