Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines.

CD8(high)CD57(+) T-cell population as an independent predictor of response to chemoradiation therapy in extensive-stage small cell lung cancer.

OBJECTIVES: Tangible clinical benefit is achieved in only a relatively small proportion of extensive-stage small cell lung cancer (SCLC) patients receiving current treatment strategies. Therefore, a more personalized use of current and novel treatment approaches is of critical importance. Individualized therapy relies on the identification of specific biomarkers predictive of response to a particular type of cancer treatment. Immune-related parameters emerge as powerful biomarkers among a variety of predictors of clinical response to various types of cancer treatment. PATIENTS AND METHODS: Using multicolor flow cytometry, we evaluated a predictive value of CD8(high)CD57(+) T-cell population and its immunosuppressive (FOXP3(+), NKG2A(+)) and cytotoxic (Perforin(+)) subsets in the peripheral blood of extensive-stage SCLC patients (n=82) treated with either chemotherapy-alone (n=24), or chemoradiation therapy (n=42), or receiving best supportive care (n=16). RESULTS: The low level (<20%) of CD8(high)CD57(+) T cells within the peripheral blood CD8(+) T-cell population and the low level (<3%) of the immunosuppressive FOXP3-positive subset within the CD8(high)CD57(+) T-cell population were independent predictors of a better response to treatment with chemoradiation therapy, but not with chemotherapy alone or best supportive care. Importantly there was no significant survival difference between SCLC patients who were: (i) treated with chemoradiation, but had an unfavourable immune profile (≥20% of CD8(high)CD57(+) T cells and ≥3% of its FOXP3-positive subset), (ii) treated with chemotherapy alone, or (iii) received best supportive care. CONCLUSIONS: We show that only a combination of chemotherapy with radiation therapy offered a considerable survival benefit that was confined to a subset of extensive-stage SCLC patients with a favourable predictive immune profile in the peripheral blood.

Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: to use or not to use?

Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens.

Immune adjuvants as critical guides directing immunity triggered by therapeutic cancer vaccines.

Tumor growth is controlled by natural antitumor immune responses alone or by augmented immune reactivity resulting from different forms of immunotherapy, which has demonstrated clinical benefit in numerous studies, although the overall percentage of patients with durable clinical responses remains limited. This is attributed to the heterogeneity of the disease, the inclusion of late-stage patients with no other treatment options and advanced tumor-associated immunosuppression, which may be consolidated by certain types of chemotherapy. Despite variable responsiveness to distinct types of immunotherapy, therapeutic cancer vaccination has shown meaningful efficacy for a variety of cancers. A key step during cancer vaccination involves the appropriate modeling of the functional state of dendritic cells (DCs) capable of co-delivering four critical signals for proper instruction of tumor antigen-specific T cells. However, the education of DCs, either directly in situ, or ex vivo by various complex procedures, lacks standardization. Also, it is questioned whether ex vivo-prepared DC vaccines are superior to in situ-administered adjuvant-guided vaccines, although both approaches have shown success. Evaluation of these variables is further complicated by a lack of consensus in evaluating vaccination clinical study end points. We discuss the role of signals needed for the preparation of classic in situ and modern ex vivo DC vaccines capable of proper reprogramming of antitumor immune responses in patients with cancer.

Therapeutic dendritic cell-based cancer vaccines: the state of the art.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells, capable of initiating proper adaptive immune responses. Although tumor-infiltrating DCs are able to recognize cancer cells and uptake tumor antigens, they often have impaired functions because of the immunosuppressive tumor milieu. Therefore, DCs are targeted by therapeutic means either in vivo or ex vivo to facilitate tumor antigen presentation to T cells and induce or promote efficient antitumor immune responses in cancer patients. This immunotherapeutical approach is defined as specific active tumor immunotherapy or therapeutic cancer vaccination. In this review we briefly discuss general aspects of DC biology, followed by a thorough description of the current knowledge and optimization trends of DC vaccine production ex vivo, including various approaches for the induction of proper DC maturation and efficient loading with tumor antigens. We also discuss critical clinical aspects of DC vaccine application in cancer patients, including protocols of administration (routes and regimens), individualization of tumor immunotherapy, prediction and proper evaluation of immune and clinical responses to immunotherapy, and the critical role of combining tumor immunotherapy with other cancer treatment strategies to achieve maximal therapeutic effects.