Synergistic Antimyeloma Activity of Dendritic Cells and Pomalidomide in a Murine Myeloma Model

Abstract

We have previously shown that immunization with tumor antigen-loaded dendritic cells (DCs) and the immunomodulating drug, lenalidomide, synergistically potentiates the enhancing antitumor immunity in a myeloma mouse model. In this study, we investigated the immunogenicity of DCs combined with pomalidomide and dexamethasone in a myeloma mouse model. MOPC-315 cells were injected subcutaneously to establish myeloma-bearing mice. Four test groups were used to mimic clinical protocol: (1) PBS control, (2) DCs, (3) pomalidomide + dexamethasone, and (4) DCs + pomalidomide + dexamethasone. The combination of DCs plus pomalidomide and dexamethasone displayed greater inhibition of tumor growth compared to the other groups. This effect was closely related with reduced numbers of immune suppressor cells including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells, with the induction of immune effector cells such as CD4+ and CD8+ T cells, memory T cells, natural killer (NK) cells, and M1 macrophages, and with the activation of T lymphocytes and NK cells in the spleen. Moreover, the level of the immunosuppressive factor vascular endothelial growth factor was significantly reduced in the tumor microenvironment. The collective findings in the murine myeloma model suggest that tumor antigen-loaded DCs combined with pomalidomide and dexamethasone synergistically enhance antitumor immunity by skewing the immune-suppressive status toward an immune-supportive status.

Cellular immunotherapy in multiple myeloma

“…The immunological mechanism of iMiDs involves the down-regulation of regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and an enhancement of the immune response by activating NK cells and T-cells [29]. We previously reported a strong synergistic effect of DC vaccination and lenalidomide [30] or pomalidomide [31] in the induction of an anti-myeloma effect in a murine myeloma model. Another method to improve DC vaccination is to combine checkpoint blockades that modulate negative regulation in the tumor microenvironment [32].…”

Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses

“…In support of our findings, the addition of DEX to the DC vaccination plus IMiDs does not have a negative antimyeloma effect compared with the combination without DEX in a model of murine MM. 20 This is the first report of a potential mechanism whereby IMiD treatment leads to the onset of itchy skin with rash-like atopy. Understanding LEN-related rashes provides valuable insight into the response to LEN treatment and may enable improved treatment regimens for MM.…”

“…There is evidence of immunomodulatory activity of IMiDs on mouse dendritic cells (DCs) 13,17 and a synergistic effect with DC vaccination in model of murine MM [18][19][20] or colon cancer, 21 however, only a few reports have examined its effects on human DC subsets. [22][23][24][25] DCs are capable of inducing Th1 or Th2 responses.…”

Autologous Hematopoietic Stem Cells Are a Preferred Source to Generate Dendritic Cells for Immunotherapy in Multiple Myeloma Patients

“…In order to increase the efficiency some investigators have attempted a combination of DC vaccine with the drug Lenalidomide for treatment of MM (29) and colon cancer (30) in murine model. In yet another study pomalidomide and dexamethasone were combined with DC vaccine and tested in murine MM model (31). Vo et al (32) have also shown that addition of Lenalidomide in different concentrations in vitro on Mo-DCs obtained from multiple myeloma patients improved the functionality of DC.…”