Peptide vaccination in clinical oncology

Tumor-associated antigens recognized by cellular or humoral effecters of th e immune system represent attractive targets for antigen-specific cancer th erapy. Different groups of cancer-associated antigens have been identified inducing cytotoxic T-lymphocyte (CTL) responses in vitro and in vivo: 1) 'C ancer-Testis' (CT) antigens, which are expressed in different tumors and no rmal testis, 2) melanocyte differentiation antigens, 3) point mutations of normal genes, 4) antigens that are overexpressed in malignant tissues, and 5) viral antigens. Clinical studies with peptides derived from these antige ns have been initiated to study the induction of specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-s pecific reactions have been defined, i.e., delayed-type hypersensitivity (D TH), CTL, autoimmune, and tumor regression responses. Early results show th at tumor-associated peptides alone induce specific DTH and CTL responses an d tumor regression after intradermal administration. GM-CSF was used as an adjuvant to enhance peptide-specific immune reactions by amplification of d ermal peptide-presenting dendritic cells. Complete tumor regressions have b een observed in the context of measurable peptide-specific CTL. However, in single cases with disease progression after an initial tumor response, eit her a loss of the respective tumor antigen targeted by CTL or of the presen ting MHC class I allele was detected, suggesting immunization-induced immun e escape. Based on these observations, cytokines to modify antigen and MHC class I expression in vivo are being tested to prevent immunoselection. Rec ently, a new CT antigen, NY-ESO-1, has been identified with a strategy util izing spontaneous antibody responses to tumor-associated antigens (SEREX). NY-ESO-1 is regarded as one of the most immunogenic antigens known today, i nducing spontaneous immune responses in 50% of patients with NY-ESO-1-expre ssing cancers. Clinical studies with antigenic constructs to induce both hu moral and cellular immune responses will show whether these are more effect ive for immunotherapy of cancer.