Eradication of post-treatment residual myeloma cells is needed to prevent relapses and immunostimulatory monoclonal antibodies (mAbs) such as anti-CD137, CTLA-4, CD40, etc, that enhance the immune response against malignancies represent a means of achieving this purpose. This study explores anti-CD137 mAbs for mutiple myeloma (MM) treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers.
The anti-tumor 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 anti-tumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human MM. 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 intra-peritoneal HOPC tumors, resulting in extended survival of mice that also became immune to re-challenge. Anti-CD137 mAbs induced complete eradications of established subcutaneous NS0-derived tumors that were dependent on IFN-γ, NK cells and CD8+ T lymphocytes. NK cells accumulated in tumor draining lymph nodes (TDLNs) and showed increased IFN-γ production. Anti-tumor 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.
Anti-CD137 mAb's immune-mediated anti-tumor activity in mouse models holds promise for myeloma treatment in humans.