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: 3.94). 06/2012; 62(1). DOI: 10.1007/s00262-012-1308-3
Source: PubMed


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.

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    • "In recent years, the great progresses in our understanding of the basic processes that control immune tolerance, as well as the more recent characterization of naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg), that tip the balance between auto- and tumor immunity, opened the door to their therapeutic application, either by enhancing their activity in autoimmune diseases [1–3], allograft rejection [3], and graft-versus-host disease (GVHD) [4, 5] or by blocking their suppressive activity in tumor immunity [6] and in vaccine development [7]. Treg therapy has the promise of avoiding many of the toxicities observed with current drug regimens. "
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    ABSTRACT: Multiple myeloma is a life-threatening haematological malignancy for which standard therapy is inadequate. Autologous stem cell transplantation results in effective cytoreduction, but patients subsequently relapse from sites of chemotherapy-resistant disease. Allogeneic transplantation may result in durable responses due to anti-tumour immunity mediated by donor lymphocytes. However, morbidity and mortality related to graft-vs-host disease remains a challenge. A promising area of investigation is the development of immunotherapeutic approaches that target and eliminate myeloma cells more selectively. A variety of tumour-associated antigens have been identified in myeloma cells that may be targeted selectively by host immunity. Vaccination strategies targeting single antigens and whole-cell approaches, which have the advantage of presenting patient-specific and potentially unidentified antigens to immune effector cells, have shown promise in clinical studies. In addition, the use of monoclonal antibodies has been evaluated in preclinical and clinical studies. Effector cell dysfunction and the increased number of regulatory T cells in patients with malignancy may limit the efficacy of immunotherapeutic approaches. Strategies to improve upon immunotherapy for multiple myeloma involve the depletion of T regulatory cells, combining active and passive immunotherapy, the use of cytokine adjuvants, and using immunotherapy in conjunction with autologous and allogeneic transplantation.
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    ABSTRACT: The promise of cellular therapy as treatment for multiple myeloma is highlighted by the observation that allogeneic transplantation results in durable remissions in a subset of patients. The potency of the graft-versus-myeloma effect is supported by the decreased risk of relapse seen in patients with graft-versus-host disease and disease response following donor lymphocyte infusions. However, the lack of specificity of the alloreactive lymphocytes limits their therapeutic efficacy and results in significant treatment-related morbidity and mortality. A major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity that selectively targets malignant cells while minimizing toxicity to normal tissues. Critical elements required to develop an effective vaccine strategy involve the identification of myeloma-associated antigens, enhancement of antigen presentation, and reversing the immunosuppressive milieu induced by the disease. Dendritic cells are potent APCs that represent an ideal platform for vaccination. Strategies for vaccine design include the loading of individual antigens as well as the use of whole tumor cells as a source of myeloma antigens. Vaccination has been examined in the postautologous transplant setting in which disease cytoreduction and depletion of Tregs is associated with enhanced vaccine response. Recent efforts have also included exploration of immune modulatory agents that target inhibitory pathways to enhance vaccine response and create a more durable antitumor immunity.
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