Clinical Experience With Gene Therapy for the Treatment of Prostate Cancer

New Directions in the Management of Advanced Prostate Cancer

RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S20 NEW DIRECTIONS IN PROSTATE CANCER MANAGEMENT Clinical Experience With Gene Therapy for the Treatment of Prostate Cancer Matthew A. Stanizzi, MD, Simon J. Hall, MD Department of Urology, The Barbara and Maurice A. Deane Prostate Health and Research Center, Mount Sinai School of Medicine, New York, NY Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients. [Rev Urol. 2007;9(suppl 1):S20-S28] © 2007 MedReviews, LLC Key words: Prostate cancer • Gene therapy • Prostate-specific antigen rostate cancer is the second most common malignancy among American men, resulting in over 27,000 deaths per year.1 Radical prostatectomy and radiation therapy are effective treatments for localized disease, although up to 30% of patients may experience disease recurrence initially manifest by an increasing prostate-specific antigen (PSA) level from either local failure or P S20 VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S21 Gene Therapy for Prostate Cancer pre-existing micrometastatic disease or both; many of these patients are treated with hormonal therapy. Once prostate cancer metastasizes clinically, treatment options are limited to hormonal therapy, which can slow symptomatic progression, but hormone-refractory disease will develop within a few years. Taxane-based chemotherapy is the first therapy to demonstrate any degree of survival benefit, although modest, for patients with hormone-refractory cancer.2,3 As a result, new treatment modalities are or missing gene responsible for cancer initiation. Because for many cancers, including prostate cancer, such genes have yet to be identified, science is exploring various other methods of cancer control through a variety of means. In general, these strategies fall into 3 distinct categories: direct tumor injection of a gene to kill cells; systemic gene delivery to target and kill metastases; or local gene expression intended to generate a systemic response, such as production of antiangiogenic proteins The key to the strategic process of successful gene therapy is the vector or the instrument by which a gene of interest (transgene) can be transported into cells. needed to address the current shortcomings of traditional therapies. With the advances in our understanding of the human genome, alteration and manipulation of genetic material to treat diseases have moved from the realm of science fiction to a distinct reality. The urologic community, no stranger to innovative therapies, has been at the forefront of exploring gene therapy for a variety of problems. Prostate cancer has attracted particular interest; as of November 2006 there are 785 approved gene therapy clinical trials, 529 for cancer treatment and 77 for prostate cancer.4 This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients. Gene Therapy: Basic Principles Gene therapy for cancer treatment can be broadly defined as any manipulation of DNA that incites events resulting in control of growth or cancer cell death. In its purest form, cancer gene therapy would be the replacement with a correct copy of a mutated or induction of antitumor immunity. The key to this process is the vector or the instrument by which a gene of interest (transgene) can be transported into cells. Nature has evolved numerous methods for cells to resist the ability of “foreign” pieces of DNA to influence cellular behavior and function. Viruses, basically packages of DNA or RNA, on the other hand, demonstrate individual and often unique processes to bypass these protective mechanisms, allowing the virus the ability to take over the functional machinery of the infected cell to replicate itself, usually killing the cell in the process. Thus, viruses have been exploited to be the most commonly used vector because they can be engineered to express genes of choice in targeted cells and not necessarily kill them. The ideal vector would be easy to manipulate and produce in high numbers, not cause human disease, and preferentially target cancer cells. Because this ideal does not exist, a variety of viruses are currently being explored (Table 1). For the purposes of this article, comments will focus on those vectors used in prostate cancer. Liposomes, double layers of lipid, can hold very large pieces of DNA, without the size constraint often encountered with viruses given the limit of how much material can be packaged within the viral capsid. Furthermore, these vectors are not immunogenic and thus could be used repetitively, especially systemically, without inducing neutralizing immune responses. The major drawback with this vector Table 1 Gene Therapy for Cancer Treatment: Viruses Currently Being Explored Liposomes Retrovirus 6 Adenovirus 12 Vaccinia Production Titer (/mL) N/A 10 10 N/A Size of Transgene
