**1. Introduction**

Multiple myeloma (MM) is a clonal B-cell malignancy that is currently incurable with con‐ ventional chemotherapy, even if high-dose chemotherapy with autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and the development of novel molecular target agents have resulted in a marked improvement in overall survival [1, 2]. Allogeneic HSCT, which induces a clinically significant immune-mediated allogeneic graft-versusmyeloma (GVM) effect, has provided the framework for the development of immunothera‐ peutic strategies [3, 4]. To prolong the survival of patients with MM, who are undergoing allogeneic HSCT, a donor lymphocyte infusion can be used successfully as a salvage therapy, which is based on the GVM effect in some cases of MM that relapse after allogeneic HSCT [5, 6]. A clinically significant immune-mediated GVM effect provides the framework for the development of immune-based therapeutic options that use antigen-presenting cells (APCs) with increased potency, such as dendritic cells (DCs), in MM [6].

DCs are the most potent APCs for initiating cellular immune responses through the stimulation of naive T cells. Because of their ability to stimulate T cells, DCs act as links between innate immunity and adaptive immunity in antitumor immune responses [7]. DCs orchestrate a variety of immune responses by stimulating the differentiation of naïve CD4+ T cells into helper T effectors such as Th1, Th2 or Th17 type [8, 9]. Cytokines secreted by DCs at the time of initial T cell stimulation play an important role in the subsequent differentiation of effector T cells. Th1 cells, through interferon-gamma (IFN-γ) production, regulate antigen presentation and immunity against intracellular pathogens [8]. DC-based vaccines have become the most attractive tools for cancer immunotherapy and have been used in more than 20 malignancies; most commonly melanoma, renal cell carcinoma, prostate cancer and colorectal carcinoma

© 2013 Lee et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[10]. Cellular immunotherapy using DCs is emerging as a useful immunotherapeutic modality to treat MM [11]. While antigen-specific cytotoxic T lymphocytes (CTLs) and immune response can be induced by DC vaccination in MM patients, clinical responses so far have been largely unsatisfying to be observed only in a minority of treated patients with MM. Progress in understanding DC biology in cancer patients and the recruitment of suppressive cells of the adaptive and innate immune system in antitumor immunity of cellular immunotherapy is leading to new concept which aims at improved immune and clinical outcomes in MM. New concept is developing to generate novel therapeutic targets that could restore DC capacity to prime T cells and trigger effective anticancer responses in combination with other therapies to offset tumor-induced suppression in MM.

of natural killer (NK) cells and NKT cells responses [16-19]. In addition, the recruitment and

increased in MM patients at diagnosis, resulting in a significant impediment of immune cells

Usually, *ex vivo* DCs were generated from circulating blood precursors (i.e. monocytes) or bone marrow progenitor cells and educated them with myeloma-associated antigens prior to

Immunoglobulin idiotype (Id) is a tumor-specific antigen that is produced by each B cell tumor clone. Id protein has been used for immunotherapy in patients with MM [23, 24]. Id vaccination could induce immune responses by both antibodies and Id-specific T cells, including CD4+ and CD8+ T cells, through the presentation of Id protein on the surface of professional APCs [24]. Id-specific CTL lines that kill autologous primary myeloma cells *in vitro* have been generated [25, 26]. Autologous DCs that were generated from MM patients have been shown to efficiently endocytose different classes of Id proteins, and autologous Id-specific CTLs that were gener‐ ated by Id-pulsed DCs were able to recognize and kill autologous primary myeloma cells *in vitro* [25, 26]. Various studies of DC-based Id vaccination in MM have been reported [27-34]. Although Id-specific CTLs and immune responses could be induced in some patients, clinical responses have rarely been observed after vaccination possibly because Id protein is a weak

