Harnessing the Immune System to Fight Cancer: The Promise of Genetic Cancer Vaccines

In spite of significant progress in recent years towards the development of new targeted therapies Cancer is still a largely unmet medical need and the leading cause of death in industrialized countries (Globocan Project, 2008). Cancer is continuously increasing and is associated with a variety of factors, including genetic predisposition, infectious agents, exposure to mutagens, as well as lifestyle factors (Minamoto et al, 1999). Cancer is linked to the occurrence of genetic and epigenetic changes (Heng et al, 2010) and indeed tumour cells harbor hundreds of these modifications as also witnessed by the recent results of genome wide analyses of cancer genomes (Sastre, 2011). This feature of cancer cells implies that they can be recognized as foreign entities and eliminated by our immune system, and is at the basis of the theory of immunosurveillance (Dunn et al, 2004). Several studies have shown that it is possible to establish clear correlates between the nature, density and location of immune cells within distinct tumour regions and the risk of disease relapse (reviewed in Mleknic et al, 2011). Compelling data have recently led to propose that an immune classification of patients, based on the density and the immune location within the tumour may have a prognostic value even superior to the standard TNM classification (Bindea et al, 2011; Fridman et al, 2011). In recent years a better knowledge of the immune system has led to an evolution of the initial concept of immunosurveillance into a more articulated theory of immunoediting (Schreiber et al, 2011). Cancer immunoediting acts as an intrinsic tumour suppressor mechanism that engages after cellular transformation has occurred and intrinsic tumour suppressor mechanisms have failed. One can envisage the existence of three sequential steps during clinical tumour evolution: elimination, equilibrium, and escape. In the first step, innate and adaptive immunity are capable of destroying transformed cells before they give rise to tumour masses. If this process is maximally efficient, then the host remains tumour free. If, however, cancer cell variants are not destroyed, they can enter into an equilibrium phase, in which their outgrowth is held in check by immunological mechanisms, which are principally due to the activation of IL12/IFN-dependent adaptive immunity, mainly driven by antigen-specific CD8+ and CD4+