Immunotherapy of malignant diseases. Challenges and strategies

In recent years, there has been growing interest in the application of immunotherapy as an alternative to chemotherapy and radiotherapy for the treatment of malignant diseases. This interest is due to a variety of factors, including revival of the immunosurveillance theory, availability of well-defined and structurally characterized human tumor-associated antigens (TAAs), progress in our understanding of the molecular pathways required for induction and maintenance of an immune response, and advances in methodologies to generate TAA-specific cytotoxic T lymphocytes (CTLs) and monoclonal antibodies (mAbs) as immunological probes. However, contrary to the positive results obtained with TAA-specific immunotherapy in animal model systems, the clinical response in patients has been disappointing. Frequently, the immune responses do not correlate with the clinical responses. Analysis of the underlying mechanisms of this dichotomy have identified the low immunogenicity of TAAs, the lack of immunological markers to predict clinical outcomes, and the ability of tumors to escape immune recognition and destruction as challenges to the development and application of immunotherapy. In this paper, we have reviewed the mechanisms underlying immune unresponsiveness to TAAs and strategies to overcome this unresponsiveness in the humoral and cellular immune responses, highlighting findings from different antigenic systems to prove the validity of these strategies. Additionally, we have addressed limitations to TAA-targeting immunotherapy as a result of the genetic instability of tumor cells, and have discussed strategies to overcome this limitation by targeting immunotherapy to molecules implicated in tumor-associated angiogenesis. Lastly, we have concluded by indicating the need to refine the implementation of clinical trials of immunotherapy, and to emphasize combination therapies to counteract the multiple tumor escape mechanisms.