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Immunotherapy of Cancer
Harvard Medical School, USA
It has been known for some time that immunotherapy is very effective in preventing and controlling tumor growth in animal model systems. The major player in these models is represented by tumor antigen-specific T cells. This information has provided the background to suggest the major role played by immunosurveillance in... read morethe control of tumor growth and by defects in immunosurveillance as one of the mechanisms underlying tumor growth.
It has been known for more than 20 years that in humans tumor antigen-specific monoclonal antibodies are effective in the treatment of some liquid and solid tumors. These clinical results are mediated by immunological and non-immunological mechanisms. Prominent among the latter is the ability of monoclonal antibodies to carry and target drugs and toxins to tumor cells and the inhibition of signalling transduction pathways. The former mechanisms include the ability of antibodies to activate NK cells and to trigger or enhance a tumor antigen-specific T cell response.
However the therapeutic effects are observed in only about 20% of patients with a given type of tumor. No biomarker is at present available to identify the patient population who is likely to experience a favourable clinical response to this type of therapy. Although the beneficial effects of tumor antigen-specific monoclonal antibody-based immunotherapy may be enhanced by combining the administration of monoclonal antibodies with that of chemotherapeutic agents and/or radiotherapy, in most, if not all the treated patients, clinical response has a limited duration because of recurrence of the disease and/or metastatic spread.
More recently a growing body of clinical evidence has shown that cell-based immunotherapy can be very effective in the treatment of various types of malignant diseases. Crucial to these exciting clinical results has been the major progress made in our understanding of i) the functional properties of T cell subpopulations, ii) the molecular basis of interactions of immune cells with tumor cells and iii) the molecular steps which lead to a tumor antigen-specific immune response.
An important role has also been played by the major technological advances which have facilitated the optimization of i) moieties to elicit and monitor a tumor antigen-specific immune response, ii) adjuvants to enhance the immunogenicity of tumor antigens, iii) monoclonal antibodies to modulate tumor antigen-specific immune response and iv) the engineering of antibodies to direct T cells to tumor cells. As a result clinical responses, some of which are long lasting, have been convincingly documented in an increasing number of patients.
Clinical and experimental evidence has shown that a major obstacle to the successful application of immunotherapy for the treatment of malignant diseases is represented by the escape mechanisms utilized by tumor cells to avoid recognition and destruction by the host’s immune system. Cellular and molecular studies have identified and characterized multiple escape mechanisms utilized by tumor cells. Among them are i) the inability of immune cells and/or antibodies to penetrate tumor masses, ii) the suppression of the generation of a tumor antigen-specific immune response and/or effector function of immune cells in the tumor microenvironment by regulatory T cells and/or suppressive cytokines, iii) the loss of targeted tumor antigens by tumor cells and/or iv) structural and/or functional abnormalities in the antigen processing machinery required for the presentation of tumor antigen derived peptides to host’s immune system.
It is also clear that escape mechanisms accumulate in tumor cells in the course of the disease, especially when the selective pressure imposed on tumor cell populations by therapeutic strategies facilitates the outgrowth of tumor cells which have acquired mechanisms to avoid immune recognition and destruction. These clinical findings emphasize the need to develop and apply targeted combinatorial strategies to counteract the multiple escape mechanisms utilized by tumor cells.