Tumor antigen immunization of sibling stem cell transplant donors in multiple myeloma

Experimental and Transplantation Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Bone Marrow Transplantation (Impact Factor: 3.47). 09/2005; 36(4):315-23. DOI: 10.1038/sj.bmt.1705057
Source: PubMed

ABSTRACT The unique antigenic determinants (idiotype (Id)) of the immunoglobulin secreted by myeloma tumor can serve as a tumor-specific antigen for active immunotherapy. Our objective was to induce tumor-specific T-cell immunity in bone marrow transplant (BMT) donors to enhance antitumor effects of allografts. We vaccinated five HLA-matched sibling donors with myeloma Id proteins isolated from recipient plasma before bone marrow harvest. Recipients were administered booster Id immunizations following transplantation. Vaccination induced donor Id and carrier-specific cellular and/or humoral immune responses. Two recipients died within 30 days of BMT from transplant-related complications. Id and carrier-specific T-cell responses were detected in all three remaining patients post-, but not pre-BMT and persisted for 18 months. All three surviving patients converted from partial to complete responses following BMT. Two of the three patients remain disease-free 7 years and 8 years after BMT, and the third died of renal failure after 5.5 years while in complete remission from myeloma. Our results suggest that myeloma Id vaccination induces specific T-cell immunity in healthy donors which may be transferable by BMT, is associated with prolonged disease-free survival of recipients, and may represent a general strategy to enhance graft-versus-tumor effect in other malignancies for which defined tumor-specific antigens exist.

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    ABSTRACT: Multiple myeloma is still a fatal disease. Despite advances in high-dose chemotherapy and stem-cell transplantation and the development of novel therapeutics, relapse of the underlying disease remains the primary cause of treatment failure. Strategies for posttransplantation immunomodulation are desirable for eradication of remaining tumor cells. To this end, immunotherapy aimed at inducing myeloma-specific immunity in patients has been explored. Idiotype protein, secreted by myeloma cells, has been the primary target for immunotherapy as it is the best defined tumor-specific antigen. This chapter focuses on novel immunotherapies that are being developed to treat patients with myeloma. I will discuss potential myeloma antigens, antigen-specific T cells, and their function on myeloma tumor cells, and T-cell-based and antibody-based immunotherapies for myeloma. Furthermore, clinical studies of T-cell-based immunotherapy in the form of vaccination, allogeneic stem-cell transplantation and donor lymphocyte infusions, with or without donor vaccination using patient-derived idiotype, and future application of donor-derived or patient-derived, antigen-specific T-cell infusion in this disease are also discussed. Based on the specificity of the immune effector molecules and cells, immunotherapies with specific T cells or therapeutic antibodies may represent novel strategies for the treatment of multiple myeloma in the near future.
    The Cancer Journal 01/2009; 15(6):502-10. DOI:10.1097/PPO.0b013e3181c51f0d · 3.61 Impact Factor
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is a curative therapy for a variety of hematological malignancies including acute and chronic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma [1]. In addition, better disease control and improved survival can be achieved in patients with multiple myeloma (MM), though it is presently unclear whether patients can be cured with HSCT [2]. However, relapse of the underlying malignant disease is still a significant clinical problem. After autologous HSCT, the relapse rate is as high as 60% while after allogeneic HSCT up to 30% of patients relapse [3]. If relapse occurs, the prognosis is generally poor. Thus, new and more effective treatments of relapse and/or means of preventing relapse are urgently needed. It is widely believed that much of the success of allogeneic HSCT for patients with leukemia and lymphoma is due to the graft-versus-leukemia (GVL) effect [4]. This belief is based on the observations that GVHD correlates with superior disease control [4] and that clinical responses result from maneuvers such as infusions of donor lymphocytes and withdrawing immunosuppression [5]. The target antigens recognized by the donor immune system are not well-characterized and certainly are not identified in routine clinical practice [6].
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