Selected anti-tumor vaccines merit a place in multimodal tumor therapies

Abstract

Multimodal approaches are nowadays successfully applied in cancer therapy. Primary locally acting therapies such as radiotherapy (RT) and surgery are combined with systemic administration of chemotherapeutics. Nevertheless, the therapy of cancer is still a big challenge in medicine. The treatments often fail to induce long-lasting anti-tumor responses. Tumor recurrences and metastases result. Immunotherapies are therefore ideal adjuncts to standard tumor therapies since they aim to activate the patient's immune system against malignant cells even outside the primary treatment areas (abscopal effects). Especially cancer vaccines may have the potential both to train the immune system against cancer cells and to generate an immunological memory, resulting in long-lasting anti-tumor effects. However, despite promising results in phase I and II studies, most of the concepts finally failed. There are some critical aspects in development and application of cancer vaccines that may decide on their efficiency. The time point and frequency of medication, usage of an adequate immune adjuvant, the vaccine's immunogenic potential, and the tumor burden of the patient are crucial. Whole tumor cell vaccines have advantages compared to peptide-based ones since a variety of tumor antigens (TAs) are present. The master requirements of cell-based, therapeutic tumor vaccines are the complete inactivation of the tumor cells and the increase of their immunogenicity. Since the latter is highly connected with the cell death modality, the inactivation procedure of the tumor cell material may significantly influence the vaccine's efficiency. We therefore also introduce high hydrostatic pressure (HHP) as an innovative inactivation technology for tumor cell-based vaccines and outline that HHP efficiently inactivates tumor cells by enhancing their immunogenicity. Finally studies are presented proving that anti-tumor immune responses can be triggered by combining RT with selected immune therapies.

Keywords: anti-tumor immunity; cancer therapy; high hydrostatic pressure; immunotherapy; multimodal; radiotherapy; vaccination; whole cell-based vaccines.

Figure 1

Challenges and changes of whole tumor cell-based vaccines. As compared to peptide-based vaccines, a high variety of relevant tumor antigens is provided by whole tumor cell-based vaccines. Therefore, the tumor antigens have not to be individually defined. However, there are some crucial challenges that may decide about the vaccine's efficiency and productivity including the immunogenic potential of tumor cell material and a reliable manufacturing process associated with a high reproducibility. Furthermore, the limited availability of tumor cell material has to be taken into account. Nevertheless, when these resolvable problems have been resolved, whole tumor cell-based vaccines will be prime immune therapies for personalized tumor treatments.

Figure 2

High hydrostatic pressure (HHP) Technology as an innovative method for the preparation of whole tumor cell-based vaccines. The basic principle of the HHP technology is displayed in (A). The tumor cell suspension, which has to be pressurized, has to be packed in a plastic wrapping. The pressure is applied to the treatment cavity and propagates through the pressure transmitting medium and also through the packaging (Yaldagard et al., 2008). Since the pressure is a vector product its acts on every material in the cavity with the same amplitude, independent of the shape of the probe. It was obvious in different experiments, that the pressure for inactivation should be at least equal or above 200 MPa. For the production of an effective whole cell-based vaccine, four main requirements have to be fulfilled (B): the vaccine has to be safe, i.e., it has to exhibit low toxicity and, especially in the case of autologous tumor cell-based vaccines, the tumor cell material has to be effectively inactivated. The vaccine has to be further highly immunogenic, i.e., it has to trigger the immune system to elicit a strong anti-tumor response accompanied by the development of an immunological memory against the tumor. Finally, the vaccine and its processing have to be in accordance with statutory provisions.