20 kB 8 kB 8 kB  25 kB In Vivo Efficiency Variable Poor High High Major Advantage Cause no disease Stable gene expression Transfects dividing and nondividing cells Can express large genes Major Disadvantage Very inefficient in vivo Infect only dividing cells Transient expression Very immunogenic VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S21 RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S22 Gene Therapy for Prostate Cancer continued is the lower level of efficiency in comparison with viral vectors. Retroviruses integrate randomly into chromosomal DNA before expressing its transgenes. Because this can only occur when cells are undergoing active mitosis, this is an inefficient process in vivo, given the relative low number of cells actively replicating in a tumor at any time. However, the progeny of successfully infected cells will continue to express its transgenes indefinitely, so this virus is best suited for creating cells that stably express promoter, restricts this activity to cells of interest to decrease the potential for toxicity. Furthermore, these vectors have been engineered to express cytotoxic genes to further the ability of the virus to kill tumor cells. Immunomodulatory Gene Therapy The gene therapy strategy that has progressed most in prostate cancer has been immunomodulatory gene therapy, with the development of ex vivo cancer vaccines proceeding Replication-incompetent adenoviruses are commonly used vectors because they express genes in a variety of cells efficiently. genes; in the area of cancer gene therapy, their use is limited to the creation of cancer vaccines ex vivo, such as GVAX® (Cell Genesys, Inc., San Francisco, CA). Replication-incompetent adenoviruses are commonly used vectors because they express genes in a variety of cells efficiently, regardless of the cell cycle status of an infected cell. This must be balanced with the relatively short duration of transgene expression and the induction of potent antiviral immune responses against the virus. This may negate the ability of repetitive dosing, especially if given intravenously, to achieve satisfactory levels of gene expression and may also result in reactions reminiscent of septic shock again, when given intravenously. Adenoviruses have also been engineered to maintain their replication competence under the control of tissue-specific promoters. The intent of using conditionally replicative adenoviruses (CRAds) takes advantage of the natural life cycle of the virus to not only kill infected cells, but also increase the number of viral particles in the first few days following injection. The use of the tissuespecific promoter, such as the PSA S22 VOL. 9 SUPPL. 1 2007 furthest in clinical trials. The original concept was to create a patientspecific vaccine by growing tumor cells from patients that were engineered by a retrovirus to express a cytokine, such as granulocytemacrophage–colony-stimulating factor (GM-CSF), to further enhance the induction of an antitumor immune response against tumor antigens expressed by the injected cells (Figure 1). The cells were growth-arrested by radiation and the cells injected under the skin. In a phase I study in highrisk patients undergoing radical prostatectomy, the process proved to be expensive and time consuming, the end product was of variable quality, and the concept was not a realistic option for large-scale production.5 However, the study did demonstrate that these vaccines induced antibodies against proteins expressed by prostate epithelial cells and the widely used human prostate cancer cells PC3 and LNCaP. This finding gave birth to GVAX®, a GM-CSF secreting vaccine created with lethally radiated PC3 and LNCaP cells. This vaccine has been given to over 200 patients in 5 different phase I/II trials.6 In 21 patients with an increasing PSA, postradical prostatectomy toxicity was limited to skin irritation and itchiness at the sites of injection and flulike symptoms.7 One patient had a 50% decline in PSA that lasted 7 months; in addition 16 patients (76%) experienced a prolongation of PSA doubling times. Proof of principle studies documented the induction of antibodies against proteins expressed by the vaccine; the presence and subsequent decline paralleled the duration of PSA changes. Initial experience in patients with metastatic hormone-refractory prostate cancer demonstrated a median survival of 26.2 weeks, which is greater than that in historical controls.6 In a follow-up study comparing differing doses of Figure 1. The classic cancer vaccine. Cancer cells are grown in culture from individual patients and infected