It has been reported that immunization with placental extracts possesses clinical efficacy toward a variety of tumor types clinically, as previously reviewed by Harandi . Unfortunately, randomized clinical trials have not been performed and the data is at best anecdotal. Conceptually, vaccination with placental extracts would be capable of eliciting immunological responses not only to marker antigens shared between the placenta and neoplasia such as hCG, MAGE, BAGE [17, 18], but also to functional proteins that tumors require to maintain malignancy. For example, stimulation of immunity against MMPs found on placental tissue may theoretically cause inhibition of tumor MMP activity and reduction in tissue invasiveness and metastasis. Indeed, while others have previously demonstrated inhibition of tumor growth after immunization with MMP-2 , it was recently observed that human melanoma cells uptake MMP-2 in an alpha v beta3-dependent manner, and present peptides thereof to HLA*0201-restricted T cells .
In addition to MMPs, placental formation in normal pregnancy is dependent on two other main functional activities, the first being suppression of immune responses in a selective or semi-selective manner, and the second being ability to rapidly induce angiogenesis to form the appropriate interface for maternal-fetal nutrient transmission. It is established that tumors also require induction of immune suppression, as well as angiogenesis for their survival, and indeed the higher immune suppression and angiogenesis found in tumors, the worse the patient prognosis is. The sharing between placental cells and cancer cells of immune suppression/immune evasion molecules such as fas ligand (Fas-L) , DAF , CD55 , IL-10 , MICA , HLA-G and indolamine 2,3 dioxygenase , as well as molecules of angiogenesis such as VEGF , placental growth factor , angiopoietin , FGF, EGF, and TGF-beta  suggests not only a functional, but also a molecular homology between placenta and cancer cells.
The knowledge that placental extracts may be stimulatory of anticancer immune responses has been postulated to account for the lower incidence of certain tumors in multi-parous women . Indeed older studies using placental immunization in mouse models have demonstrated some efficacy in tumor inhibition as reviewed by Harandi . Our approach to utilization of placental extracts was mindful of the Immunostimulatory Hypothesis proposed by Prehn , suggesting that the immune response may in some cases actually contribute to tumor growth. With this in mind, we sought to specifically use a potent means of inducing a "danger signal" while concurrently providing a multivalent tumor antigenic source. Based on the hyperacute nature of xenogenic rejection , the multitude of data supporting superior breaking of tolerance using xenogenic variants of self-proteins [44–46], and the fact that autoimmune disease is evoked only by xenogeneic self antigens in animal models of autoimmune disease [47, 48], we decided to immunize C57/BL6 mice with xenogenic placental extracts (XPE) and observe antitumor effects.
We have demonstrated that immunization with a preparation of xenogenic placental extract induced a CD4-dependent immune response capable of inhibiting growth of B16 melanoma cells in the C57/BL6 mouse. Demonstration of CD8 activity in the induction of tumor regression was performed in experiments showing that freshly isolated CD8 cells from immunized mice were capable of inducing both tumor cell, as well as xenogeneic trophoblast apoptosis cascades. Immune-mediated clearance seemed to be specific to the XPE since immunization with control porcine liver extracts did not mediate protection. Additionally, the xenogeneic component of XPE seems to be critical since apoptosis-inducing cells were not detected in mice immunized with allogeneic placental extracts. Although we did not elucidate specific antigenic targets of xenoplacental immunization, preliminary data seems to suggest that inhibition of neoangiogenesis may be one of the potent mechanisms. Studies using purified immunoglobulin from XPE immunized mice demonstrate the ability to inhibit in vitro proliferation of endothelial cells. This work is still in progress and will be reported in a subsequent publication.
The ability of XPE to inhibit tumor growth may not be surprising given the high concentration of endothelial cells in placental tissue, and previous reports that immunization with xeno-endothelial cells causes anticancer responses [25, 49]. However, the potent ability of XPE to act as a Th1 and Th2 adjuvant for HEL-specific recall responses is surprising. Indeed it has been speculated that xenogenic antigens may intrinsically be stimulatory of dendritic cell function, however to our knowledge, this is the first report actually demonstrating this. Future experiments will assess the effect of XPE on dendritic cell maturation, and function in vitro in order to identify whether the XPE was actually giving a direct signal to dendritic cells, or whether the augmentation of DC activation occurs after the re-introduction of pulsed DC in vivo. Nevertheless, it appears that XPE has a potent immune enhancing property since it was able to potentiate the anti-B16 response of the B16 lysate vaccine in addition to the anti-HEL response.
Although numerous tumor antigens are currently under intense investigation, the ability for a multi-epitopic composition such as XPE to induce immunity that is transferable to naïve recipients is somewhat surprising given the lack of immunological adjuvants or multi-injection regimens used in other studies. In conclusion, XPE appears to be a potent stimulator of anticancer immune responses in a CD4 and CD8 T cell dependent manner. The characterization of both cross-reactive tumor antigens, as well as the apparent ability to act as an immunological adjuvant, will provide interesting new avenues of research, with the possibility of developing novel, clinically applicable therapeutics from a relatively benign antigenic source.