Lenalidomide enhances anti-myeloma cellular immunity.

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA, 02215, USA, .
Cancer Immunology and Immunotherapy (Impact Factor: 3.64). 06/2012; 62(1). DOI: 10.1007/s00262-012-1308-3
Source: PubMed

ABSTRACT Lenalidomide is an effective therapeutic agent for multiple myeloma that exhibits immunomodulatory properties including the activation of T and NK cells. The use of lenalidomide to reverse tumor-mediated immune suppression and amplify myeloma-specific immunity is currently being explored. In the present study, we examined the effect of lenalidomide on T-cell activation and its ability to amplify responses to a dendritic cell-based myeloma vaccine. We demonstrate that exposure to lenalidomide in the context of T-cell expansion with direct ligation of CD3/CD28 complex results in polarization toward a Th1 phenotype characterized by increased IFN-γ, but not IL-10 expression. In vitro exposure to lenalidomide resulted in decreased levels of regulatory T cells and a decrease in T-cell expression of the inhibitory marker, PD-1. Lenalidomide also enhanced T-cell proliferative responses to allogeneic DCs. Most significantly, lenalidomide treatment potentiated responses to the dendritic cell/myeloma fusion vaccine, which were characterized by increased production of inflammatory cytokines and increased cytotoxic lymphocyte-mediated lysis of autologous myeloma targets. These findings indicate that lenalidomide enhances the immunologic milieu in patients with myeloma by promoting T-cell proliferation and suppressing inhibitory factors, and thereby augmenting responses to a myeloma-specific tumor vaccine.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The adaptive immune system is clearly capable of recognizing and attacking malignant plasma cells in patients with multiple myeloma (MM). However, MM patients evidence severe defects of humoral as well as cellular immunity and it is likely that the profound immune dysregulation typical for this malignancy contributes to its eventual escape from natural immune control. One of the factors responsible for the immune dysfunction in MM might be the programmed death 1 (PD-1) protein. The physiological role of PD-1 is to guarantee T cell homeostasis by limiting T cell activation and proliferation. Accordingly, binding of the ligand PD-L1 to PD-1 expressed on the surface of activated T cells delivers an inhibitory signal, reducing cytokine production and proliferation. Using the same mechanism, PD-L1/PD-1 interactions have been shown in a number of animal models to confer tumor escape from immune control. Recently, clinical trials have suggested a significant therapeutic impact of PD-1/PD-L inhibition on a variety of solid tumors, e.g. by the application of monoclonal antibodies. We show here that based on the (1) broad expression of PD-1 and its ligands in the microenvironment of myeloma, (2) data indicating an important role of the PD-1 pathway in the immune evasion by MM cells, and (3) preclinical results providing a strong rationale for therapeutic PD-1/PD-L inhibition in this malignancy, MM may be very well suited for an immunotherapy, e.g. a monoclonal antibody, targeting PD-1 and/or its ligands.Leukemia accepted article preview online, 23 October 2013; doi:10.1038/leu.2013.310.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2013; · 10.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Immunomodulatory drugs (IMiDs) are effective therapeutic agents with direct inhibitory effects on malignant B- and plasma cells and immunomodulatory effects on the T cell activation. This dual function of IMiDs makes them appealing candidates for combination with a cancer vaccine. We investigated the immune stimulatory effects of lenalidomide, administrated to mice in doses which provided comparable pharmacokinetics to human patients, on the potency of a novel fusion DNA lymphoma vaccine. The combination was curative in the majority of mice with 8d pre-established syngeneic A20 lymphomas, compared with vaccine or lenalidomide alone and induced immune memory. In vivo depletion experiments established the requirement for effector CD8+ and CD4+ T cells in protective immunity. Unexpectedly, lenalidomide alone was also associated with reduced numbers of systemic MDSC and Treg in tumor-bearing, but not naïve mice, an effect that was independent of simple tumor burden reduction. These results confirm and extend results from other models describing the effect of lenalidomide on enhancing T-cell immunity highlight the potency of this effect, and provide a rational for clinical application. Independently, a novel mechanism of action reversing tumor-induced immune suppression by MDSC is suggested.Leukemia accepted article preview online, 14 June 2013; doi:10.1038/leu.2013.177.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2013; · 10.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both "passive" (e.g. strategies relying on the administration of specific T cells) and "active" vaccines (e.g. peptide-directed or whole-cell vaccines) have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines) are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target "immunosuppressive checkpoints" (anti-CTLA-4, PD-1, etc.) is likely to improve and maintain immune response induced by vaccination.
    Rambam Maimonides medical journal. 10/2014; 5(4):e0024.