Introduction

In recent years, there has been a major emphasis on the development and application of active specific immunotherapy for the treatment of malignant diseases [1, 2], This trend reflects several reasons. First, the realization of the limitations of chemotherapy [3] in the treatment of malignant diseases has stimulated interest in testing alternative therapeutic modalities developed with antitumor associated antigen (TAA) monoclonal antibodies (mAb) and with cytotoxic cells [4-7]. Second, the identification of TAA with antibodies and cytotoxic T lymphocytes (CTL) and the characterization of their molecular properties [8-16] have provided well defined and standardized moieties to be used as immunogens in trials of active specific immunotherapy and as markers to monitor the immune response elicited in immunized patients. Lastly, the significant progress made in our understanding of the molecular events which lead to the development of an immune response [17] and the availability of cytokines [18] involved in these interactions have facilitated the development of immunization strategies to implement active specific immunotherapy of malignant diseases.

Since most, if not all, the TAA used as immunogens in patients with malignant diseases are self-antigens [19, 20], one of the major challenges facing active specific immunotherapy of malignant diseases is the development of strategies effective in breaking tolerance to a self-antigen. Among the many approaches, which are being tested, one relies on the immunization of hosts with antigens which are similar, but not identical to the original TAA. The working hypothesis underlying this strategy is that variants of poorly immunogenic TAA expressed by tumor cells may be immunogenic and may prime an immune response that cross reacts with the original TAA. The immunogens which have been shown to be effective in inducing immunity to a self-antigen include: (i) xenogeneic TAA which display a high degree of homology, but not complete identity in their amino acid sequence with a self-antigen [21, 22]; (ii) peptides derived from the amino acid sequence of the TAA which have been changed in the anchor residues to increase their affinity to MHC class I antigens and/or in amino acids that contact T-cell receptor [23-25]; and (iii) anti-idiotypic (anti-id) antibodies, which bear the internal image of TAA [26]. Since our work has focused on the evaluation of anti-id mAb as immunogens to implement active specific immunotherapy in patients with malignant melanoma [27], in this review we will first briefly discuss the rationale and the advantages and disadvantages of the use of anti-id antibodies as immunogens in active specific immunotherapy of malignant diseases. Then, we will review the results of clinical trials performed in patients with solid tumors, with anti-id antibodies which bear the internal image of TAA expressed by solid tumors. In the third section of this review, we will discuss the clinical significance of the cellular and humoral immunity elicited by anti-id antibodies. Finally, we will describe our approaches to overcome the limitations of active specific immunotherapy of malignant diseases with anti-id antibodies which bear the internal image of TAA.

Results obtained with anti-id antibodies related to human TAA systems and in patients with malignant diseases will be the focus of this review. Data obtained

Figure 1. Mimicry of a TAA determinant by an anti-id mAb. An 'internal image' anti-id mAb, elicited by an anti-TAA mAb, expresses an idiotope displaying a similar, but not identical shape as the epitope recognized by the anti-TAA mAb.

in animal model systems will be described and/or discussed only when they contribute to our understanding and interpretation of findings in humans.

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