Gene Therapy Prolongs PSA Doubling Time in Prostate Cancer Patients
Authors: Timothy C Thompson, Ron Rodriguez
Journal: Molecular Therapy (2007)

Over the last decade, the use of adenoviral vector-mediated gene therapy for prostate cancer has become the focus of many laboratory and clinical scientists. Protocols involving systemic injections of replication-competent adenovirus have been tested in preclinical studies and evaluated in clinical trials1Small EJ Carducci MA Burke JM Rodriguez R Fong L van Ummersen L et al.A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer.Mol Ther. 2006; 14: 107-117Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar and reviewed in the literature.2Lupold SE Rodriguez R Adenoviral gene therapy, radiation, and prostate cancer.Rev Urol. 2005; 7: 193-202PubMed Google Scholar, 3MacRae EJ Giannoudis A Ryan R Brown NJ Hamdy FC Maitland N et al.Gene therapy for prostate cancer: current strategies and new cell-based approaches.Prostate. 2006; 66: 470-494Crossref PubMed Scopus (23) Google Scholar, 4Kaliberov SA Buchsbaum DJ Gene delivery and gene therapy of prostate cancer.Expert Opin Drug Deliv. 2006; 3: 37-51Crossref PubMed Scopus (6) Google Scholar Although these approaches are important for direct targeting of metastatic disease, significant challenges remain for their successful application. Alternative approaches have involved intratumoral or in situ delivery of replication-competent or replication-defective adenoviral vectors. Replication-defective vector approaches include delivery of drug-activating genes along with a prodrug, genes that are directly cytotoxic, or cytokine genes that act indirectly. In general, these approaches are based on accessibility of the prostate gland to adenoviral vector delivery through standard urological protocols and the capacity to evaluate therapeutic impact through various methods, such as the measurement of prostate-specific antigen (PSA) in the serum. Freytag and Kim and their team of investigators have systematically developed a unique and optimized approach to in situ gene therapy for prostate cancer. Their system makes use of two separate drug-activating genes, cytosine deaminase (CD) and herpes simplex virus thymidine kinase (TK), and two independent prodrugs, 5-fluorocytosine (5-FU) and ganciclovir (GCV), in the context of an oncolytic, replication-competent adenoviral vector.5Freytag SO Rogulski KR Paielli DL Gilbert JD Kim JH A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy.Hum Gene Ther. 1998; 9: 1323-1333Crossref PubMed Scopus (316) Google Scholar, 6Rogulski KR Wing MS Paielli DL Gilbert JD Kim JH Freytag SO Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization.Hum Gene Ther. 2000; 11: 67-76Crossref PubMed Scopus (178) Google Scholar The activity of their agent, called Ad5-CD/TKrep, has been tested in a clinically relevant orthotopic mouse prostate cancer xenograft model, and its effectiveness has been shown to be further enhanced by radiation therapy.5Freytag SO Rogulski KR Paielli DL Gilbert JD Kim JH A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy.Hum Gene Ther. 1998; 9: 1323-1333Crossref PubMed Scopus (316) Google Scholar, 6Rogulski KR Wing MS Paielli DL Gilbert JD Kim JH Freytag SO Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization.Hum Gene Ther. 2000; 11: 67-76Crossref PubMed Scopus (178) Google Scholar, 7Freytag SO Paielli D Wing M Rogulski K Brown S Kolozsvary A Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model.Int J Radiat Oncol Biol Phys. 2002; 54: 873-885Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Their system has multiple potential applications. Two of the most important and timely of these have been tested in phase I clinical trials. These involve the use of Ad5-CD/TKrep together with radiation therapy for combination primary therapy8Freytag SO Stricker H Pegg J Paielli D Pradhan DG Peabody J et al.Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.Cancer Res. 2003; 63: 7497-7506PubMed Google Scholar and in situ delivery of Ad5-CD/TKrep in patients who are not helped by radiation therapy and who have a rising serum PSA.9Freytag SO Khil M Stricker H Peabody J Menon M DePeralta-Venturina M et al.Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer.Cancer Res. 2002; 62: 4968-4976PubMed Google Scholar In this issue, Freytag et al.10Freytag SO Strickler H Peabody J Pegg J Paielli D Movasas B et al.Five-year follow up of clinical trial of replication-competent adenovirus-mediated suicide gene therapy for the treatment of locally recurrent prostate cancer: effect of gene therapy on PSA doubling time.Mol Ther. 2007; 15: 636-642Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar report the results of a 5-year follow-up of men who received Ad5-CD/TKrep at the initial point of biochemical PSA failure after irradiation failure. They showed a significant increase in the PSA doubling time (PSADT), thus allowing a net prolongation of the time before androgen ablation therapy.10Freytag SO Strickler H Peabody J Pegg J Paielli D Movasas B et al.Five-year follow up of clinical trial of replication-competent adenovirus-mediated suicide gene therapy for the treatment of locally recurrent prostate cancer: effect of gene therapy on PSA doubling time.Mol Ther. 2007; 15: 636-642Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Investigators have struggled to develop the most workable and effective approach to treat prostate cancer with adenoviral vectors. The use of prostate-specific promoters and specific cytotoxic or cytokine gene(s) has followed a rational course. One of the most critical considerations is the specific clinical application for which the protocol is designed. For prostate cancer it is important to carefully evaluate the specific “clinical state” for which the approach is best suited and to optimize the standard treatment that the patient has received or that would subsequently be available after gene therapy.11Shaffer DR Scher HI Prostate cancer: a dynamic illness with shifting targets.Lancet Oncol. 