GTMB 7 - Gene Therapy & Molecular Biology

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Cai et al: Lung cancer gene therapyby delivery of protease gene, such as mouse macrophagemetalloelastase (Gorrin-Rivas et al, 2000; 2001) andporcine pancreatic elastase 1 (Matsuda et al, 2000), havebeen demonstrated as an effective alternative in differentcancers.3. TIMPsTIMP-1, TIMP-2, and TIMP-3 are natural matrixmetalloproteinase (MMP) inhibitors that prevent thedegradation of extracellular matrix proteins (Anand-Apteet al, 1997; Moses et al, 1990; Takigawa et al, 1990). Thein vivo efficiency of TIMP-2 has been evaluated in murinelung cancer LLC, and colon cancer C51 in syngeneic miceas well as in human breast cancer in athymic mice (Li etal, 2001). A single intratumoral injection of Ad-TIMP-2significantly reduced tumor growth rates by 60-80% andtumor-associated angiogenesis index by 25-75%, and wasaccompanied by significantly prolonged survival. Lungmetastasis of LLC tumor was inhibited by >90%.Pulmonary metastasis was significantly reduced in amurine melanoma metastasis model following 4 weeks ofintramuscular injection with plasmid encoding TIMP-1compared to controls treated with the plasmid DNA vectoralone. Further therapeutic effects were realized bycombination treatment with IL-2 (Shi et al, 2002). Genetransfer based on nontoxic cationic cholesterol derivativesindicated potent antitumor efficiency of TIMP-2 andTIMP-3 in HCC xenograft in nude mice (Tran et al, 2003).However, if TIMPs are to be utilized in antiangiogenesistherapy, close consideration should be given to a studysuggesting an angiostatin-producing role for MMP-9(Pozzi et al, 2002).4. Combination strategiesMany of the endogenous inhibitors involved incancer gene therapy succeed merely in slowing tumorgrowth, and need to be used in combination therapy forgreater effectiveness (Shi et al., 2003). A combinationapproach has been attempted with tricistronic retroviralvectors encoding two inhibitors of angiogenesis expressedin a rat glioblastoma cell line: N-terminal fragment of ratprolactin and a secret form of human platelet factor 4(Spf4). The results suggested that, in order to successfulcounteract tumor progression, antiangiogenetic strategyshould be combined with other strategies (Ciafre et al,2002). Another multigene therapy presented dormant anderadicated tumors by inhibition of angiogenesis usingendostatin gene together with cytotoxic HSV-tk genetherapy (Pulkkanen et al, 2002). Adeno-associated virusmediatedgene transfer, when combined with ionizingradiation, enhanced inhibition of tumor growth (Shi et al,2003). When assessing antitumor immune responseagainst the recombinant protein of angiostatin andendostatin, Li et al, (2001, 2001) demonstrated that thehost’s immune response may potentiate the antitumoreffects of antiangiogenic agents. Angiostatin gene therapypreceded by an in situ gene transfer of T-cell costimulatorB7.1 eradicates pre-established tumors and a systemicchallenge of cancer cells (Sun et al, 2001). More than anendogenous inhibitor, IL-12 is stronglyimmunomodulatory. When multigene therapy usingangiostatin plus IL-2 was performed, a synergistictherapeutic effect was noted (Wilczynska et al, 2001).B. Inhibition of proangiogenic factors1. Endothelial cell-specific ligand/receptortyrosine kinase systemsKeeping tumors from proangiogenic stimuli andinterrupting the resultant angiogenesis can be achieved bygene therapy to damage endothelial cell-specificligand/receptor tyrosine kinase systems. One of thesesystems consists of vascular endothelial growth factor(VEGF) and its two receptors flt1 and flk1/KDR, andanother consists of angiopoietin-1 and its receptor tie2.The antisense strategy to inhibit transcription of VEGF(Im et al, 1999) and angiopoietin-1 (Shim et al, 2001)produced controlled tumor growth in vivo by inhibitingtumor angiogenesis.The possibility of blocking VEGF and angiopoietin-1 function by gene delivery to produce a soluble form oftheir receptors has recently attracted attention. Hoshida etal, (2002) have