Clinical Adenoviral Gene Therapy for Prostate Cancer

Abstract

Prostate cancer is at present the most common malignancy in men in the Western world. When localized to the prostate, this disease can be treated by curative therapy such as surgery and radiotherapy. However, a substantial number of patients experience a recurrence, resulting in spreading of tumor cells to other parts of the body. In this advanced stage of the disease only palliative treatment is available. Therefore, there is a clear clinical need for new treatment modalities that can, on the one hand, enhance the cure rate of primary therapy for localized prostate cancer and, on the other hand, improve the treatment of metastasized disease. Gene therapy is now being explored in the clinic as a treatment option for the various stages of prostate cancer. Current clinical experiences are based predominantly on trials with adenoviral vectors. As the first of a trilogy of reviews on the state of the art and future prospects of gene therapy in prostate cancer, this review focuses on the clinical experiences and progress of adenovirus-mediated gene therapy for this disease.

Introduction

P rostate cancer is the most commonly diagnosed malignancy in European men, and one of the main causes of cancer-related mortality (Ferlay et al., 2007). The number of men dying each year of prostate cancer is growing gradually because of an aging population. The majority of prostate tumors are diagnosed as organ-confined disease, and are treated with curative intent by radical prostatectomy or radiation therapy. However, curative treatment of localized prostate cancer fails in about 20 to 50% of the patients, resulting in a biochemical recurrence and ultimately progressive, metastatic disease with a fatal outcome (Djavan et al., 2003). Once the disease has spread beyond the prostate, no curative treatments are currently available. Because most prostatic tumors depend on androgens for their growth, androgen ablation and/or antiandrogen therapy is the “gold standard” treatment for advanced disease. Most patients initially respond favorably to this therapy, but virtually all patients relapse with fatal hormone refractory cancer within 1–3 years. At this stage of the disease, only palliative treatment is available that may delay, but not prevent, painful bone metastases, renal obstruction, and bone marrow insufficiency.

The incidence of prostate cancer has significantly increased because of widespread use of the prostate-specific antigen (PSA)-based screening tool. It was reported by the European Randomized Study of Screening for Prostate Cancer that screening reduces the relative risk of prostate cancer death by at least 20% (Schroder et al., 2009). Because of screening, the early detection of prostate cancer is now also resulting in a shift from metastatic toward localized disease at diagnosis. As a result, the number of curable patients is rising. Improvement of the cure rate by primary treatment of localized prostate cancer aiming at a reduction of disease-related mortality without introducing higher morbidity will therefore influence the quality of life of a large and increasing number of patients and their relatives, and may also limit health care costs. Thus, there is an apparent strong need to enhance the cure rate of primary therapy. This may be achieved by adjuvant therapy aiming at the reduction of tumor size before surgery or radiotherapy, attack on presumed micrometastases, or treatment of local recurrent disease after primary therapy. Adjuvant hormone therapy or chemotherapy is associated with severe and unpleasant side effects and the clinical benefits for early-stage prostate cancer are still not well defined (for review see Mazhar et al., 2006; Pendleton et al., 2007). As stated previously, for advanced prostate cancer that has spread to other parts of the body no curative therapy is currently available. To improve the treatment of localized and advanced prostate cancer new treatment modalities are currently being explored, including gene therapy. Various forms of gene therapy for prostate cancer have been tested in a clinical setting, including suicide gene therapy, oncolytic adenovirus therapy, and immunogene therapy using viruses or plasmids as carriers for vaccines or immunostimulators. An overview of the outcome of the majority of these trials, up to 2007, was published by Freytag and colleagues (2007b). In most of these trials, human adenoviruses were used as the gene therapy product. Especially for localized disease, adenovirus-mediated gene therapy is an attractive candidate adjuvant treatment. The prostate is relatively easy to access for intratumoral administration, enabling a local attack on the tumor cells without major side effects. In almost all adenovirus-mediated gene therapy trials for prostate cancer, the vector was indeed administered locally in patients with localized prostate cancer or locally recurrent prostate after radiotherapy, as described in more detail in this review. Systemic delivery as a treatment for metastasized prostate cancer has been applied in one trial only.