2003; 4: 407-414Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Investigators must also be prepared to follow through with all necessary experiments and tests involved in clinical protocol development so as to ultimately gain FDA approval for their clinical trial. These challenges involve an interactive and talented translational research team. In today's funding environment these teams are difficult to establish and maintain. In their new study, Freytag et al. injected increasing doses of Ad5-CD/TKrep (1010Freytag SO Strickler H Peabody J Pegg J Paielli D Movasas B et al.Five-year follow up of clinical trial of replication-competent adenovirus-mediated suicide gene therapy for the treatment of locally recurrent prostate cancer: effect of gene therapy on PSA doubling time.Mol Ther. 2007; 15: 636-642Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar–1012Timme TL Fujita N Wang HY Naruishi K Kadmon D Amato RJ Miles BJ Ayala G Wheeler TM Teh BS Butler EB Thompson TC et al.Cytokine Gene Therapy for Genitourinary Cancer. Humana Press, Totowa, NJ2006Google Scholar viral particles) directly into localized prostate cancer lesions and administered a 1- or 2-week course of 5-FU and GCV in men with recurrent prostate cancer subsequent to standard radiation therapy. Follow-up evaluations included serum PSA analysis, and the median PSA follow-up was 5 years in this cohort. These men showed a significant increase in PSADT, a surrogate endpoint with significant prognostic power. In all evaluable subjects, the PSADT significantly increased from a mean of 16 to 31 months. Importantly, the initial decline in PSA shortly after gene therapy, together with the increased PSADT in these patients, resulted in a delay in the projected onset of androgen suppression therapy (AST) by an average of 2 years. AST is palliative and leads to the development of androgen-insensitive, metastatic disease in nearly all patients. In addition, AST is associated with significant morbidities. The results of this study therefore raise the possibility that intratumoral administration of Ad5-CD/TKrep could provide an attractive treatment option for selected patients experiencing PSA relapse subsequent to definitive radiation therapy. The results of this study are somewhat surprising, because they suggest that treatment with the adenoviral vector, which should have affected only the infected tumor cells and their immediate neighbors, somehow affected the disease course even of uninfected cells—long after the actual viral vectors were cleared from the body. There are multiple potential mechanisms by which this might occur, including the activation of antitumor immunity, the dissociation of PSA secretion from disease progression, and/or the selection of tumor cells with a less aggressive phenotype. Of these possibilities, stimulation of antitumor immunity is most attractive; however, this study was not designed to address this issue. The study was a small (n = 16) retrospective analysis of patients designed for phase I/II analysis and as such must be interpreted with caution. Nonetheless, this is the first demonstration of any long-term clinical benefit to prostate cancer patients with a gene therapeutic. The data on PSA progression seem to be consistent and are not driven by one or two outlier patients and hence appear very credible in this preliminary study. The report raises many issues that require further study. It remains to be established whether the effect was mediated through induction of antitumor immunity. It must also be established whether the effect requires the CD or TK transgene, or whether it can occur with any adenoviral vector. It is unclear whether viral replication was required for this activity or whether repeat intratumoral injection could further augment efficacy. It would be interesting to determine whether addition of a cytokine gene might increase this activity or as a single-gene approach mimic the effects. Finally, it must be established which patients would derive the most benefit from such an approach. Increasingly there has been waning support from industry and through federally funded grants to pursue the development of oncolytic or replication-defective adenovirus-mediated cancer therapy. Freytag, Kim, and colleagues have made an important preliminary observation at a most critical time in adenoviral vector–mediated cancer gene therapy—and one that strongly supports the continuation of this type of work. Further multi-institutional studies are needed to more rigorously test these protocols. Long-term follow-up may reveal possible systemic effects that potentially involve antitumor immune responses.12Timme TL Fujita N Wang HY Naruishi K Kadmon D Amato RJ Miles BJ Ayala G Wheeler TM Teh BS Butler EB Thompson TC et al.Cytokine Gene Therapy for Genitourinary Cancer. Humana Press, Totowa, NJ2006Google Scholar