with a retrovirus that expresses GM-CSF. Cells expressing GM-CSF, a cytokine that enhances antigen presentation, are expanded and lethally radiated to ensure they cannot grow when injected back into the subcutis. REVIEWS IN UROLOGY X-RAYs GM-CSF RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S23 Gene Therapy for Prostate Cancer vaccine, 32% (6/19) of patients in the highest dose group experienced PSA declines, whereas 43% (31/72) of all patients experienced stabilization of bone scans.7 Again, the safety profile was favorable. These encouraging results are the basis for an ongoing phase III trial comparing GVAX® versus docetaxel plus prednisone in patients with metastatic hormonerefractory prostate cancer. A second approach that also has had extensive clinical testing is the use of immunogenic viruses expressing candidate antigens such as PSA. The concept is to exploit the innate immunogenicity of a virus, which would preclude its use in other forms of gene therapy, to drive the coincident recognition of the transgene expressed by the virus, usually PSA, as an additional target for the immune system. Several groups have used vaccinia virus expressing PSA as the candidate antigen in 81 patients with either increasing PSA postradical prostatectomy or hormone-refractory disease in 3 phase I clinical trials.8-10 Toxicity was limited to skin changes at the site of injection and no doselimiting toxicity (DLT) was noted. Mechanistic studies demonstrated the ability of treatment to induce T cells against PSA. Using the definition of a stable PSA as increases up to 50% of initial value, 14 of 33 men had stable disease for at least 6 months.9 A phase II study addressed the potential for therapeutic benefit in patients with an increasing PSA postprostatectomy via 3 different injection schemes of a vaccinia and fowlpox viruses expressing PSA.11 The endpoint of the study was to determine PSA responses (decrease or normalization) and biochemical progression, defined as greater than 50% increase in PSA over baseline at 6 months postvaccine. By this definition 43% (29/64) of patients remained progression free, although no PSA reductions were ob- served. One injection scheme appeared superior but this was not statistically significant. An interim analysis of a second phase II trial in patients with hormone-refractory cancer noted modest decreases in PSA in 5 of 16 patients within 3 months of vaccination.12 A small number of patients treated for more than 6 months have stable disease. A further variation on this concept has been reported in 3 phase II trials combining standard treatments of radiation therapy, antiandrogen therapy, or chemotherapy with vaccine with the primary goal of determining whether these treatments could adversely affect the immune stimulatory activities of vaccine.13-15 In this instance, vaccine consisted of a mixture of 2 vaccinia viruses, one expressing PSA and the second expressing a costimulatory molecule B7-1 to augment T cell expansion with booster injections of a fowlpox virus expressing PSA. In all 3 instances combination therapy did not negatively impact on the induction of T cells against PSA, laying the groundwork for combining this approach with standard therapies. This process has most recently evolved with creation of both vaccinia and fowlpox viruses expressing 3 costimulatory molecules, B7-1, ICAM-1, and LFA-3, in addition to PSA to further enhance the environment to stimulate T cells against PSA. Ten patients with hormone-refractory prostate cancer were treated in a phase I clinical trial.16 As before, treatment was well tolerated with skin lesions at the site of injection as the most common side effect. Patients were observed for 8 weeks and no PSA responses were experienced in this time. At present, there are plans for a phase III trial called Paradigm in men with nonmetastatic hormonerefractory cancer, using these vectors. A variation on this theme has also been reported using the vaccinia virus to express both MUC-1, a transmembrane glycoprotein that is abnormally glycosylated in prostate cancer and IL-2. Sixteen patients who were experiencing PSA recurrence after definitive surgical or radiation therapy were treated in a phase I clinical trial.17 Treatment was well tolerated with minimal side effects. One patient experienced an objective PSA response. In addition, this patient demonstrated upregulation of IL-2 and T-cell receptors, increased CD4/CD8 ratio, augmentation of T-helper cells, and induction of natural killer cells, indicative of immune stimulation. Lastly, in the arena of immune stimulation, both a nonviral vector and an adenovirus have been utilized to deliver a cytokine, IL-2, directly into the prostate to stimulate antitumor immunity, mostly in patients as neoadjuvant