In this first of the trilogy of reviews on the state of the art and future prospects of gene therapy in prostate cancer, we summarize advances in clinical adenovirus-mediated gene therapy for prostate cancer.

Prostate Cancer Gene Therapy Trials Using Replication-Deficient Adenoviral Vectors

The first adenoviral gene therapy trials for prostate cancer were based primarily on suicide gene therapy using replication-deficient vectors and involved local delivery as the route of administration (Table 1). In the majority of these phase I and phase I/II trials, the safety of adenovirus-mediated gene therapy was studied as an adjuvant therapy to primary treatment in patients with localized prostate cancer and a high risk of recurrence or to combat locally recurrent disease after radiotherapy. All trials reported that intraprostatic administration of a replication-deficient adenoviral vector is well tolerated. No dose-limiting toxicity was observed and adenovirus-associated side effects involved mainly flulike symptoms. Cytopathic effects in the prostate, including apoptosis and necrosis, were reported in various studies (Ayala et al., 2000, 2006; Miles et al., 2001; Teh et al., 2001; Kubo et al., 2003; Trudel et al., 2003). In addition, in a trial of the CTL102 virus, expression of the nitroreductase transgene in resected tumors was described for all dose levels (Patel et al., 2009). A number of trials, all conducted in patients with local recurrence after radiotherapy or metastasized disease (Table 1), have described clinical effects of suicide gene therapy with a replication-deficient adenoviral vector, using the serum PSA level and related parameters such as PSA doubling time as surrogate response markers. In patients with locally recurrent prostate cancer after radiotherapy, a significant prolongation of the mean PSA doubling time as well as a PSA reduction was found (Herman et al., 1999; Shalev et al., 2000; Miles et al., 2001). Long-term follow-up of patients with hormone-refractory metastasized prostate cancer treated locally with osteocalcin promoter-driven suicide gene therapy showed a PSA response in one of six treated patients, lasting for 1 year (Shirakawa et al., 2007). Nasu and colleagues reported an increase in the PSA doubling time as well as an obvious decrease in the serum PSA level in nonmetastasized patients with local recurrence after hormonal therapy (Nasu et al., 2007). Furthermore, a trend toward an increase in the time to progression, based on PSA kinetics, was reported by Patel and colleagues (2009). For the trials using gene therapy as an adjuvant treatment to primary therapy for localized prostate cancer, clinical effects were not described. This may be due to the fact that efficacy is difficult to assess because of the slow progression of the disease, the lack of a proper control group of patients, and the small size of the patient groups included in the trials. Long-term follow-up will be required to compare the clinical outcome or survival of these patients with the outcome of the general population of patients treated with surgery or radiotherapy only. Interestingly, a common observation reported in these trials as well as in the trials of recurrent and advanced disease is the induction of both a local and systemic immune response, including infiltration of T and B cells and other immune cells in the prostate and an increase in systemic cytokine levels (Ayala et al., 2000, 2006; Miles et al., 2001; Kubo et al., 2003; van der Linden et al., 2005). Van der Linden and colleagues provided evidence of an antiadenovirus immune response (van der Linden et al., 2005). These observations were confirmed by an extensive immunological characterization study performed by Onion and colleagues in patients with locally recurrent disease treated with CTL102/CB1954 suicide gene therapy (Onion et al., 2009). This group also demonstrated an increase in the number of T cells responsive to prostate-specific antigens such as PSA and prostate-specific membrane antigen in a number of treated patients. Thus, the immune responses observed in the various trials may well be associated with antitumor immunity.

Table 1.

