Article

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

Gene Therapy Unit, Centro de Investigación Médica Aplicada, Pamplona, Spain.
Clinical Cancer Research (impact factor: 7.74). 12/2008; 14(21):6895-906. DOI:10.1158/1078-0432.CCR-08-0285 pp.6895-906
Source: PubMed

ABSTRACT 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.
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.
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.
The immune-mediated antitumor activity of anti-CD137 mAb in mouse models holds promise for myeloma treatment in humans.

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Keywords

anti-CD137 mAb treatment
 
clinical trials
 
human multiple myeloma
 
i.p. HOPC tumors
 
IFN-gamma production
 
immune-mediated antitumor activity
 
mouse models
 
mouse plasmacytomas
 
mouse syngeneic disseminated myeloma
 
multiple myeloma treatment
 
myeloma treatment
 
natural killer cells
 
NS0 cell lines
 
post-treatment residual myeloma cells
 
preclinical models
 
s.c. NS0-derived tumors
 
specific cell populations
 
study explores anti-CD137 mAbs
 
systemic tumor burden
 
tumor rejection