therapy with radical prostatectomy.18,19 Treatment was well tolerated with both vectors, with only 1 patient in the adenovirus trial experiencing flulike symptoms. Review of pathology demonstrated an inflammatory response consisting of T lymphocytes with areas of tumor necrosis. PSA responses were only valid in the few patients with recurrent cancer treated with liposomalmediated IL-2, whereby 6 of the 9 also had lower-than-baseline PSA levels at week 10 after treatment.18 In Situ Gene Therapy Because gene mutations responsible for prostate cancer development have yet to be identified, tumor suppressor gene therapy such as with p53 for lung or colon cancer has not been used in prostate cancer. In its place, other routes of killing cancer cells have been pursued, with the use of the prodrug activation or “suicide gene therapy” system the most prevalent to be tested in humans. The basis for this approach is the expression of the prodrug activation enzyme, itself VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S23 RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S24 Gene Therapy for Prostate Cancer continued innocuous, which converts an equally nontoxic prodrug into a toxic drug to kill the cell. The most commonly explored in clinical trials uses the thymidine kinase gene from the herpesvirus (HSV-tk), which initiates a cascade of events converting antiherpetic agents, ganciclovir or valacyclovir, into cytotoxic agents (Figure 2). An added bonus is the phenomenon known as the bystander effect, whereby more cells are killed than were transduced by the gene. For the HSV-tk system, a variety of mechanisms appear responsible, from gap junction transport of the cytotoxic end product to stimulation of innate and acquired immunity.20-22 A number of phase I/II clinical trials have reported results in over 150 patients using a replication-incompetent adenovirus to deliver HSV-tk (Ad.HSV-tk) into cells following transrectal injection in patients with radiorecurrent prostate cancer or as neoadjuvant therapy with radical prostatectomy.23-27 A dose-limiting toxicity was experienced in the initial trial in 1 patient, but in subsequent experience with lower doses of vector toxicity is most commonly fevers, chills, and flulike symptoms for 1 to 2 days. Reductions were detected in 78% of patients with radiorecurrent disease PSA, averaging a 28% reduction that was associated with a significant prolongation of PSA doubling times from 15.9 to 42.5 months.26 Some patients underwent repeat cycles of vector injection followed by prodrug therapy without enhanced toxicity and PSA declines seen in approximately 30% of retreated patients. Examination of biopsy or surgically excised material demonstrated the presence of necrosis, apoptosis, and T cells reminiscent of those seen in preclinical models.25,27,28 Furthermore, treatment also resulted in longterm enhancement of activated CD8 T cells in peripheral blood.26,29 Although the target of these immune S24 VOL. 9 SUPPL. 1 2007 HSV-tk
GCV: Mechanism of Action HSV-tk Nondiffusible PGCV GCV phosphorylation P GCV converted to nucleoside analogue • Inhibits DNA synthesis • Cell cycle arrest Bystander effect • Gap junction transport of PGCV • Endocytosis of surrounding dead cells containing PGCV • Induction of natural killer and T cell responses Figure 2. How the HSV-tk plus prodrug system kills cells. GCV, ganciclovir; HSV-tk, herpesvirus. cells, tumor cells or adenovirus, and its association with treatment effect and/or outcome is unclear, these findings raise the possibility that similar to preclinical models, this treatment approach induces immune responses that may serve as the basis for combination therapies in the future. This Ad.HSV-tk treatment has been expanded to combination therapy with radiation therapy in a 3-armed phase I/II trial, because activated ganciclovir can act as a modest radiation sensitizer.30 Arm A enrolled 29 low-risk patients treated with intensity-modulated radiotherapy (IMRT), Arm B enrolled 26 high-risk patients treated with IMRT and hormonal therapy, and Arm C enrolled 4 lymph node–positive patients who received the Arm B regimen with the addition of 45Gy to the pelvic lymph nodes.31 There was no enhancement of toxicity with combination therapy over that of each therapy alone. In both Arms A and B, prostate biopsy results became negative in 100% of patients by 18 months. In Arm 3, 3 of 4 had biochemical failure within 7 months due to distance metastasis, although biopsy of the prostate gland showed no residual disease. These data were superior to historical REVIEWS IN UROLOGY controls and are the basis for further exploration of this combination approach. To enhance the margin of safety and restrict expression of potentially cytotoxic genes to targeted