Prostate Cancer Gene Therapy Trials with Replication-Deficient Adenoviral Vectors

Vector	Mechanism of action	Disease stage	Setting	Ref.
AdIL-2	Activation of immune system by expression of IL-2	High-risk localized PCa^a (12 patients)	One intraprostatic injection cycle 4 weeks before RP	Trudel et al. (2003)
Adv-HSV-tk + GCV	Activation of cytotoxic prodrug GCV by expression of HSV-tk	Low- and high-risk localized PCa (30 patients)	One to three intraprostatic injection cycles + RP, radiotherapy, or radiotherapy + hormonal therapy	Teh et al. (2001)
		High-risk localized PCa (23 patients)	One intraprostatic injection cycle 2–4 weeks before RP	Ayala et al. (2006)
		High-risk localized PCa (12 patients)	One intraprostatic injection cycle 3 weeks before RP	van der Linden et al. (2005)
		Locally recurrent PCa after radiotherapy (18 patients)	One intraprostatic injection cycle	Herman et al. (1999)
		Locally recurrent PCa after radiotherapy (36 patients^b)	One to three intraprostatic injection cycles	Miles et al. (2001)
		Locally recurrent PCa after hormonal therapy (8 patients)	One intraprostatic injection cycle	Nasu et al. (2007)
Ad-OCT-TK + VAL	Activation of cytotoxic prodrug VAL by OC promoter-driven expression of HSV-tk	Locally recurrent PCa and hormone-refractory metastatic PCa (11 patients)	One or two intralesional injection cycles	Kubo et al. (2003)
		Metastatic PCa (6 patients)	Two intralesional injection cycles	Shirakawa et al. (2007)
CTL102 + CB1954	Activation of cytotoxic prodrug CB1954 by expression of nitroreductase	Localized PCa (20 patients)^c	One intraprostatic injection cycle	Patel et al. (2009)
		Locally recurrent PCa after primary treatment (19 patients)	One intraprostatic injection cycle (5 patients) or two intraprostatic injection cycle (14 patients)	Patel et al. (2009)

Abbreviations: CB1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide; GCV, ganciclovir; HSV-tk, herpes simplex virus thymidine kinase; IL-2, interleukin-2; OC, osteocalcin; PCa, prostate cancer; RP, radical prostatectomy; VAL, valacyclovir.

The risk refers to the risk of recurrence after primary treatment (radical prostatectomy or radiotherapy).

The first 18 patients have already been described in the publication by Herman et al. (1999).

These patients were treated with CTL102 only 2–5 days before radical prostatectomy in order to assess nitroreductase expression as well as safety and tolerability of the virus.

The trials described previously demonstrated the safety and feasibility of adenovirus-mediated gene therapy for prostate cancer. However, it then also became clear from clinical experiences in gene therapy for solid tumors in general that the efficacy of replication-deficient adenoviral vectors is limited because of short-lasting activity. Clearly, more powerful vectors were needed to achieve a critical level of the adenovirus concentration at the target site for efficient infection of target cells and transgene transduction. At the same time, the safety of these vectors should be warranted to avoid harmful damage to healthy tissues. These new insights resulted in the development of oncolytic adenoviruses, viruses with a favorable safety profile that can kill specific tumor or tissue cells via transductional or transcriptional targeting. Numerous clinical trials have been conducted or are ongoing to test oncolytic adenoviruses as a targeted therapy for various types of cancer, including prostate cancer. An overview of the oncolytic adenovirus trials conducted in prostate cancer is presented in the next section.

Prostate Cancer Gene Therapy Trials Using Oncolytic Adenoviruses

In the United States, several phase I trials have been performed for prostate cancer, using three different oncolytic adenoviruses (Table 2). These viruses were all well tolerated without serious complications. The first trial of oncolytic adenovirus therapy for prostate cancer was conducted by DeWeese and colleagues. They tested the prostate-specific oncolytic adenovirus CV706 in 20 patients with locally recurrent prostate cancer after radiation therapy (DeWeese et al., 2001). Replication of CV706 is restricted to prostate cells by means of PSA promoter-controlled expression of the E1A gene. Furthermore, CV706 lacks the E3 gene. In the trial, the virus was locally administered at 20 to 80 deposits, using a brachytherapy technique. The five patients treated with the two highest doses of CV706 experienced a PSA serum level decrease of 50% or more, which was sustained for at least 4 weeks in four patients. This trial provided the first data suggesting that oncolytic adenovirus therapy has an effect on prostate cancer.

