Active immunization against cancer with dendritic cells: The near future (2001)

DCs are antigen-presenting cells that regulate several components of the immune system. The mature or terminal stage of DC development induces specific T-cell immunity and resistance to experimental tumors in vivo. However, DC maturation is induced by inflammatory and microbial stimuli, so it is unlikely that mature DCs normally present antigens from tumor cells in cancer patients. Accordingly, clinical studies have begun in which DCs are generated ex vivo, charged with tumor antigens, exposed to maturation stimuli and reinfused to immunize patients. This approach has the potential to control responses to cancer antigens in a specific and nontoxic manner, in both vaccination and therapeutic settings. DCs can mobilize several immune resistance mechanisms. These include CD8+ CTLs, CD4+ helper T cells, NK and NKT cells. Each of these lymphocytes recognizes targets through a distinct mechanism and has the capacity to kill tumor cells and release valuable protective cytokines like IFN-γ. CD4+ T cells also provide essential help for the expansion and maintenance of CD8+ cytolytic cells, while NK and NKT cells can eliminate targets that dampen presentation on MHC class I to escape CTL recognition. The stimulation and concerted action of these classes of lymphocytes can now be studied directly in patients, using ex vivo–derived DCs. Several findings have emerged from studies of healthy volunteers who have been immunized with DCs charged with model antigens, KLH protein and influenza virus matrix peptide. Mature DCs elicit a polarized Th1 type of CD4 T-cell response, only a single injection being required. Vaccination with antigen-bearing DCs also markedly improves the functional affinity of CD8+ T cells. These findings are important in the context of immunotherapy because Th1 cells are more efficient helper cells in experimental models of viral infection and tumors, while high-affinity CTLs should improve recognition of tumor-derived peptides. An important caution also has surfaced when DCs are not adequately differentiated. Immature DCs can silence adaptive T-cell responses, e.g., by inducing IL-10–producing, T-reg cells. DC-based active immunization does not result in major short-term toxicity in healthy subjects or cancer patients. Tumor-specific T-cell responses have been induced and detected in fresh blood specimens without the need for restimulation in vitro. However, the immune responses observed in the first protocols are still smaller than those seen naturally in acute viral infections. Occasional clinical regressions have been noted in these initial feasibility studies, particularly in melanomas, pediatric tumors, lymphomas, prostate cancers and renal cell cancers. This information, coupled with progress in DC biology, suggests many ways to improve the efficacy of include and DC maturation and of DC of DC to and and the of distinct DC valuable control in active immunization protocols is to include of DCs with a viral to that the DCs and the immune are of the first vaccination protocols have DCs charged with tumor peptides. are in to DCs to a of for the MHC These include and viral of and tumor cell An approach the of tumor cells. Immature DCs are to tumor cells, and prostate cell the of tumor cells to presentation of on both MHC class I and of DCs. in cancer can be with ex DC for the are the to which is to immune and the need to mobilize several adaptive and in Th1 type CD4+ helper NK and NKT cells. is also being in DCs directly in vivo. 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