Vaccines for multiple myeloma

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3.1. Myeloma Cells and Tumor Antigens

MM, characterized by the clonal expansion of malignant plasma cells, is a fatal disease. It constitutes 10% of hematological malignancies in the United States and is more prevalent than lymphocytic leukemia, myelocytic leukemia, or Hodgkin's disease. Myeloma B lymphocytes are mature B cells. They may express, on the cell surface, Id Ig as well as MHC class I and II molecules and are sensitive to regulatory signals provided by cellular and humoral components of the Id-specific immune network (47). The majority of tumor cells in MM, however, are bone marrow-infiltrating myeloma plasma cells, which may not express surface Ig. Myeloma plasma cells secrete the idiotypic M-com-

ponent and express cytoplasmic Ig, which carries Id determinants. It has been shown that cytoplasmic Ig in mouse B-lymphoma and plasmacytoma cells is processed intracellu-larly and that degraded Id peptides are presented on the cell surface in the context of MHC molecules (48). Moreover, myeloma plasma cells may express MHC class I antigens (49,50); adhesion molecules, such as CD44, CD56, CD54, and VLA-4 (51,52); signaling or costimulatory molecules CD40 and CD28 (50,53,54); and the Fas antigen (CD95) (55). Some of the plasma cells also express HLA-DR, CD80, and CD86 (50). Our study showed that myeloma plasma cells were able to activate alloreactive T cells and present the recalled antigens, purified protein derivative, and tetanus toxoid to autologous T cells (50). Therefore, it is conceivable that myeloma plasma cells may also be subject to immune regulation, at least by the cellular components of the immune network (47).

Id proteins are myeloma-specific antigens and should evoke an immune response in patients (56). To prove this point, various approaches have been used (57-60). The presence of Id-specific T cells in the peripheral blood of patients with MM or with the benign form of the disease, monoclonal gammopathy of undetermined significance (MGUS), has been studied by detecting Id-induced T-cell proliferation and cytokine secretion with the enzyme-linked immunospot (ELISPOT) assay. Our results showed that Id-specific T cells could be detected in 90% of patients with MM or MGUS (61-63) and these T cells responded to peptides corresponding to complementarity-determining region (CDR) I-III of heavy and light chain of the autologous Id protein (64,65). Furthermore, we demonstrated that Id-specific T helper 1 (Th1)-type cells (interferon [IFN]-y- and/or interleukin [IL]-2-secreting cells) were significantly higher in patients with indolent disease (MGUS and MM stage I) than in those with advanced MM (stages II/III). In contrast, cells secreting the Th2-subtype cytokine profile (IL-4 only) were seen more frequently in patients with advanced MM (stages II/III) (66). Others have also reported a similar pattern of cytokine secretion (67). To examine whether Id-specific T cells can recognize myeloma cells, we generated Id-specific CTL lines from myeloma patients (68). The results showed that Id-specific CTLs not only recognized and lysed autologous Id-pulsed DCs but also significantly killed autologous primary myeloma cells (Fig. 1). The CTLs lysed the target cells mainly through the perforin-mediated pathway (data not shown). Consistent with these results, Li and coworkers (69) also showed that Id-specific CTLs, which consisted of both CD4+ and CD8+ T cells, lysed autologous myeloma cells, but not normal B cells or K562 cells. Thus, these studies provide a rationale for Id-based immunotherapy in MM.

Myeloma tumor cells may contain a multitude of tumor antigens that can stimulate an increased repertoire of antitumor T cells, possibly leading to stronger antimyeloma responses. To explore the possibility of using myeloma cells as the source of tumor antigens for immunotherapy in MM, we also generated autologous myeloma lysate-specific CTLs by culturing T cells with autologous DCs pulsed with myeloma tumor lysate (70). The CTL lines proliferated to autologous primary myeloma cells and DCs pulsed with autologous, but not allogeneic, tumor lysate (Fig. 2), and secreted predominantly IFN-a and tumor necrosis factor (TNF)-a, indicating that they belonged to the type-1 T cells (Th1 and T cytotoxic-1 [Tc1]). As depicted in Figure 3, CTLs had strong cytotoxic activity against autologous tumor lysate-pulsed DCs and primary myeloma cells. CTLs from some patients had no cytotoxic activity against Id-pulsed DCs but slightly lysed the allogeneic primary tumor cells, suggesting that Id was not necessarily

Fig. 1. Representative results depicting the cytotoxicity of Id-specific CTL lines generated from two patients against DCs pulsed with the autologous Id (Auto-Id-DCs), an allogeneic Id protein from the other patient (Allo-Id-DCs), unpulsed DCs (DCs only), or autologous primary myeloma cells (Auto-PC) or allogeneic myeloma cells (ALLO-PC), and K562. The effector-to-target cell ratio was 20:1.

Fig. 1. Representative results depicting the cytotoxicity of Id-specific CTL lines generated from two patients against DCs pulsed with the autologous Id (Auto-Id-DCs), an allogeneic Id protein from the other patient (Allo-Id-DCs), unpulsed DCs (DCs only), or autologous primary myeloma cells (Auto-PC) or allogeneic myeloma cells (ALLO-PC), and K562. The effector-to-target cell ratio was 20:1.

a part of the lysate antigens and that there were shared tumor antigens among patients. No killing of autologous peripheral blood mononuclear cells (PBMCs), purified B cells, or Epstein-Barr virus-transformed B-cell lines was observed. Consistent with our results, a recent study also showed that myeloma bone marrow-derived T cells, after ex vivo stimulation with autologous tumor-loaded DCs, could kill autologous myeloma cells, but not nonmyeloma cells in the bone marrow, myeloma cell lines, DCs loaded with Id protein, or allogeneic myeloma cells (71). Collectively, these data demonstrate that CTLs induced by tumor lysate-pulsed DCs specifically kill autologous tumor cells, but not normal PBMCs or B cells, and provide a rationale for vaccination with tumor cell-pulsed DCs in myeloma patients.

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