Personalized vaccination against ovarian cancer: what are the possibilities?

The basis of immunology is the discrimination between self and nonself. All pathogens have molecular signatures that can be recognized by the host’s immune system and activate immune responses. Vaccinations against viruses and bacteria, which have successfully exploited this vulnerability, have become an integral part of preventive healthcare. With regard to cancer therapy, prophylactic vaccines against human papilloma virus have evolved over the last decade for the prevention of cervical cancer and have become part of routine vaccination schedules [1]. Theoretically, vaccines for ovarian cancer patients directed against private tumor neo-antigens derived from nonsynonymous somatic mutations is a promising treatment strategy. Such an approach will activate endogenous immune cells to recognize specific tumor associated antigens (TAAs), thus killing cancer cells with minimal harm to the surrounding healthy tissue. Additionally, by increasing the pool of available tumor-specific T cells, therapeutic cancer vaccines could contribute to combination immunotherapy. There is still an ongoing debate about the immunogenicity of ovarian cancer. Some evidence indicates that a proportion of these tumors express a large number of known TAAs [2], have immunoreactive gene signatures, and are infiltrated by intraepithelial tumor–infiltrating lymphocytes (TILs) [3]. On the other hand, others have demonstrated that ovarian tumors have a very heterogeneous and comparatively low mutational load, thus making immune recognition of neo-antigens dubious [4]. In spite of this comparatively low mutational load, however, one type of ovarian tumor, epithelial ovarian cancer (EOC), is susceptible to immune recognition [2,3]. Unfortunately, the projected potential of cancer vaccines based on these preclinical findings has not translated into the clinical setting thus far. The explanation for this can be the wrong choice of antigens or can be related to the inability of tumor-specific T cells to home in the tumor microenviroment. For example, barriers that prevent T cell homing in ovarian tumors include the peripheral tolerance mediated by regulatory T cells (T Reg) or the vascular endothelial growth factor A (VEGF-A) mediated vascular endothelial barrier [5]. Another major reason for clinical failure includes that most molecularly defined tumor vaccines, up till now, have used a single ‘self’ antigen. Therefore, the poor outcome of this approach in the clinical trials could be credited, at least in part, to immune-selection of antigen loss variants after vaccination. There are two main classes of targetable TAAs in ovarian cancer: the shared common TAAs and the exclusive, individually mutated neo-antigens. The shared antigens can be separated into three main groups: the overexpressed antigens, which are normal surface proteins expressed in elevated levels on cancer cells but in lower levels in normal cells (i.e. mesothelin); tissue-specific TAAs, which are shared between tumors and the normal tissue of their origin; and TAAs whose expression is normally restricted to male germline cells (i.e. cancer testes (CT) antigens such as NY-ESO-1) [6]. In the past decades, the mutation-based cancer vaccines were restricted to using synthetic peptides featuring frequent driver mutations in many human cancers such as mutated p53 or Ras [7]. Also, the available pool of immunogenic mutations increased very slowly and most of the published shared immunogenic mutations were limited to small subsets of cancer patients [8]. Further, there was no feasible concept to use individual mutations. Instead, the therapeutic application of TAAs was focused mainly on shared TAAs. One example of a shared TAA tested in early phase clinical trials is the cancer testes antigen NY-ESO -1 [9]. In this small phase I trial decitabine, which has been shown to enhance NY-ESO-1 expression, was used in combination with a NY-ESO-1 vaccine and liposomal doxorubicin chemotherapy in recurrent ovarian cancer. Stable disease was noted in 50% (5/10 patients) that lasted a median of 6.3 months and a partial response was seen in 1 patient with duration of response of only 5.8 months [9]. Since then others have studied cancer testes antigens with conflicting results in clinical trials [10]. They have also found that some of the CT antigens are expressed at low levels in some normal tissues and that no single CT antigen is universally expressed and that the frequency and expression levels can be heterogeneous across tumors [10]. The high-avidity T cell clones recognizing these shared antigens may be deleted by central tolerance mechanisms, which may be one other explanation of the unsatisfactory outcome of clinical vaccination trials [11]. On the other hand, the current technological breakthroughs and extensive deep sequencing analyses have discovered that solid tumors contain as few as tens to several thousand private non-synonymous somatic mutations, and these mutations are different even among tumors from the same histologic subtype [12]. These neo-antigens result from the large number of somatic mutations that are fully tumor