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)-cl ass II molecules without coexpression of costimulatory B7 molecules on tumor cells, which impairs activation of T- and B-cells and, (b) rele ase of prostaglandins and other factors from tumor cells, that may inh ibit proliferation and function of helper T-cells; and (2) in the effe rent pathway; (c) release of tumor antigens, which blocks cytotoxic ce lls and antibodies and release of proteolytic enzymes, which degrades specific antibodies; (d) reduced expression of MHC-class I molecules b y tumor cells, which inhibits their recognition by cytotoxic T-lymphoc ytes (CTL); and (e) cell membrane-associated inhibitors of complement factors that block complement-mediated lysis. Altogether, the chance f or a successful tumor therapy by tumor vaccines has to be estimated to be low. Alternatives would be to use tumor antigens as tumor cell tar gets for cytotoxic compounds with differing action from the cytotoxic mechanisms used by the immune system. The problems of low tumor locali zation rates of tumor-specific monoclonal antibodies, immune resistanc e of the tumor cells, and general toxicity of cytotoxic drugs may be s olved by a biphasic therapeutic approach called immune specific enzyme -mediated chemotherapy. It uses, in a first phase, an appropriate anti body-enzyme fusion protein and, in the second phase, a nontoxic prodru g that is cleaved at the tumor site by the enzyme of the fusion protei n into the cytotoxic drug.