Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma

Abstract

The therapeutic efficacy of dendritic cell (DC)-based immunotherapy may be potentiated in combination with other anticancer therapies that enhance DC function by modulating immune responses and the tumor microenvironment. In this study, we investigated the efficacy of DC vaccination in combination with lenalidomide and programmed death (PD)-1 blockade in a model of murine myeloma. MOPC-315 cell lines were injected subcutaneously to establish myeloma-bearing mice and the following five test groups were established: PBS control, DCs, DCs + lenalidomide, DCs + PD-1 blockade, and DCs + lenalidomide + PD-1 blockade. The combination of DCs plus lenalidomide and PD-1 blockade more potently inhibited tumor growth compared to the other groups. This effect was associated with a reduction in immune suppressor cells (such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells) and an increase in immune effector cells [such as CD4+ and CD8+ T cells, natural killer (NK) cells, and M1 macrophages] in the spleen. Functional activities of cytotoxic T lymphocytes and NK cells were also enhanced by the triple combination. Levels of immunosuppressive cytokines, such as TGF-β and IL-10, were significantly reduced in the tumor microenvironment. These findings suggest that the combination of DCs plus lenalidomide and PD-1 blockade synergistically establishes a robust anti-myeloma immunity through a two-way mechanism, which inhibits immunosuppressive cells while activating effector cells with superior polarization of the Th1/Th2 balance in favor of the tumor immune response. This result should provide an experimental ground for incorporating check point inhibitors to existing immunotherapeutic modalities against multiple myeloma.

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

“…The fundamental goal of immunotherapy in the treatment of MM is to boost tumor-specific immunity and eliminate malignant cells. Based on in vitro and preclinical studies, DC-based tumor vaccines have the potential to induce antimyeloma immunity mediated by CTLs ( 11 , 35 ). However, eliciting a clinically meaningful antitumor effect is challenging and the results remain inconclusive, with validation required in larger prospective randomized controlled studies ( 36 ).…”

“…Mouse models of myeloma are known to play a critical tool for studying the mechanisms of disease resistance, pathogenesis, and the development of new therapeutics against malignancies ( 35 , 40 – 42 ). This study has some limitation to interpret data due to subcutaneous injection of MOPC-315 cells for making plasmacytoma rather than BM involvement model for myeloma.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…200-205 The latter include (1) immune checkpoint blockers such as the anti-PD-1 mAbs pembrolizumab and nivolumab, 206-208 the anti-PD-L1 mAbs durvalumab and atezolizumab, 209-211 and the anti-CTLA4 mAb ipilimumab; 137,186,212-215 (2) immunostimulatory antibodies such as utomilumab, which stimulates TNF receptor superfamily member 9 (TNFRSF9; best known as 4-1BB or CD137) signaling, 28,216-218 or the CD27 agonist varlilumab; 28,216,219,220 and immunomodulatory agents such as lenalidomide. 221-224 In line with preclinical and clinical data demonstrating that multi-epitope vaccines are generally more powerful than their single-epitope counterparts, 117,225 the most common vaccination strategy employed by these studies consists in targeting simultaneously multiple TAAs (20 studies). Alongside, 15 studies are investigating the safety and efficacy of PPV, often consisting of MHC-matched peptides chosen from the immune repertoire of the patient before treatment.…”

Tumor-Associated Macrophages in Hematologic Malignancies: New Insights and Targeted Therapies

“…An early study showed lenalidomide suppressed the secretion CCL2 from NLCs and inhibited the survival support of NLCs for CLL cells in vitro [84]. A recent in vivo study showed that lenalidomide in combination with dendritic cell vaccination and anti-PD-1 blocking antibody decreased M2-TAMs with an associated reduction in TGF-β and IL-10 in the spleen of myeloma-bearing mice [85]. In several clinical trials for B-cell lymphoma, lenalidomide showed promising clinical efficacy either as a single agent or in combination with other immunotherapeutic agents [86][87][88][89].…”