vaccines targeting these newly identified CIC oncoantigens may extend vaccine efficacy.36 Models for Oncoantigen Validation During the long-lasting relationship between a tumor and its environment, antibodies against oncoantigens play diverse roles. These roles are prominent precisely because an oncoantigen is both a tumor target and a molecule with a functional role in tumor progression.55 The importance of vaccine-elicited antibod- ies against oncoantigens is one of the lessons emerging from the studies on genetically engineered mice developing autochthonous cancers. Immunization experiments carried on these mice, on the other hand, illustrate the limit of an anti-oncoantigen vaccine. It can keep an incipient tumor at bay for a very long time.23 However, the efficacy of vaccine-induced protection fades when the vaccine is first administered to mice already bearing clinically evident tumors.23,57 In a therapeutic setting the protection afforded by an effective oncoantigen vaccine is often similar to that observed in “successful” clinical trials with anti-tumor vaccines: a statistically significant delay in tumor progression, but of little weight in the life of a patient. Since experimental models are so critical in assessment of the weight of the immune mechanisms involved in tumor protection, those that ever more closely reproduce the human situation should be sought. Genetically engineered mice with profound and stable immunodeficiencies have been transplanted with a human immune system and used to investigate and manipulate, in a murine context, human immunity against human tumors.62 Even in their present, imperfect state of development, these mice can be used not only to study the development of human immune components, but also to better define a few critical features of vaccines against oncoantigens (Fig. 4). Lastly, it should be borne in mind that many aspects of the immune response can be captured by mathematical models ranging from system-level models that describe the immune system as a whole to extremely fine-grained ones that analyze a single cellular or molecular response.64 The latest generation of models is beginning to tackle practical problems. Both the general field of vaccines and tumor immunology especially can derive great practical benefits.65 Climbing Over the Limit Experiments with genetically engineered mice have furnished bitter evidence of the limit of DNA vaccines against oncoantigens. When an oncoantigen vaccine is administered to a healthy mouse genetically predestined to die because of a specific cancer, repeated boosts keep it tumor free for a period of time that may equate its natural life span. However, when the same vaccine is administered to a mouse with more advanced stages of microscopic lesions, the protection gradually fades away.66 As mentioned above, vaccine combination with adjuvants of different kind variously extends the efficacy of vaccine-elicited protection.25,26 A further extension is obtained by manipulating the sequence coding for the antigen protein.45 However, as the time of the first vaccine administration approaches the stages of a clinical tumor diagnosis, vaccine efficacy disappears. A pattern of this kind is shared by different combinations of vaccine in genetically engineered mice confining the exploitation of oncoantigen vaccines to the awkward field of tumor prevention.58 It also spurs the search for a way to make oncoantigen vaccine of significance in tumor therapy. Probably multiple factors contribute to the shortfall of vaccine efficacy. The progression of tumor renders the microscopic lesions and incipient tumors less permeable to immune attack. Moreover, a series of factors released by the tumor together with the increasing overexpression of the targeted oncoantigen results in an expansion Figure 4. Human immune system-engrafted (HIS) mice for validation of oncoantigen vaccines. Human hematopoietic stem cells implanted in severely immunodeficient mice give rise to a (more or less) functional human immune system (A) that can be subsequently vaccinated with human tumor antigens to investigate and manipulate in an experimental context human anti-tumor immunity, (B and C). Note that most current protocols use human progenitors from cord blood for the engraftment, hence the final step shown in the figure, i.e. challenge with human (adult) tumor cells, could entail MHC allogeneic interactions. Human immune system-engrafted mice are undergoing continuous improvements, because the interactions of xenogeneic human and murine molecules is not always functional. Novel models include additional genes encoding for human MHC, to humanize antigen presentation, or human species-specific cytokines to enhance human cell long-term survival and functional differentiation.63 322 OncoImmunology Volume 1 Issue 3