Development of Dendritic Cell-based Tumour Vaccines with High Efficacy for Clinical Applications

Abstract

Despite limited success has been achieved to date, the concept of DC-based tumour immunotherapy deserves further exploration. Such a live cell approach is understandably and inevitably very sensitive to the immunosuppressive tumour microenvironment. In order to develop a novel DC-based tumour vaccine with high efficacy and stability, we have designed, tested and compared different ways of enhancing DC immunogenicity by molecular modifications and functional conditioning of the cell vectors, targeting the positive and negative arms of immune regulation. In particular, findings from our ongoing studies of the cellular and molecular mechanisms underlying autoimmunity have also offered some important insights as to how such self-reactivity could be alternatively switched on, and more effectively redirected for the induction of immunity against tumours (the ‘altered self’). We show evidence that the most effective way to enhance its efficacy is by blocking the negative regulators of DC functions. The vaccines delivered by DCs devoid or knock-down of IL-10, a potent immunosuppressive cytokine expressed by DC, are superior over the conventional DC vaccine in triggering anti-tumour immunity. These DCs lacking IL-10 (IL-10-/-) are found to be immunologically heightened, expressing enhanced levels of surface MHC class II molecules and Th1-related cytokines. By inducing tumour-specific killing and through the establishment of immunological memory, the IL-10-/-DC vaccines could evoke strongly both therapeutic and protective immunity in animal models. This approach has now been tested by us in 7 different experimental models of liver (hepatoma) and skin (melanoma) cancers [1-3]. We propose to translate it clinically and timely into the treatment of malignancy in man. 1. Huang FP et al. Guiding the 'misguided' - functional conditioning of dendritic cells for the DC-based immunotherapy against tumours. Eur J Immunol. 2011. 41(1): p. 18-25. 2. Chen YX et al. A crucial role for dendritic cell (DC) IL-10 in inhibiting successful DC-based immunotherapy: superior antitumor immunity against hepatocellular carcinoma evoked by DC devoid of IL-10. J Immunol, 2007. 179(9): p. 6009-15. 3. Huang FP et al. PCT patent (WO2008/071093) http://www.wipo.int/pctdb/en/wo.jsp?WO=2008071093; USPTO patent (Ref No: 20090010948) http://www.uspto.gov/patft/index.html.