In vivo transfection and/or cross-priming of dendritic cells following DNAand adenoviral immunizations for immunotherapy of cancer - changes in peripheral mononuclear subsets and intracellular IL-4 and IFN-gamma lymphokine profile

In order to provoke an immune response, a tumor vaccine should not only max imize antigen specific signals, but should also provide the necessary 'co-s timulatory' environment. One approach is to genetically manipulate tumor ce lls to either secrete lymphokines (GM-CSF, IL-12, IL-15) or express membran e bound molecules (CD80, CD86). Furthermore, patient dendritic cells can be loaded with tumor-associated antigens, or peptides derived from them and u sed for immunotherapy. Genetic modification of dendritic cells can also lea d to presentation of tumor-associated antigens. Transfection of dendritic c ells with DNA encoding for such antigens can be done in vitro, but transfec tion efficiency has been uniformly low. alternatively, dendritic cells can also be modulated directly in vivo either by 'naked' DNA immunization or by injecting replication-deficient viral vectors that carry the tumor specifi c DNA: Naked DNA immunization offers several potential advantages over vira l mediated transduction. Among these are the inexpensive production and the inherent safety of plasmid vectors, as well as the lack of immune response s against the carrier. The use of viral vectors enhances the immunogenicity of the vaccine due to the adjuvant properties of some of the viral product s. Recent studies have suggested that the best strategy for achieving an in tense immune response may be priming with naked DNA followed by boosting wi th a viral vector. We have successfully completed a phase I and phase II cl inical trials on immunotherapy of prostate cancer using naked DNA and adeno viral immunizations against the prostate-specific membrane antigen (PSMA) a nd phase I clinical trial on colorectal cancer using naked DNA immunization against the carcinoembryonic antigen (CEA). The vaccination was tolerated well and no side effects have been observed so far. The therapy has proven to be effective in a number of patients treated solely by immunizations. Th e success of the treatment clearly depends on the stage of the disease prov ing fo be most efficient in patients with minimal disease or no metastases. A panel of changes in the phenotype of peripheral blood lymphocytes and th e expression of intra-T-cell lymphokines seems to correlate with clinical i mprovement. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.