Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma

Oihana Murillo, Ainhoa Arina, Sandra Hervas-Stubbs, Anjana Gupta, Brandon McCluskey, Juan Dubrot, Asís Palazón, Arantza Azpilikueta, Maria C. Ochoa, Carlos Alfaro, Sarai Solano, José L. Pérez-Gracia, Babatunde O. Oyajobi, Ignacio Melero

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6895-6906
Number of pages12
JournalClinical Cancer Research
Volume14
Issue number21
DOIs
StatePublished - Nov 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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