Cancer immunotherapy in clinical oncology

The identification of tumor-associated antigens recognized by cellular or h umoral effecters of the immune system has opened new perspectives for cance r therapy. Different groups of cancer-associated antigens have been describ ed as targets for cytotoxic T lymphocytes (CTLs) in vitro and in vivo: 1) c ancer-testis (CT) antigens, which are expressed in different tumors and nor mal testis; 2) melanocyte differentiation antigens; 3) point mutations of n ormal genes: 4) antigens that are overexpressed in malignant tissues; and 5 ) viral antigens. Clinical studies with peptides derived from these antigen s have been initiated to induce specific CTL responses in vivo. Immunologic al and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e., delayed-type hypersensitivity (DTH). CTL, autoimm une, and tumor regression responses. Preliminary results demonstrate that t umor-associated peptides alone elicit specific DTH and CTL responses leadin g to turner regression after intradermal injection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was proven effective in enhancing peptid e-specific immune reactions by amplification of dermal peptide-presenting d endritic cells. Long-lasting complete tumor regressions have been observed after induction of peptide-specific CTLs. However, in single cases with dis ease progression after an initial tumor response, either a loss of the resp ective tumor antigen targeted by CTLs or of the presenting major histocompa tibility complex (MHC) class I allele was detected as a mechanism of immune escape under immunization. Based on these observations, cytokines to enhan ce antigen and MWC class I expression in vivo are being evaluated to preven t immunoselection. Recently, a strategy utilizing spontaneous antibody resp onses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1, which is regarded as one of the most immunogen ic antigens known today inducing spontaneous immune responses in 50% of pat ients with NY-ESO-1-expressing cancers. Clinical studies involving antigeni c constructs that induce both antibody and CTL responses will show whether these are more effective for immunotherapy of cancer.