Active immunization against cancer with dendritic cells: The near future

DCs1 are antigen-presentin g cells that regulat e several components of the immune system. The mature or terminal stage of DC developmen t induces specific T-cell immunity and resistanc e to experimenta l tumors in vivo. However, DC maturation is induced by inflammator y and microbial stimuli, so it isunlikely that mature DCsnormally 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 response s to cancer antigens in a specific and nontoxic manner , in both vaccination and therapeuti c settings. DCs can mobilize several immune resistanc e mechanisms. These include CD8 CTLs, CD4 helper T cells, NK and NKT cells. Each of these lymphocytes recognizes target s through a distinct mechanis m and has the capacit y to kil l tumor cells and release valuabl e protective cytokines like IFN-g. CD4 T cells also provide essentia l help for the expansion and maintenanc e of CD8 cytolytic cells, while NK and NKT cells can eliminate target s that dampen presentatio n 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 markedl y improves the functional affinity of CD8 T cells. These findings are important in the context of immunotherapy becaus e Th1 cells are more efficient helper cells in experimental model s of viral infection and tumors, while high-affinity CTLs shoul d 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 resul t in major shortterm toxicity in healthy subject sor cancer patients. Tumor-specific T-cell response s have been induced and detected in fresh blood specimens without the need for restimulation in vitro. However, the immune response s observed in the first protocol s are still smaller than those seen naturall y in acute viral infections. Occasional clinical regression s have been noted in these initial feasibility studies, particularl y in melanomas , pediatri c tumors, lymphomas, prostat e cancer s and renal cell cancers . This information, coupled with progres in DC biology, suggest s many ways to improve the efficacy of this new therapy. Some relevant topics include antigen loading and DC maturation procedures , frequency and route of DC injection, efficiency of DC homing to lymphoid tissues and their longevity once there and the role of distinct DC subsets . A valuabl e positive control in active immunization protocols is to include an aliquot of DCs pulsed with a viral peptide to verify that the DCs and the patient’s immune system are measurabl y competent. Most of the first vaccination protocol s have used DCs charged with synthetic, HLA-binding tumor peptides. Many methodsare in place to allow DCs to proces abroader array of peptides appropriate for the patient’s MHC haplotype. These include transfection (RNA, DNA and viral vectors) , select pathways of adsorptive endocytosis , exosomes and tumor cell fusion. An intriguing new approach involves the processing of whole tumor cells. Immature DCs are able to internalize tumor cells, including melanoma, EBV lymphoma and prostat e carcinoma cell lines. Following maturation, theprocessing of tumor cells leads to presentatio n of multiple epitopes on both MHC class I and II product s of DCs. Basic issues in human cancer immunology can be investigated with ex vivo–based DC immunization. Some topics for the near future are the extent to which tumor-specific tolerance is an obstacl e to immunetherapy and theneed to mobilizeseveral adaptive and innate mechanisms in tandem, including Th1 type CD4 helper T, NK and NKT cells. Progres is also being made in manipulating DCsdirectly in vivo. Thiswil l help to design vaccine adjuvant s that improve presentatio n of tumor cells in patients. Although tumorschallengetheimmunesystem in formidableways relative to infectious diseases , it is now feasibl e to use active immunotherap y and DC biology to manipulat e and study the human respons e to cancer.