McCluskey, B. (Brandon)

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    Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma
    (American Association for Cancer Research, 2008) Dubrot, J. (Juan); Alfaro, C. (Carlos); Solano, S. (Sarai); McCluskey, B. (Brandon); Perez-Gracia, J.L. (Jose Luis); Oyahobi, B.O. (Babatunde O.); Murillo, O. (Oihana); Gupta, A. (Anjana); Azpilicueta, A. (Arantza); Hervas-Stubbs, S. (Sandra); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Palazon, A. (Asís); Arina, A. (Ainhoa)
    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-gamma, natural killer cells, and CD8(+) T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-gamma 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.