Anticancer vaccination strategies

Tumors often upregulate the expression of molecules that are normally suppressed or expressed at much lower levels in adult tissues, the so-named tumor-associated antigens (TAAs) [1]. Some ‘self-reactive’ T lymphocytes capable of T-cell receptor (TCR)-mediated recognition of these antigens and of mediating tumor rejection survive thymic selection and can be detected in peripheral blood and lymphoid tissues. Indeed, cases of spontaneous immune-mediated tumor regressions are reported, especially for melanoma, renal cell carcinoma and tumors presenting with neurological paraneoplastic syndromes, especially non-small-cell lung cancer [1–3]. However, in most cases, the immune system fails to recognize and destroy tumor cells, possibly due to the inefficiency of these as antigen-presenting cells (APCs), and to the lack of contact between tumor cells and the immune system [4, 5]. Now that knowledge of the immune system has improved, new perspectives for the development of active antitumor immunization strategies have been proposed. The main goal of these approaches is to expand in the patients CD8+ cytotoxic T lymphocytes (CTLs) capable of rejecting tumor cells via recognition of tumor-associated antigenic epitopes expressed by human leukocyte antigen (HLA) class I molecules on the cancer cells. However, optimal immunotherapeutic approaches should probably also prime CD4+ helper T cells, given the key role that these cells play in the control of immune responses [1]. The antigenic material used in anticancer vaccinations can be in the form of whole tumor material (either allogeneic or autologous) or of specific TAAs, which are delivered as DNA (naked or comprised in recombinant viruses), RNA, protein or HLA class I/II restricted peptide epitopes [1]. Many of these antigenic materials can be injected directly, often coupled to immunostimulatory cytokines or adjuvants, or used for ex vivo loading of APCs, usually dendritic cells (DCs) (Figure 1). These are specialized APCs with the capacity to initiate an immune response by presenting antigen-derived epitopes to T lymphocytes in a highly immunogenic fashion [6–9]. All of the antitumor vaccination approaches are believed to ultimately depend on the presentation of tumor-derived antigen(s) to T cells by DCs in the patient’s lymphoid tissues [10]. For the biology of DCs and the applications of ex vivo manipulated DCs to cancer immunotherapy we refer the reader to the review by Lesterhuis et al. [11] in this Supplement. Here, we mainly focus on the non-DC-based approaches that are currently evaluated for specific cancer immunotherapy. Autologous/allogeneic tumor cells as a tumor vaccine