demonstrated that the intratumoraladministration of adenovirus-mediated soluble flt-1(sFLT-1) gene results in a regional tumor suppressioneffect. Using intramuscular injection of adenoviral vectorsexpressing sFLT-1, they demonstrated subcutaneousgrowth inhibition in five out of six human lung carcinomacell lines tested in nude mice (Takayama et al, 2000). Asimilar strategy was used by Mahasreshti et al, (2001),who showed that adenovirus-mediated sFLT-1 genetherapy inhibited s.c. ovarian tumor growth, and i.p.injection increased survival in a murine model of ovariancarcinoma. Mori et al, (2000) demonstrated that repeatedintraperitoneal transduction of a soluble flt-1 gene usingHVJ-cationic liposomes suppressed peritoneal metastasesof some cancers, thereby contributing to a longer survivalperiod.In vivo studies of the soluble form of flk-1 (sFLK-1)showed that the growth of neuroblastoma cells wasinhibited by retroviral mediated expression of sFLK-1(Davidoff et al, 2001) or by inoculation with fibroblastwhich produced retroviral vectors encoding sFLK-1(Davidoff et al, 2000). Tseng et al, (2002) evaluated theantitumor effects of the in vivo administration of anadenovirus vector encoding sFLK1 in 3 murine models ofpancreatic adenocarcinoma. Intravenous injection of AdsFLK1resulted in smaller tumor volumes in subcutaneoustumor models both in immunocompetent and SCID mice.The treatment also contributed to longer survival in themetastatic model. A recent investigation employed anAAV vector to transfer the sFLK1 gene. Intraportalinjection of this vector preceded the intrarenal ororthotopic renal tumor implant, and resulted in growthrestriction of tumors or tumor rejection (Davidoff et al,2002).After generating an adenoviral vector encodingsoluble Tie2 gene, Lin et al, demonstrated that i.v.injection of this vector significantly inhibited the growthof subcutaneous primary tumors, as well as experimentalor spontaneously occurring lung metastases (Lin et al,262
Gene Therapy and Molecular Biology Vol 7, page 2631998). Hangai et al, (2001) produced a high plasma levelof soluble Tie2 in mice by a single intramuscular injectionof adenovirus expressing soluble Tie2. This treatmentinhibited intraocular neovascularization, providing apotential approach to treat metastatic cancer using anangiogenesis inhibitor gene.However, not all attempts to target the angiogenesisof cancer using gene therapy strategy have been effective.Some studies have produced negative results even whencontinuous, high levels of protein were produced (Eistereret al, 2002; Pawliuk et al, 2002). Kuo et al, (2001)generated adenoviral vectors encoding angiostatin,endostatin, and the ligand-binding ectodomans of Flk1,Flt1, and neuropilin, and evaluated them in severaldifferent preexisting murine tumor models by systemicdelivery. Ad-Flk1 and Ad-Flt1 resulted in approximately80% inhibition of preexisting tumor growth in murine andhuman tumors. By contrast, adenoviruses encodingangiostatin, endostatin, or neuropilin were significantlyless effective. Regulier et al, (2001) compared theadenoviral delivery of endostatin, proliferin-related protein(PRP), and interferon-inducible protein 10 (IP10) genes ina murine B16F10 melanoma model in immunocompetentmice. Ad-PRP or Ad-IP10 was significantly more efficientthan Ad-endostatin, leading to complete tumor rejectionand prolonged survival in a high proportion of treatedanimals.2. Endothelial progenitor cells targetsThe modification of bone marrow-derived cells withtherapeutic genes has recently provided long-term targetedangiogenesis inhibition. Davidoff et al, (2001) transducedmurine bone marrow cells with a retroviral vectorencoding sFlk1. Tumor growth in mice challenged 3months after transplantation with tsFlk-1-expressing bonemarrow cells was significantly inhibited. De Palma et al,(2003) showed that when tumors were grown in mice intowhich bone marrow progenitors transduced with lentiviralvectors expressing genes from transcription-regulatoryelements of Tie2/Tek gene were transplanted, these Tie2-expressing