cells only, many groups have explored the use of tissue-specific promoters to control gene expression by adenoviral mediated gene therapy in preclinical models. To date, only 1 such vector has gone to clinical trial for prostate cancer patients, using the Osteocalcin (OC) promoter-driven expression of HSV-tk.32 This promoter is expressed prevalently in prostate cancer cells and adjacent fibromuscular stromal cells in locally recurrent prostate cancer and in osteoblasts in prostate cancer with bone metastasis. Conceptually, this vector could thus be used to target metastatic lesions in addition to the primary cancer. In a phase I clinical trial, the virus was injected in 11 patients, 2 into the prostate, 5 into bony lesions, and 4 in lymph node metastasis. No serious toxicity was noted, although pathologic examination of follow-up biopsy material demonstrated necrosis, apoptosis, and induction of T cells in 64% of treated patients.32 RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S25 Gene Therapy for Prostate Cancer Replication Competent Viral Vectors A number of investigators are exploiting the natural life cycle of the adenovirus not only to induce oncolysis of infected cancer cells, but also to expand on the injection dose of virus to enhance the numbers of target cells exposed to virus and thus maximize the therapeutic effect. However, wild type adenovirus has a predilection to infect the liver and cause a potentially fatal hepatitis. To enhance safety in this field, especially if such a vector were to be given intravenously, investigators have either taken advantage of natural mutants with specificity for oncolysis in tumor cells such as ONYX-015, which only replicates and kills cells with p53 mutations,33 or have placed adenoviral replication under control of tissuespecific promoters. To date, the only adenovirus vector to go to clinical trial in prostate cancer patients used a prostate-specific enhancer (PSE) sequence that resides at the 5 end of the human PSA gene to control viral replication34 (Figure 3). Initial experience in a dose-escalation phase I study was performed in 20 patients with radio-recurrent cancer. In contrast to the studies using Ad.HSV-tk, patients received a modified, needle template similar to that used for radioactive seed implantations. No dose-limiting toxicity was encountered, with fevers and chills being the most common issue, especially at the higher doses.35 Sixty-five percent (13/20) of patients experienced a reduction in PSA of greater than 30% with 5 having reductions of greater than 50%, all in the 2 higher doses, suggesting a dose response. More recently, this vector was dosed intravenously in a phase I trial as a single infusion in 23 patients with hormone-refractory prostate cancer.36 Dose-limiting toxicity of mild liver inflammation associated in some Liver cell Prostate cell Figure 3. Mechanism of action for CG7870. This vector is a replication-competent adenovirus. The genes that control replication have been placed under the control of a prostate-specific enhancer. Therefore, this virus can infect any cell, such as a hepatocyte, but cannot replicate. When it infects a prostate cancer cell anywhere in the body it replicates until the cell lyses and hundreds of new viral particles can infect surrounding cells, again replicating and killing only prostate cells. instances with D-dimer elevation (a marker for disseminated intravascular coagulation) and elevated IL-6 levels as a marker of antiviral response were experienced at a relatively high dose of vector. Although there was evidence in the serum of viral replication in 70% of the patients, no partial or complete PSA responses were detected; only a modest decrease in serum PSA of 25% to 49% was observed in 5 of the patients, seen more frequently at higher doses of vector. At present, there are plans to test this vector in 2 phase II trials, one in combination with radiation therapy and a second in combination with taxanebased chemotherapy. The use of CRAds has further evolved with the construction of a vector that also expresses transgenes to direct further cell kill. The one that has progressed to clinical trial expresses 2 suicide genes: HSV-tk and cytosine deaminase (CD). The latter converts 5-fluorocytosine into 5fluorouracil (5FU), which is a potent radiosensitizer. An individual cell expressing CD is a minifactory producing high levels of 5FU in the local tissues at levels higher than can be safely given intravenously.37 Because the byproduct of HSV-tk plus ganciclovir is also a radiation sensitizer, this double-suicide gene therapy vector has the potential for significant enhancement of radiation effects in addition to cytotoxic effects from the individual prodrug byproducts and the replication competence