Cancer vaccines have been used under several different formulations without unequivocally showing the superiority of one formulation over the others. By taking the past and successful experience gathered from antiviral vaccines, immunological adjuvants were used as local compounds enabling the injected vaccine to recruit inflammatory cells at the site of injection before vaccine degradation by subcutaneous enzymes.

This allows the TAA to persist locally and thus helps antigen-presenting cells to present such antigens to the immune system usually to the lymph nodes driving the region of vaccine injection.

In early trials, cellular vaccines were mostly used in combination with different adjuvants (e.g., BCG, KLH, Montanide) since they were easily obtainable from autologous or allogeneic cancer cells usually after in vitro stabilization of a cancer cell line. This choice was based on the unproved hypothesis that randomly selected neoplastic cells were representative of the antigenic profile of patient’s tumor mass. These cell vaccines usually failed to show therapeutic activity in appropriate phase III trials [11].

Subsequently, cancer cells were genetically modified to express and release gene products (e.g., Chemokines as IL-2, IL-4, IL-7, IL-12, GM-CSF) able to help the in vivo TAA recognition by T cells and their expansion [12]. However, even after such manipulation, no clear and reproducible increase of the clinical response was obtained in phase II studies [12]. The only vaccine that reached the phase III trial in prostate cancer patients (Vital-2 G-Vax, Cell Genesis) was also disappointing since the study had to be discontinued due to more deaths occurring in the vaccinated arm compared to the placebo arm (see Medical News Today, August, 31, 2008). The reason for this imbalance in death was not identified; nonetheless it is known that very high doses of GM-CSF, released by the cell vaccine, may impair rather than increase patients’ antitumor immune response [13]. However, a successful phase III trial was performed during the last few years leading to its approval by the FDA (Provenge) (see below).

A major problem that came out from the many early studies was the lack or weakness of immune response in mice and patients receiving self-TAAs as vaccines usually combined with immunological, nonspecific adjuvants (e.g., Montanide). A large number of studies were therefore conducted in the last two decades pioneered by the observation of Ferrone’s and Garrido’s groups [17, 18] on the downregulation of class I and II HLA on most tumor cells of a variety of human solid tumors like melanoma, colorectal cancer, etc. This alteration will remove crucial molecules necessary for the TAA presentation to the patient’s immune system. Table 2.3 lists the many different mechanisms of tumor escape that have been described in the last few years and that could have prevented an efficient immune response specifically targeting the appropriate TAAs expressed by cancer cells [19]. A new possibility has been reported in melanoma by different authors describing that BRAF-MAPK signaling is generating cancer-immune evasion [20, 21] though the reverse (i.e., immunostimulation) has been more recently found [22, 23]. In the last few years, the main focus was on the role of myeloid-derived suppressor cells (MDSC) [24, 25] and Tregs [26] as main mechanisms of immune escape by tumor cells. A recent adjunct to the plethora of escape mechanisms is the inflammasome component Nirp3 underlining the complex relationship between inflammation and cancer [27] that impairs vaccine-induced immunity. However, one should consider that several mechanisms may be activated by tumor cells either simultaneously or one after the other according to modifications that occur in the tumor microenvironment and in different tissues in which tumor cells are growing even during different types of therapy [28]. A recent additional mechanism of tumor escape has been described that includes tumor cell secretion of sterol metabolites (LXR ligands), which inhibit the expression of CCR7 on the cell surface of dendritic cells (DCs), thereby disrupting DC migration to the lymph nodes and dampening the antitumor immune priming event [29]. Presently, the major research efforts are directed to find compounds that may help in restoring the full anticancer potential of the immune system [19, 30].

During the last few years, however, new knowledge has been gained on the mechanisms of antitumor immunization and tumor immune escape in cancer patients enrolled in earlier vaccination protocols. Such new information has allowed to overcome some of the hurdles that were identified earlier. Thus several phase II and even phase III vaccination protocols came to their conclusion or to an advanced ad interim evaluation stage and provided clinical evidence of benefit for patients with melanoma and other tumors (Table 2.4). Of note, a phase III protocol of vaccination for metastatic prostate cancer patients with autologous dendritic cells loaded with a hybrid molecule made of GM-CSF and PAP (Provenge) [31] was approved by the FDA.