GTMB 7 - Gene Therapy & Molecular Biology

Gene Therapy and Molecular Biology Vol 7, page 265antitumor effects by facilitating the interaction betweenDCs and tumors, enhancing the maturation of DCs,inducing secretion of cytokines, and consequentlyproducing T-cell-dependent systemic immunity. Thesefindings suggest that CD40L gene therapy approaches forthe treatment of lung cancer should be pursued.2. (1,3) Galactosyl epitopes (·Gal)The role of (1,3) Galactosyl epitopes (·Gal) inexnograft rejection has been closely studied (Sandrin andMcKenzie 1994). Unfer et al, (2003) have demonstratedthat immunity to ·Gal provided protection in mice againstchallenge with genetically modified colon cancer cellsexpressing ·Galactosyl-transferase. These resultsdemonstrate the potential for a cancer gene therapy thatuses the innate immunity to Gal antibody in humans todestroy tumors as xenografts.3. Dendritic cell-based vaccineAntigen presentation by dendritic cells (DC) iscrucial for the induction of primary T cell-mediatedimmune responses in vivo. To further augment a cellularimmune response against tumor antigens, attempts havebeen made to increase antigen presentation capacity bygenetically modifying DCs with cytokine genes or tumorassociatedantigen genes (Sharma et al, 2003; Eppler et al,2002). In two murine lung cancer models adenoviral IL-7-transduced DCs (DC-AdIL-7) were administratedintratumorally. Compared with other intratumor therapiessuch as AdIL-7, DC-AdIL-7 therapy was more effective inachieving systemic antitumor responses and enhancingimmunogenicity, and in induction of splenocyte GM-CSFand IFN-γ, although both treatments resulted in completetumor eradication (Miller et al, 2000). Its potential is nowbeing evaluated in clinical trials. In a metastatic livercancer model, local delivery of DCs transduced with theIL-12 gene was able not only to inhibit colorectal tumorgrowth in vivo, but also to mount systemic antitumorimmune responses, evidenced by enhanced production ofIFN-γ by T lymphocytes isolated from both spleen anddraining lymph nodes (Satoh et al, 2002). Liu et al, (2002)demonstrated that DCs transfected with AdV-CD40L(DC(CD40L)) could stimulate enhanced allogeneic T-cellproliferation and Mut1-specific CD8(+) cytotoxic T-cellresponses in vitro. Vaccination of Mut1 peptide-pulsedAdV-CD40L-transfected DC (CD40L) induced anaugmented antitumor immunity in vivo by completeprotection of mice (8/8) from challenge of both low andhigh doses of Lewis lung carcinoma cells. However, moreinvestigation into the role of DC maturation, as well as itstiming and sequence, is needed before it can be used inclinical applications.VI. ConclusionFor successful gene therapy to lung cancer or othercancers, gene delivery systems play a key role. It is wellrecongized that at current developing stage of cancer genetherapy, gene delivery technology is still a major obstacleto success of the cancer therapy, although majorimprovements in all areas of vector development havebeen achived. Further work on technology issues isnecessary. Much has yet to be learned before safe,efficient, stable, economic, convenient gene deliverysystems with an appropriate regulation system eithertargeting specific tissues or cells to obtain long-term geneexpression or targeting tumor directly is developed.As the molecular biology of lung cancerpathogenesis and progression becomes increasinglyunderstood, and as techniques for gene cloning andidentification improve, a number of possible approaches tolung cancer gene therapy are emerging, which havedemonstrated promise in pre-clinical tests. Only some ofthese approaches have been mentioned here. Clinical trialsindicate that different types of combined modalities mayhave to be tailored to deal with specific sub-populations orindividuals. In other words, an optimal outcome willprobably depend on a combination of several genes orcombination of gene therapy and conventional treatments.The crux is how to best combine these novel approachesso that they produce such an optimal outcome. The diversenature of lung cancer suggests that molecular staging ofindividual cases will provide the best direction forcombined modality treatment. Most importantly, althoughthey are not always a reliable indicator of clinicaloutcome, carefully tested and controlled studies on animalmodels should be conducted to optimize the protocolsbefore clinical trials are made.AcknowledgmentsThis study was supported by grants awarded byHKU Research Committee and the PRC’s Ministry ofScience and Technology to R.A. Xu. 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