Peptide vaccination in clinical oncology

Tumor-associated antigens recognized by cellular or humoral effecters of the immune system represent attractive targets for antigen-specific cancer therapy. Different groups of cancer-associated antigens have been identified inducing cytotoxic T-lymphocyte (CTL) responses in vitro and in vivo: 1) 'Cancer-Testis' (CT) antigens, which are expressed in different tumors and normal 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 antigens have been initiated to study the induction of specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e., delayed-type hypersensitivity (DTH), CTL, autoimmune, and tumor regression responses. Early results show that tumor-associated peptides alone induce specific DTH and CTL responses and tumor regression after intradermal administration. GM-CSF was used as an adjuvant to enhance peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Complete tumor regressions have been observed in the context of measurable peptide-specific CTL. However, in single cases with disease progression after an initial tumor response, either a loss of the respective tumor antigen targeted by CTL or of the presenting MHC class I allele was detected, suggesting immunization-induced immune escape. Based on these observations, cytokines to modify antigen and MHC class I expression in vivo are being tested to prevent immunoselection. Recently, a new CT antigen, NY-ESO-1, has been identified with a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX). NY-ESO-1 is regarded as one of the most immunogenic antigens known today, inducing spontaneous immune responses in 50% of patients with NY-ESO-1-expressing cancers. Clinical studies with antigenic constructs to induce both humoral and cellular immune responses will show whether these are more effective for immunotherapy of cancer.