Vaccination for treatment of tumors: a critical comment

Tumors are resistant to the immune response as evidenced by both their progressive growth in patients despite specific humoral and cellular immune responses to tumor antigens and by the moderate clinical effect of active specific immunotherapy with tumor vaccines tested to date. This "immune resistance" may be due to various reasons, among which the most important ones are: (1) in the afferent pathway of the immune response, (a) expression of major histocompatibility complex (MHC)-class II molecules without coexpression of costimulatory B7 molecules on tumor cells, which impairs activation of T- and B-cells and, (b) release of prostaglandins and other factors from tumor cells, that may inhibit proliferation and function of helper T-cells; and (2) in the efferent pathway; (c) release of tumor antigens, which blocks cytotoxic cells and antibodies and release of proteolytic enzymes, which degrades specific antibodies; (d) reduced expression of MHC-class I molecules by tumor cells, which inhibits their recognition by cytotoxic T-lymphocytes (CTL); and (e) cell membrane-associated inhibitors of complement factors that block complement-mediated lysis. Altogether, the chance for a successful tumor therapy by tumor vaccines has to be estimated to be low. Alternatives would be to use tumor antigens as tumor cell targets for cytotoxic compounds with differing action from the cytotoxic mechanisms used by the immune system. The problems of low tumor localization rates of tumor-specific monoclonal antibodies, immune resistance of the tumor cells, and general toxicity of cytotoxic drugs may be solved by a biphasic therapeutic approach called immune specific enzyme-mediated chemotherapy. It uses, in a first phase, an appropriate antibody-enzyme fusion protein and, in the second phase, a nontoxic prodrug that is cleaved at the tumor site by the enzyme of the fusion protein into the cytotoxic drug.