In general, the production of DC vaccines using whole tumor antigens has become a promising tool for immunotherapy against MM. There are several types of myeloma-associated antigen for loading onto DCs: loading with myeloma lysates [35, 36], loading with dying myeloma cells [37-39], transfection with myeloma-derived RNA [40], pulsing with myeloma-derived heat shock protein (HSP) gp96 [41, 42], and hybridization with myeloma cells [43, 44]. These techniques have the advantage of allowing the presentation of multiple epitopes to MHC on DCs, therefore inducing polyclonal T cell responses from many potentially unknown tumorassociated antigens (TAAs) and reducing the probability of immune escape by a single TAA. Various myeloma-associated antigens that may induce immune responses from DC-based vaccines have been identified in MM patients. MUC1-specific CTLs that were induced *in vitro* using peptide-pulsed DCs or plasma cell RNA-loaded DCs efficiently killed not only target cells pulsed with the antigenic peptide but also MM cells [40, 45]. DCs transfected with

been reported in MM patients [20, 21]. More recently, the proportion of CD14+

myeloid-derived suppressor cells (MDSCs) and CD4+

**3. Current DC vaccination research in MM**

antigen and immature DCs have been used in some studies [27].

**3.2. Myeloma-associated antigens-based DC immunotherapy**

PTD-NY-ESO-1 protein can induce CD8+

related to cancer immunotherapy [22].

vaccination to patients with MM.

**3.1. Idiotype-pulsed DCs**

CD25+ regulatory T cells (Tregs) in the suppression of tumor immunity has

Cellular Immunotherapy Using Dendritic Cells in Multiple Myeloma: New Concept to Enhance Efficacy

HLA-DR-

http://dx.doi.org/10.5772/54100

forkhead box P3 (FoxP3)+ Tregs cells was

cellular antitumor immunity superior to that

/ low 181

expansion of CD4+

#### **2. Dendritic cell in myeloma immunity**

DCs have a potent antigen-specific T cell stimulatory capacity and therefore should be considered to the one of the promising antitumor immunotherapeutic options. In tumorspecific immunity, secreted products or fragments from tumor cells enter into DCs through the endosome and are processed and presented on MHC class molecules of DCs [12]. Processed antigens presented on these molecules of DCs are recognized by CD4+ T helper cells, which not only enhance to the CD8+ T cell response but also facilitate to develop a humoral immune response for surface antigens expressed on the tumor cells. The antigens presented on MHC class I are recognized by CD8+ CTLs, which have a direct cytotoxic effect on tumor cells. Unfortunately, patients with MM have basically dysfunctional DCs that are functionally defective, evidenced by the decreased number of circulating precursors of DCs as well as the impaired T cell stimulatory capacities compared with normal controls [13, 14]. The defective functions of DCs in patients with MM are partially attributed to the production of IL-6 and other tumor-derived factors. DCs in MM patients are a target of tumor-associated suppressive factors, such as IL-10, transforming growth factor- beta (TGF-β), vascular endothelial growth factor (VEGF), and IL-6, resulting in their aberrant functions and impaired development of effector functions in tumor-specific lymphocytes [15]. There were only few patients with MM who responded clinically to vaccination with antigen-loaded autologous DCs. There may be several reasons for this failure from MM patients itself. MM is believed to induce immunopa‐ resis that interferes with DC function and hence affects the effective antitumor immune responses in these patients. They are able to escape immune surveillance by down-regulation of immune markers as well as through the production of immunosuppressive cytokines by the tumor cells or by activation of suppressor cells such as regulatory T cells and myeloid cells. Myeloma cells can produce immuno-inhibitory cytokines, such as IL-10, TGF-β, VEGF, and IL-6, which play major roles in the pathogenesis of MM [15]. In addition, the survival and proliferation of myeloma cells are partially facilitated by impaired endogenous immune surveillance against tumor antigens, including the abrogation of DC function, by constitutive activation of the signal transducer and activator of transcription 3 (STAT3) [13]. Impairment in both humoral and cellular immunity in MM is associated with impaired B cell responses; decreased T cell numbers including CD4+ T cells and impaired CTL responses; and dysfunction of natural killer (NK) cells and NKT cells responses [16-19]. In addition, the recruitment and expansion of CD4+ CD25+ regulatory T cells (Tregs) in the suppression of tumor immunity has been reported in MM patients [20, 21]. More recently, the proportion of CD14+ HLA-DR- / low myeloid-derived suppressor cells (MDSCs) and CD4+ forkhead box P3 (FoxP3)+ Tregs cells was increased in MM patients at diagnosis, resulting in a significant impediment of immune cells related to cancer immunotherapy [22].
