Dendritic Cell-Based Cancer Gene Therapy

Abstract

In view of their potent antigen-presenting capacity and ability to induce effective immune responses, dendritic cells (DCs) have become an attractive target for therapeutic manipulation of the immune system. The application of tumor-associated antigen (TAA)-expressing DCs for cancer therapy has been the subject of intensive translational investigation. Previous clinical trials demonstrated tumor-specific immune responses without any significant toxicity. However, the clinical success has been modest, because only a limited number of immunized patients demonstrated cancer regression. Considerable progress has been made in the knowledge of DC biology, which opens new avenues for the development of optimized clinical protocols. One such promising approach that might carve its place in the future of DC-based therapy is the use of gene-modified DCs. DCs engineered to express TAAs allow multiepitope presentation by both major histocompatibility complex (MHC) class I and II molecules of full-length TAAs independent of the patient's HLA constitution, as opposed to peptide vaccination strategies. Besides transgene TAA expression, DCs can be genetically modified (1) to express a variety of immune-potentiating molecules (e.g., costimulatory molecules, cytokines, and chemokines) or (2) to downregulate negative modulators of DC functioning, all allowing an enhancement of their immunogenic potential. In the present review, gene delivery systems for DCs are discussed, as well as the various transgenes used for genetic modification of DCs. Moreover, a detailed review of the already published trials using gene-modified DCs is presented and future DC-based strategies targeting multiple layers of the complex cellular immune response are highlighted.

NK Cells: Key to Success of DC-Based Cancer Vaccines?

“…DC-based therapy originates from the unique capacity of DCs to present captured antigens to T cells, which is essential for generating specific T cell immunity [51][52][53][54]. Loading of DCs with tumor-associated antigens (TAAs) has therefore become an attractive therapeutic tool in order to generate tumorspecific T cells.…”

Interferon-α in acute myeloid leukemia: an old drug revisited

“…24,26 Several cytokines have been implicated in modulating DC function, type I IFN among them. 27,28 They have been shown to enable cross-priming of naive T cells, both by licensing DC to present exogenous antigens in an immunostimulatory way and by acting directly on T cells (Table 1). 29,30 In addition to naive T cell priming, IFN-a can also contribute to the generation of an antigen-specific cytotoxic T cell response by promoting the endogenous expression of the leukemiaassociated antigen proteinase-3/myeloblastin in myeloid leukemic cells (Figure 1).…”

Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination

“…DC have been intensively investigated as cellular adjuvants for therapeutic cancer vaccination, and since the first reported trial in lymphoma patients in 1996 (16), DC have shown an unsurpassed capacity to induce in vivo antitumor responses. However, the overall clinical response rate, if any, remains very low (17). This poor clinical outcome could be, at least in part, ascribed to the fact that most clinical DC trials to date have been performed in end-stage cancer patients, often with bulky tumor loads and a compromised immune system caused by intensive treatment schedules and/or advanced disease stage (18).…”