Idiotypic vaccination for B-cell malignancies as a model for therapeutic cancer vaccines: From prototype protein to second generation vaccines

Background and Objectives. Cancer vaccines are aimed at inducing tumor-specific immunity by immunizing patients with tumor cells or their antigenic components, known as tumor-associated antigens (TAA). Antigens which are either mutated or selectively or abundantly expressed in malignant, but not in normal, cells are considered as TAA. Each patient's B-cell malignancy is usually derived from a single expanded B-cell clone, which expresses an immunoglobulin (Ig) with a unique idiotype (Id, variable regions of Ig). Therefore, Id can be regarded as a TAA and a potential target in clinical vaccination approaches. Although use of tumor-derived Id as an immunogen to elicit antitumor immunity against B-cell malignancies is an attractive idea, the broader use of idiotypic vaccines has been hampered by the fact that autologous Id is not only a weakly immunogenic, self antigen, but is also patient-specific so that the vaccine must be individually prepared for each patient. In this review we will first summarize the latest data from the clinical tests of experimental idiotypic vaccines and discuss issues relevant to the clinical application of cancer vaccines in general; we will then critically review new trends and achievements in the development of the second generation vaccine formulations. Evidence and information sources. The authors of the present review are currently working in the field of B-cell tumor immunotherapy and have contributed original papers to peer-reviewed journals. The material analyzed in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. State of Art. The results from a number of experimental models and clinical trials have demonstrated that vaccination with tumor-derived Id can induce immune responses directed against the tumor. Idiotypic vaccines can be divided into two types, although both are at the experimental stage: traditional and second generation, based on the methods of production and vaccine delivery. Second generation vaccines utilizing genetically engineered protein and DNA formulations have, for the first time, opened up the possibility of streamlining production of simpler and effective custom-made idiotypic vaccines. The use of various adjuvants and exogenous carriers is being replaced by more potent genetic carriers which target Id and various co-stimulatory molecules to professional antigen presenting cells (APC), particularly dendritic cells (DC). Perspectives. Id is the only widely accepted tumor marker and is a promising therapeutic target for immunotherapy of B-cell malignancies. It has been unequivocally established that Id vaccination of patients with follicular lymphoma administered when patients have minimal residual disease, has antitumor effect and potential to improve the clinical outcome. Consequently, the applicability of Id vaccines for other B-cell malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma needs to be tested. Idiotypic vaccines should be tailored to target preferentially various subsets of immune cells, such as DCs, which would up take and properly process and present Id, activating both arms of the immune system, humoral and cellular. Moreover, the vaccine should induce the production of a milieu of inflammatory cytokines and lymphokines at the delivery site to elicit a T helper type 1 (Th1) immune response. Components of the inflammatory response can be used to target DCs in vivo, activating the so-called danger signal for circumventing the poor immunogenicity of self-tumor antigens. For example, chemotactic factors of innate immunity are able to deliver Id to APC and render this otherwise non-immunogenic antigen immunogenic. The strategies developed for Id vaccines can be used as a general strategy for eliciting T-cell immunity to other weakly immunogenic, clinically relevant self-tumor antigens.