Multiple myeloma is a blood cancer that arises in the bone marrow from malignant plasma cells. Although treatments have dramatically improved during the last decade, multiple myeloma remains an incurable disease responsible for more than 10 000 deaths per year in the United States. CD137 is a costimulatory molecule expressed on activated T cells and NK cells. We recently established that agonist monoclonal antibodies (mAbs) against CD137 (clone 3H3) significantly reduce tumor burden and improve survival in a mouse model of multiple myeloma1. We found that anti-CD137 mAb therapeutic activity requires the presence of both CD8 T cells and NK cells but is independent of Fc receptors. Moreover, we observed increased numbers of T cells in the bone marrow of anti-CD137 mAb treated mice. CD8 T cells were increased while the percentage of Tregs was reduced. Thus, anti-CD137 mAbs protect mice against multiple myeloma by inducing potent NK cell and CD8 T cell responses.
In the present study, we investigate further the therapeutic interest and the potential limitations of anti-CD137 mAbs. To this aim, we used multiple myeloma cell lines derived from Vk*MYC transgenic mice. Wild-type (WT) mice intravenously injected with Vk*MYC cells develop a disease very similar to human multiple myeloma. High percentages of malignant plasma cells are observed in the bone marrow and in the spleen 5 weeks after injection and disease progression can be followed by the level of serum gamma-globulin (M protein). We first observed that, although early anti-CD137 mAb treatment efficiently protected the mice against multiple myeloma, this treatment loses efficacy when given more than 3 weeks after Vk*MYC cell injection. Interestingly, CD4 cell depletion restores the efficacy of late anti-CD137 mAb treatment, indicating that Treg-mediated suppression may limit the therapeutic efficacy of anti-CD137 mAbs. In line with previous studies, we observed that NK cell numbers in the spleen are dramatically reduced 12 days after the initiation of anti-CD137 mAb treatment. NK cell numbers are also decreased in other organs including liver, lung and blood. Importantly, we found that NK cells are still poorly represented in the spleen 3 weeks after the last treatment with anti-CD137 mAbs. Finally, we observed that anti-CD137 mAb treatment induced T cell activation and increases T cell infiltration in the liver. Consistent with the cases of severe hepatitis observed in patients treated with anti-CD137 mAbs, we noted that some of anti-CD137 mAb treated mice that had survived multiple myeloma developed severe liver damage. Such liver damage could be observed more than 100 days after the last therapy with anti-CD137 mAbs.
In conclusion, we report several side effects induced by anti-CD137 mAbs treatment that last long after the treatment has been interrupted. These results encourage being particularly careful when administrating this drug to patients. Our study demonstrates the utility of mouse models to investigate the anti-tumor benefits versus toxicity of immunotherapies. We are planning to use this approach to assess the therapeutic efficacy of anti-CD137 mAbs in combination with other treatments. We speculate that the prior reduction of tumor burden by chemotherapy or stem cell transplantation will allow better efficacy of anti-CD137 mAbs at lower doses. The use of mice injected with multiple myeloma cell lines will help determining which combination allows efficient anti-tumor responses at late multiple myeloma stages with limited toxicity.
1 Guillerey C*, De Andrade LF*, Vuckovic S, Miles K, Ngiow SF, Yong MCR, Teng MWL, Colonna M, Ritchie DS, Chesi M, Bergsagel PL, Hill GR, Smyth MJ*, Martinet L* Immunosurveillance and therapy of multiple myeloma is CD226-dependent; Journal of Clinical Investigation, May 1;125(5):2077-89.
Citation Format: Camille Guillerey, Lucas Ferrari de Andrade, Slavica Vuckovic, David Ritchie, Marta Chesi, Leif Bergsagel, Geoffrey R. Hill, Ludovic Martinet, Mark J. Smyth. Anti-CD137 mAb therapy of multiple myeloma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B155.
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