PubMed2001
The concept of immunotherapy of cancer is more than a century old, but only recently have molecularly defined therapeutic approaches been developed. In this review, we focus on the most promising approach, active therapeutic vaccination. The identification of tumour antigens can now be accelerated by methods allowing the amplification of gene products selectively or preferentially transcribed in the tumour. However, determining the potential immunogenicity of such gene products remains a demanding task, since major histocompatibility complex (MHC) restriction of T cells implies that for any newly defined antigen, immunogenicity will have to be defined for any individual MHC haplotype. Tumour-derived peptides eluted from MHC molecules of tumour tissue are also a promising source of antigen. Tumour antigens are mostly of weak immunogenicity, because the vast majority are tumour-associated differentiation antigens already 'seen' by the patient's immune system. Effective therapeutic vaccination will thus require adjuvant support, possibly by new approaches to immunomodulation such as bispecific antibodies or antibody-cytokine fusion proteins. Tumour-specific antigens, which could be a more potent target for immunotherapy, mostly arise by point mutations and have the disadvantage of being not only tumour-specific, but also individual-specific. Therapeutic vaccination will probably focus on defined antigens offered as protein, peptide or nucleic acid. Irrespective of the form in which the antigen is applied, emphasis will be given to the activation of dendritic cells as professional antigen presenters. Dendritic cells may be loaded in vitro with antigen, or, alternatively, initiation of an immune response may be approached in vivo by vaccination with RNA or DNA, given as such or packed into attenuated bacteria. The importance of activation of T helper cells has only recently been taken into account in cancer vaccination. Activation of cytotoxic T cells is facilitated by the provision of T helper cell-derived cytokines. T helper cell-dependent recruitment of elements of non-adaptive defence, such as leucocytes, natural killer cells and monocytes, is of particular importance when the tumour has lost MHC class I expression. Barriers to successful therapeutic vaccination include: (i) the escape mechanisms developed by tumour cells in response to immune attack; (ii) tolerance or anergy of the evoked immune response; (iii) the theoretical possibility of provoking an autoimmune reaction by vaccination against tumour-associated antigens; and (iv) the advanced age of many patients, implying reduced responsiveness of the senescent immune system.