GTMB 7 - Gene Therapy & Molecular Biology

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Sanlioglu et al: Adenovirus mediated gene therapy for prostate carcinomaProstate-derived tumor models were used to evaluate theeffects of AdHSV-tk gene therapy as an adjuvant tosurgery (Sukin et al, 2001). Lung nodules of prostatecancer cells were generated by intravenous injection oftumor cells in order to evaluate systemic effects.Following resection of subcutaneous tumors, AdHSV-tkwas delivered to the resection site. Toxicity, local tumorrecurrence, survival, and lung nodule formation wereevaluated in animals; increased survival and decreasedrecurrence accompanied by no systemic toxicity wereobserved. Adjuvant AdHSV-tk gene therapy resulted in asignificant reduction in lung nodules as well. This studysuggested that AdHSV-tk gene therapy might be beneficialas an adjuvant for patients undergoing surgical treatmentof cancer.XIII. Current progress to overcomerate-limiting steps in adenovirus-mediatedgene therapy for prostate carcinomaThe success of adenovirus mediated gene therapy forprostate carcinoma is effected by several factors includingthe level of expression of the receptor which facilitates theentry of the viral vectors into the cells, penetration oftransgenes to surrounding tissues, and finally theexpression of the delivered gene. Enhancing these factorshas been the focus of many laboratories working onadenovirus-mediated gene therapy for prostate carcinoma.Although a limited number of studies have beencompleted regarding these issues, effectiveness of prostatecancer gene therapy will certainly benefit from theprogress in this field.A. Receptor abundanceThe presence of the coxsackie adenovirus cellsurface receptor, CAR, is required for an effectiveadenovirus infection of target cells. CAR expressionpatterns of normal prostate and prostate carcinoma werecompared using immunohistochemical approaches in orderto assess the feasibility of adenovirus mediated genetherapy for prostate cancer (Rauen et al, 2002). While arobust membrane staining for CAR was detected in themetastatic prostate specimens with higher Gleason scores,just lumenal and lateral cell membrane staining weredetected in the benign prostate epithelia. Therefore,adenovirus mediated gene delivery should be moreeffective for aggressive prostate tumors than it is forbenign cases.B. Penetration of hybrid therapeutictransgenes to the surrounding tissueDespite the fact that adenovirus could transduce cellsvery efficiently in vitro, adenovirus mediated genedelivery is restricted by the inefficient transduction ofsurrounding cells for a given tumor. In order to overcomethis obstacle, an important intercellular transport proteinnamed VP22, was first fused to the therapeutic transgeneof interest (p53 gene) and then cloned into adenovirusvector (Roy et al, 2002). Infection of p53 negative humanprostate cancer cells (LNCaP) by this approach generatedvery efficient gene delivery of p53, inducing apoptosis notonly in the infected cells but also in the surroundinguninfected cells.C. Enhancement of transgene expressionthrough transcriptional regulationAlthough the use of prostate specific promoters isnecessary to limit the transgene toxicity, the low level oftransgene expression directed by these promotersrepresents a barrier to gene therapy. The observation,which led to the idea that chemotherapeutics enhanced thetransgene expression from viral promoters, represented anew approach to overcome this barrier. Two recombinantadenovirus constructs were used to deliver p21WAF-1/CIP1 and p53 protein c-DNA under the control ofcytomegalovirus promoter to the metastatic androgenindependent prostate cancer cells treated withchemotherapeutic agents docetaxel or paclitaxel (Li et al,2002b). Both chemotherapeutics appeared to enhanceadenovirus mediated transgene expression in androgenindependent prostate cancer cell lines. This increase intransgene expression was attributed to the enhancement ofCMV promoter activity rather than the increased viraluptake. Therefore, the observed synergy of gene therapywith these chemotherapeutics may become useful whenthe transgene expression is a limiting factor for thetreatment of the metastatic androgen independent prostatecancer. The possible use of other chemotherapeutic agentsand their effect on prostate specific promoters should alsobe explored.XIV. Summary of clinical trialsThere are 636 clinical protocols involving 3496patients employed in gene therapy worldwide as reportedto the Journal of Gene Medicine website by the year 2002.403 clinical studies (63.4 %) with regard to gene therapyfor cancer were tested on 2392 (68.5 %) patients.Adenovirus was the vector of choice in 171 of theseprotocols (27 %), and 644 patients (18.4 %) received theadenovirus vector for gene therapy. 