Immune responses to tumour antigens: implications for antigen specific immunotherapy of cancer

Tumour associated antigens recognised by cellular or humoral effectors of t he immune system are potential targets for antigen specific cancer immunoth erapy. Different categories of cancer antigens have been identified that in duce cytotoxic T lymphocyte (CTL) responses in vitro and in vivo, namely: ( 1) "cancer testis" (CT) antigens, expressed in different tumours and normal testis, (2) melanocyte differentiation antigens, (3) point mutations of no rmal genes, (4) self antigens that are overexpressed in malignant tissues, and (5) viral antigens. Clinical studies with peptides and proteins derived from these antigens have been initiated to study the efficacy of inducing specific CTL responses in vivo. Immunological and clinical parameters for t he assessment of antigen specific immune responses have been defined-delaye d type hypersensitivity (DTH), CTL, autoimmmune, and tumour regression resp onses. Specific DTH and CTL responses and tumour regression have been obser ved after the intradermal administration of tumour associated peptides alon e. Peptide specific immune reactions were enhanced after using granulocyte macrophage stimulating factor (GM-CSF) as a systemic adjuvant by increasing the frequency of dermal antigen presenting Langerhans cells. Complete tumo ur regression has been observed in the context of measurable peptide specif ic CTL. However, in single cases with disease progression after an initial tumour response, either a loss of single antigens targeted by CTL or of the presenting major histocompatibility complex (MHC) class I allele was detec ted, pointing towards immunisation induced immune escape. Cytokines to modu late antigen and MHC class I expression in vivo are being evaluated to prev ent immunoselection. Recently, a new CT antigen, NY-ESO-1, has been identif ied on the basis of spontaneous antibody responses to tumour associated ant igens. NY-ESO-1 appears to be one of the most immunogenic antigens known to date, with spontaneous immune responses observed in 50% of patients with N Y-ESO-1 expressing cancers. Clinical studies have been initiated to evaluat e the immunogenicity of different NY-ESO-1 constructs to induce both humora l and cellular immune responses in vivo.