Potent Immunomodulatory Drug Lenalidomide Synergistically Enhance the Effect of Dendritic Cell Vaccination on Multiple Myeloma in Mouse Model,

Lenalidomide augment both the adaptive and innate immune system via the co-stimulation of T cells and augmentation of NK and NKT cells, and also can inhibit the frequency and function of suppressor cell. Therefore, lenalidomide could be used to enhance immune response against cancer. Cellular therapy with dendritic cells (DCs) is emerging as a useful immunotherapeutic modality to treat multiple myeloma (MM). The purpose of this study was to investigate the immunomodulatory effects of lenalidomide in combination with dendritic cells vaccine to treat MM in vivo mouse model.

We used the MOPC315 myeloma murine model to generate tumor-specific CTLs responses by a DC vaccine in combination with lenalidomide. MOPC315 cells were injected subcutaneously into the right flank of 6 to 8-week old mice. After tumor growth, lenalidomide (50 mg/kg/day) were injected intraperitoneal at a three consecutive days to cover the DCs vaccination at day 8, 12, 16, 20. The tumor growth inhibition effect was evaluated to reveal the synergistic effect of DCs and lenalidomide. Using cytotoxic assay, we identified the antitumor effect of splenocytes from vaccinated mice and secretion of IFN-g or IL-10 in response to tumor antigens. The frequency of CD4⁺, CD8⁺, NK cells, Gr1⁺CD11b⁺ MDSCs, and regulatory T cells in spleens of vaccinated mice were also examined. We then examined the anti-angiogenesis of lenalidomide by measuring the levels of VEGF and TNF-a on tumor tissues of vaccinated mice.

The combination of lenalidomide and DCs vaccine efficiently inhibited tumor growth in mouse myeloma model when compared to single therapeutic agent. The cytotoxic assay revealed that the antitumor effects of DCs plus lenalidomide in vaccinated mice were from not only CTLs but also NK cells, respectively. These vaccinated mice exhibit the reduction of suppressor cells including MDSC and regulatory T cell in spleens. In contrast, the reduction of MDSC and regulatory T cells resulted in the increasing proportion of CD4⁺ and CD8⁺ T cell in the spleen, and the production of Th1 cytokines (IFN-g) rather than Th2 cytokines (IL-10) in response to tumor antigens. Lenalidomide also enhance the innate immune response by modulating NK cell number and function. In addition, the treatment of lenalidomide can reduce the production of angiogenesis inducing factors including TNF-a and VEGF in tumor-bearing mice. Furthermore, vaccination with DCs plus lenalidomide also inhibited tumor growth in the mice that challenged with MOPC cells compared to control.

These results suggest that a treatment combining the immunomodulatory drug lenalidomide with a DC vaccine can improve antitumor immunity in a mouse cancer model by inhibiting immunosuppressor cells and recovering effector cells, as well as superior polarization of the Th1/Th2 balance in favor of Th1.

No relevant conflicts of interest to declare.