mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients

BACKGROUND: In an effort to raise protective antiviral immunity, dendritic cell (DC) immunotherapy was evaluated in 6 adults infected with human immunodeficiency virus (HIV)-1 and stable under antiretroviral therapy (HAART). DESIGN & METHODS:: Autologous monocyte-derived DC electroporated with mRNA encoding Gag and a chimeric Tat-Rev-Nef protein were administered, while patients remained on HAART. Feasibility, safety, immunogenicity and antiviral responses were investigated. RESULTS: DC vaccine preparation and administration were successful in all patients and only mild adverse events were seen. There was a significant increase post-DC as compared to pre-DC vaccination in magnitude and breadth of HIV-1-specific interferon (IFN)-gamma response, in particular to Gag, and in T-cell proliferation. Breadth of IFN-gamma response and T-cell proliferation were both correlated with CD4+ and CD8+ polyfunctional T-cell responses. Importantly, DC vaccination induced or increased the capacity of autologous CD8+ T-cells to inhibit superinfection of CD4+ T-cells with the vaccine-related IIIB virus and some but not all other HIV-1 strains tested. This HIV-1-inhibitory activity, indicative of improved antiviral response, was correlated with magnitude and breadth of Gag-specific IFN-gamma response. CONCLUSIONS: Therapeutic immunization with DC was safe and successful in raising antiviral cellular immune responses, including effector CD8+ T-cells with virus inhibitory activity. The stimulation of those potent immunological and antiviral effects, which have been associated with control of HIV-1, underscores the potential of DC vaccination in the treatment of HIV-1. The incomplete nature of the response in some patients helped to identify potential targets for future improvement, i.e. increasing antigenic spectrum and enhancing T-cell response

NK cells : key to success of DC-based cancer vaccines?

The cytotoxic and regulatory antitumor functions of natural killer (NK) cells have become attractive targets for immunotherapy. Manipulation of specific NK cell functions and their reciprocal interactions with dendritic cells (DCs) might hold therapeutic promise. In this review, we focus on the engagement of NK cells in DC-based cancer vaccination strategies, providing a comprehensive overview of current in vivo experimental and clinical DC vaccination studies encompassing the monitoring of NK cells. From these studies, it is clear that NK cells play a key regulatory role in the generation of DC-induced antitumor immunity, favoring the concept that targeting both innate and adaptive immune mechanisms may synergistically promote clinical outcome. However, to date, DC vaccination trials are only infrequently accompanied by NK cell monitoring. Here, we discuss different strategies to improve DC vaccine preparations via exploitation of NK cells and provide a summary of relevant NK cell parameters for immune monitoring. We underscore that the design of DC-based cancer vaccines should include the evaluation of their NK cell stimulating potency both in the preclinical phase and in clinical trials