Immunotherapy with autologous dendritic cells (DCs) engineered ex vivo to become immunogenic or tolerogenic recently has been used in an array of human diseases. However, optimizing the DC generation process to achieve a product with maximal clinical efficacy has been challenging. Manufacturing issues to be resolved include the type and characteristics of DC lots generated in patients with different diseases; the type of antigens or cells used for DC loading; the combination of cytokines and media used for DC maturation; and assay selection for measuring DC potency. Standardized release criteria for clinical-grade DC are not yet available, and given the current state of knowledge about DC biology, may be premature to mandate. Similarly, to evaluate immunological efficacy following adoptive transfers of antigen-loaded DC, standardized monitoring assays are needed. Although several single-cell–based immune assays and multiplex cytokine platforms are available, the choice and quality control of monitoring assays remain problematic. Improvements in the manufacturing and evaluation of clinical-grade DC products and in the design and quality of monitoring assays are needed to adequately assess the therapeutic impact of DC-based interventions in future clinical trials.
Recent advances in molecular immunology and preclinical studies in experimental animals suggest that immunizations based on transfers of antigen-loaded dendritic cells (DCs) offer promise for therapy of malignant diseases. In fact, DCs have been used in active immunotherapy of cancer for more than a decade, and DC-based products have been delivered to more than 1,000 cancer patients enrolled in more than 150 clinical trials.1–3 Active immunotherapy with DCs for human diseases, including cancer, is based on the accumulated evidence that DCs represent nature's best antigen-presenting cell (APC). DCs recognize, process, and present foreign antigens to T cells in the effector arm of the immune system.4 They can drive primary and secondary immune responses. Immature DCs capture and internalize antigens via receptor and nonreceptor-mediated mechanisms.5 A complex molecular array of cell components referred to as the antigen-processing machinery (APM) processes the internalized antigens to yield peptides that are subsequently expressed on the cell surface in association with major histocompatibility complex (MHC) molecules and β2 -microglobulin as a trimolecular complex.6 Mature DCs, equipped with surface molecules facilitating cellular interactions, present these peptides to cognate T cells.7–9 When the antigenic peptides are tumor derived, activation of tumor-specific cytolytic T lymphocytes (CTLs) occurs, and the immune system is primed to recognize the tumor and possibly to eliminate it. Clearly, the processing of antigens by DCs and their presentation to T cells are key to successful immunizations in cancer and other diseases.
Subtypes of Dendritic Cells
A confocal microscope image of human immature dendritic cell (DC) stained with labeled antibodies specific for CD11c (red) and HLA-DR (green). The nucleus (blue) is stained with DAPI.
The division of labor evident among DCs suggests that the DC population is heterogenous. DCs can be broadly divided into two subtypes—myeloid and plasmacytoid—based on phenotype and function.10,11 Myeloid DCs are monocyte-derived DCs that are functionally categorized as DC1. They polarize T cells toward T helper (Th1) functions and can mediate both MHC I– and MHC II–restricted presentation of tumor epitopes, which is considered necessary for optimal immunotherapy of cancer. 3,12–14 Plasmacytoid DCs have DC2 activity and polarize T cells toward Th2 functions. Because DC-driven polarization determines the quality of T-cell responses, the source and type of DCs selected for active immunotherapy are very important. Because plasmacytoid DCs tend to induce tolerance, they are considered to be an appropriate cell type for treating autoimmune diseases. Thus, the DC type best suited for active immunotherapy may vary depending on therapeutic application.
Clinical Results to Date
DC products have been used for therapy of infectious diseases, including chronic HIV-1 infections,15,16 autoimmune diseases,17 post-transplant graft versus host disease (GVHD),18 and various cancer types.13,14 Results from numerous Phase 1 trials indicate that DC-based immunotherapy is feasible, safe, and well tolerated. However, clinical results are often inconclusive, in part because the subjects enrolled in these trials had an advanced-stage disease but also because of the lack of product standardization, resulting in tremendous phenotypic and functional differences in administered therapeutic DC products.