of the VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S25 RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S26 Gene Therapy for Prostate Cancer continued adenovirus. The first phase I study injected the vector using transrectal ultrasonography into 16 men with radiorecurrent prostate cancer.38 No dose-limiting toxicity was encountered with flu-like symptoms, common but transient, as in other adenovirus trials. Because 2 prodrugs were given, side effects of anemia, neutropenia, and thrombocytopenias were more common than in earlier 1-drug trials but were mild. Posttreatment biopsy specimens depicted changes consistent with treatment effect, while 44% (7/16) of patients experienced decreases in PSA, 3 of which were greater than 50%. This trial was followed up with a second phase I trial using the same vector in combination with radiation therapy in moderate- to highrisk prostate cancers.39 Fifteen patients were injected via a transrectal approach with a fixed dose of vector with the variable being the length of prodrug therapy from 1 to 4 weeks. Toxicities were common but mild, with no dose-limiting toxicities experienced, and no worsening of bladder, prostate, or rectal symptoms over those of radiation alone. Follow-up biopsy specimens demonstrated persistence of transgene expression for up to 3 weeks, longer than expected, with implications that prodrug therapy should be continued for longer periods to maximize therapeutic benefits without enhanced toxicity. This concept was furthered by the finding that the mean PSA half-life in patients administered prodrugs for more than 1 week was significantly shorter than that of patients receiving prodrugs for only 1 week: 0.6 months versus 2.0 months. Furthermore, this PSA half-life was shorter than that reported for patients treated with conventional-dose 3dimensional cathode ray therapy alone: 2.4 months. These observa- S26 VOL. 9 SUPPL. 1 2007 tions will undoubtedly be used in upcoming trials. On the Horizon The ultimate success or failure of cancer gene therapy will be realized by the further advancement in the development of vectors that more efficiently target tumor cells. Review of clinical trials to date has demonstrated the evolution from simple replication-incompetent vectors to more sophisticated vectors that preferentially act in tumor cells. However, these vectors are not targeting cancer cells; only the transgene expression or ability to replicate is restricted. A more thorough understanding of how viruses gain entry into cells has resulted in several new pathways to retarget viral vectors to cancer cells, with much of this work performed with adenovirus. Initial attempts involved chimeric antibodies to the knob of the virus linked to a ligand, such as epidermal growth factor; this served to block natural binding of the virus to its receptor, coxsackieadenovirus receptor (CAR), and provide a new means for vector binding to an intended target.40 Although somewhat cumbersome, it served to retarget vector uptake to cells overexpressing epidermal growth factor receptor, such as cancer cells. This approach has further evolved by genetically re-engineering the fiber to express a candidate ligand for cell surface binding. An example of this would be a fiber that expresses a peptide that preferentially binds to alphaV integrins, which are especially expressed by endothelial cells within tumors41 (Figure 4). Lastly, many cancers do not express CAR at sufficiently high levels to promote efficient transduction, so science has been creating chimeric adenovirus vectors expressing capsid or fiber proteins from alternative serotypes of adenovirus that gains entry to cells via different pathways unaffected by the malignant phenotype.40 This would also serve to decrease the amount of adenovirus that ends up in the liver following intravenous delivery because it has both a fenestrated endothelium and hepatocytes, which are rich in CAR. Alternatively, investigators are exploiting other viruses, both wild type and natural mutants, that appear to Figure 4. Cellular binding sites for adenovirus. Adenovirus gains entry to cells via a 2-step process: the knob at the end of the fiber binds to the coxsackie-adenovirus receptor (CAR) followed by interactions from the base of the fiber with integrins in the cellular membrane. Genetically, the sequences for the H1 loop, which binds to CAR, can be removed and replaced with sequences that bind to other surface proteins, thus reprogramming binding. Alternatively, the entire knob can be replaced with knobs from other serotypes of adenovirus that have natural predilection for certain cell types. REVIEWS IN UROLOGY Fiber Adenovirus knob • binding site for CAR • can be entirely replaced by knob from other adenovirus serotypes RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S27 Gene Therapy for Prostate Cancer preferentially act in cancer cells. Examples include the reoviruses that replicate in tumor cells with the activated gene of the ras family or rassignaling pathway, which is frequently overactive in cancer cells, while sparing normal cells, or vesicular stomatitis virus, which displays inherent specificity for replication in tumor cells due to their attenuated antiviral responses. 