mononuclear (TEM) cells had a distinguishablephenotype and were present selectively at angiogenic sites.An HSV-tk & GVC approach targeting TEM cells resultedin substantial inhibition of angiogenesis and slower tumorgrowth without systemic toxicity. This experimentdemonstrated that targeting exogenous genes to tumorangiogenesis could be achieved by transplantation ofgenetically-modified hematopoietic stem cells.V. ImmunotherapyA. DNA vaccine1. Tumor-associated genesCarcinoembryonic antigen (CEA) is a cell surfacetumor marker present in a variety of cancers, includinglung cancer. The antitumor effects of an oral DNA vaccineencoding human CEA were obtained in mice, whenboosted with an antibody-IL2 fusion protein. This vaccinebroke peripheral T-cell tolerance toward CEA expressedby Lewis lung carcinoma stably transduced with CEA,resulting in eradication of subcutaneous tumors in 100%of mice and prevention of experimental pulmonarymetastases in 75% of experimental animals in prophylacticsettings (Niethammer et al, 2001). Song et al, (2000)demonstrated that intramuscular injection of a CEAplasmid without coinjection of IL-12 plasmid could notachieve complete resistance to a tumor challenge inwildtype mice by CEA-positive Lewis lung carcinomacells, while injection of the IL- 12 plasmid alone was notprotective. Luo et al, (2003) improved naked CEA DNAvaccine by absorbing it onto cationic microparticles,which are more immunogenic. Boosting with GM-CSFplasmid increased the vaccine’s efficacy, resulting in acomplete rejection of tumor cells in 50% of mice.Utilizing conventional and transgenic mice, Grosenbach etal, (2001) demonstrated that the use of cytokines anddiversified prime and boost regimens could be combinedwith the use of recombinant pox virus vectors expressingsignal 1, such as B7.1, and multiple costimulatorymolecules to further amplify T-cell responses toward moreeffective vaccine strategies. Three different costimulatorymolecule transgenes (B7-1, ICAM-1, and LFA-3) wereused, and the two unique vectors rV-CEA-TRICOM(recombinant vaccinia vector) and rF-CEA-TRICOM(recombinant fowlpox vector). A similar conclusion wasreached by Aarts et al, (2002), who evaluated a diversifiedvaccination protocol consisting of rV-CEA/TRICOM andrF-CEA/TRICOM on transgenic mice. A Phase I clinicaltrial on colorectal cancer using naked DNA immunizationagainst the CEA showed that the vaccination was toleratedwell. The success of the treatment, which has proved to beeffective in a number of patients treated solely byimmunizations, clearly depends on the stage of thedisease. The treatment is most efficient in patients withminimal disease or no metastases (Mincheff et al, 2001).In patients with metastatic carcinoma, clinical study hasshown that ALVAC-CEA B7.1, a canarypox virusencoding the gene for CEA and for B7.1, is safe andstabilizes the disease for up to 13 months (von Mehren etal, 2001). This approach may be a promising strategy forlung cancer vaccines, as immunofluorescence assayshowed that no cell surface expression of CD80 proteinwas detected at all in 31 human NSCLC cell lines(Wroblewski et al, 2001).MUC1 is a cell surface glycoprotein, expressed inmost epithelial tissues and normal lung tissue, and hasbeen shown to be preserved in most NSCLC cell lines andtumors. However, it is not expressed in normal lymphnodes. Vaccination of mice with naked DNA of MUC1produced long-term tumor growth suppression (Johnen etal, 2001), and also suppression of the development of lungmetastases, in which natural killer cells are the majoreffector cells (Kamata et al, 2002). When a similar vaccinewas given in a tumor-bearing mice model, it wasinsufficient to suppress tumor growth. However, theaddition of activated but nonprimed dendritic cells (DCs)obtained from syngeneic mice markedly suppressed tumorgrowth, and prolonged survival time (Kontani et al, 2002).2. Tumor vasculature targets263
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GTMB 7 - Gene Therapy & Molecular Biology

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