22 out of 171 clinicalprotocols were engaged in adenovirus mediated genetherapies targeting the prostate only as summarized inTable 1. 13 of these were reported to be in Phase I, 3 trialsin Phase II and the rest (5) were in Phase I/II. There is noPhase III clinical study reported using adenovirus vectorstargeting prostate yet. Some of the adenovirus mediatedgene therapy approaches were complemented either withradiotherapy or radical prostatectomy. The percentage ofthe choice of gene therapy modalities targeting prostate isprovided in Figure 3. The use of selectively replicatingadenovirus constructs leads other approaches followed bysuicide gene therapy. This is partly because not long agoastonishing results were obtained with selectivelyreplicating adenovirus constructs in the preclinical animalmodels. It is also interesting to note that two of theseclinical trials utilize suicide gene therapy in combinationwith the selectively replicating adenovirus approach126
Gene Therapy and Molecular Biology Vol 7, page 127(Figure 3). No clinical studies have been carried out usingthe death ligand-mediated gene therapy approach andadenovirus vectors up to date. However we should not besurprised if such trials are being initiated and we encountersome of these in the near future. Although preliminaryresults are very encouraging from these clinicalinvestigations, clear conclusions can be drawn only uponcompletion of these studies.Considering all these preclinical and clinical studies,we concluded that great progress in adenovirus mediatedgene therapy for prostate carcinoma has been made withinthe last 3 years. While the molecular mechanismsresponsible for prostate carcinoma are not fullyunderstood, the effectiveness of gene therapy is still quiteamazing. As more data become available on theunderstanding of prostate carcinoma, we anticipate thatmore effective treatment modalities will be developedusing adenovirus to target prostate cancer.Table 1. A summary of ongoing clinical trials of adenovirus mediated gene therapy targeting prostate as of 2002. The datawas collected from the Journal of Gene Medicine web site (www.wiley.co.uk/genmed/clinical) and published with thepermission from ©John Wiley and Sons 2002.Country Investigator Mode of Therapy PhaseCanada A. K. Stewart Immunotherapy (IL-2) ICanada J. Dancey Immunotherapy (IL-2) IUSA Peter T. Scardino Suicide gene therapy (HSV-tk) + radiotherapy IUSA Simon J. Hall Neo-adjuvant suicide gene therapy (HSV-tk) + radical prostatectomy IUSA Arie Belldegrun Tumor suppressor gene therapy (p53) IUSA Christopher J.LogothetisTumor suppressor gene therapy (p53)USA Dov Kadmon Neo-adjuvant suicide gene therapy (HSV-tk) + radical prostatectomy IUSA Jonathan W. Simons Selectively replicating adenovirus (CN706) II/IIUSA Thomas A. Gardner Suicide gene therapy (HSV-tk) IUSA Jae Ho Kim Suicide gene therapy (CD/Tk) with selectively replicating adenovirus +radiotherapyUSA E. Brian Butler Suicide Gene Therapy (HSV-tk) + radiotherapy I/IIUSA Jeffrey R. Gingrich Neo-adjuvant CDK inhibitor (p16) + radical prostatectomy IUSA Martha K. Terris Selectively replicating adenovirus (CV787) + Radiotherapy I/IIUSA George Wilding Selectively replicating adenovirus (CV787) I/IIUSA Alan Pollack Tumor suppressor gene therapy (p53) + radiotherapy IIUSA Thomas A. Gardner Selectively replicating adenovirus with osteocalcin promoter (Ad-OC-E1A)USA David M. Lubaroff Immunotherapy (PSA) IUSA Brian J. Miles Immunotherapy (IL-12) + radiotherapy IUSA Theodore L.DeWeeseSelectively replicating adenovirus (CV706)IIUSA Eric J. Small Selectively replicating adenovirus (CV787) + chemotherapy IIUSA Svend O. Freytag Neo-adjuvant suicide gene therapy (CD/Tk) with selectively replicating Iadenovirus + RadiotherapyUSA John M. Corman Selectively replicating adenovirus (CG7060) + radiotherapy I/IIII127
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