42,43 There are natural mutants of herpesviruses that also have a predilection for replication in tumor cells, which in turn have been engineered to express transgenes, making these vectors more potent anticancer vehicles.44 With the rapid growth in understanding of how these viruses function and their genomes are manipulated, there is no question that trials of the future will expand to a more advanced generation of vectors. Conclusion In a relatively short time, various gene therapy strategies have moved from in vitro and animal models to progression through clinical trials. It appears that use of GVAX® either alone or in combination with conventional therapies may soon be a reality. Likewise, several other approaches appear ready to be explored in conjunction with present treatments to improve outcomes for patients with prostate cancer. The future of this evolving field will depend on the growing understanding of the immune system, the viral life cycle, and molecular biology. 11. References 12. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2006. CA Cancer J Clin. 2006;56:106-130. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:15131520. Tannock IF, de Wit R, Berry WR, et al; for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351:1502-1512. Office of Biotechnology Web site. Available at: http://www4.od.nih.gov/oba. Accessed November 2006. Simons JW, Mikhak B, Chang JF, et al. Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res. 1999;59:5160-5168. Simons JW, Sacks N. Granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy: the GVAX vaccine for prostate cancer. Urol Oncol. 2006;24: 419-424. Simons JW, Carducci MA, Mikhak B, et al. Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naïve prostate cancer. Clin Cancer Res. 2006;12:3394-3401. Sanda MG, Smith DC, Charles LG, et al. Recombinant vaccinia-PSA (PROSTVAC) can induce a prostate-specific immune response in androgenmodulated human prostate cancer. Urology. 1999;53:260-266. Eder JP, Kantoff PW, Roper K, et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res. 2000;6:1632-1638. Gulley J, Chen AP, Dahut W, et al. Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. Prostate. 2002;53:109-117. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Kaufman HL, Wang W, Manola J, et al. Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2004;22:2122-2132. Brand TC, Tolcher AW. Management of high risk metastatic prostate cancer: the case for novel therapies. J Urol. 2006;176:S76-S80. Gulley JL, Arlen PM, Bastian A, et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res. 2005;11:33-53. Arlen PM, Gulley JL, Todd N, et al. Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J Urol. 2005;174:539-546. Arlen PM, Gulley JL, Parker C, et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res. 2006;12:1260-1269. Dipaola R, Plante M, Kaufman H, et al. A phase I trial of pox PSA vaccines (PROSTVAC®-VF) with B7-1, ICAM-1, and LFA-3 co-stimulatory molecules (TRICOM™) in patients with prostate cancer. J Transl Med. 2006;4:1. Pantuck, AJ, Van Ophoven A, Gitlitz BJ, et al. Phase I trial of antigen-specific gene therapy using a recombinant vaccinia virus encoding MUC-1 and IL-2 in MUC-1 positive patients with advanced prostate cancer. J Immunother. 2004; 27:240-253. Belldegrun A, Tso C, Zisman A, et al. Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology. Hum Gene Ther. 2001;12:883-892. 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Induction of potent antitumor natural killer cell Main Points • Treatment options for metastatic prostate cancer are limited to hormonal therapy, which provides only a modest survival benefit. • Gene therapy in prostate cancer treatment can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. • The gene therapy strategy that has progressed most in prostate cancer has been immunomodulatory gene therapy, with the development of ex vivo cancer vaccines proceeding furthest in clinical trials. • The future of this evolving field will depend on the growing understanding of the immune system, the viral life cycle, and molecular biology. VOL. 9 SUPPL. 1 2007 REVIEWS IN UROLOGY S27 RIUS0003(Watson)_02-14.qxd 2/15/07 3:53 AM Page S28 Gene Therapy for Prostate Cancer continued 23. 24. 25. 26. 27. 28. 29. 30. 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