Table 2.

Prostate Cancer Gene Therapy Trials with Oncolytic Adenoviruses

Vector	Mechanism of action	Disease stage	Setting	Ref.
Ad5-CD/TKrep + 5-FC + GCV	Conditional replication due to absence of E1B gene in cells with mutated p53 pathway + double suicide gene therapy	Intermediate- to high-risk PCa^a (15 patients)	One intraprostatic injection cycle + radiotherapy	Freytag et al. (2003)
		Locally recurrent PCa after radiotherapy (16 patients)	One intraprostatic injection cycle	Freytag et al. (2002)
Ad5-yCD/mutTK_SR39 rep-ADP + 5-FC + GCV	Conditional replication due to absence of E1B gene in cells with mutated p53 pathway + double suicide gene therapy	Intermediate- to high-risk PCa^a (9 patients)	One or two intraprostatic injection cycles + radiotherapy	Freytag et al. (2007a)
CV706	Prostate-specific replication controlled by PSA promoter	Locally recurrent PCa after radiotherapy (20 patients)	One intraprostatic injection cycle	DeWeese et al. (2001)
CG7870	Prostate-specific replication controlled by rat probasin promoter for E1A and PSA promoter-enhancer for E1B	Hormone-refractory metastatic PCa (23 patients)	One intravenous injection cycle	Small et al. (2006)

Abbreviations: 5-FC, 5-fluorocytosine; ADP, adenovirus death protein; CD, cytosine deaminase; GCV, ganciclovir; PCa, prostate cancer; PSA, prostate-specific antigen; RP, radical prostatectomy; TK, thymidine kinase.

The risk refers to the risk of recurrence after primary treatment (radical prostatectomy or radiotherapy).

The next trials were published by Freytag and colleagues, who have extensively studied an oncolytic adenovirus expressing two suicide genes (Table 2). The first-generation virus, Ad5-CD/TKrep, lacking both the adenoviral E1B and E3 genes, was tested as salvage therapy in 16 patients with recurrent prostate cancer after radiotherapy (Freytag et al., 2002) and as adjuvant therapy in 15 patients with newly diagnosed, intermediate- to high-risk prostate cancer treated by three-dimensional conformal radiation therapy (Freytag et al., 2003). Short-term follow-up of the patients with recurrent disease showed a transient decrease in the PSA level in 10 of 16 cases (Freytag et al., 2002). In some patients, this PSA response was associated with histopathological findings of tumor destruction. Interestingly, this clinical benefit was confirmed by a report on the 5-year follow-up of these patients (Freytag et al., 2007c). In 14 evaluable subjects, a significant increase in the PSA doubling time from a mean of 17 to 31 months was observed, and the need for salvage androgen suppression therapy was delayed by an average of 2 years. Furthermore, indications for dose dependency of these clinical responses were found. The most likely explanation for this promising long-term clinical benefit is the induction of antitumor immunity, as postulated by the investigators (Freytag et al., 2007c). Although immunological end points were not included in this trial, further research on the characteristics of the immune response triggered by oncolytic adenovirus therapy is clearly warranted. Analysis of the short-term clinical effects in the trial studying Ad5-CD/TKrep as an adjuvant in patients with newly diagnosed prostate cancer treated with radiotherapy is hindered by the fact that the primary treatment already results in a decline of the PSA level. On the basis of PSA kinetics, observations in this trial might suggest that oncolytic adenovirus therapy may positively interact with radiotherapy in patients who received more than 1 week of prodrug therapy (Freytag et al., 2003).

In a similar setting as the second trial with Ad5-CD/TKrep, involving nine patients, Freytag and colleagues then tested a second-generation virus called Ad5-yCD/mutTK_SR39 rep-ADP that expresses improved suicide genes as well as the adenovirus death protein (Freytag et al., 2007a). The safety profile of Ad5-yCD/mutTK_SR39 rep-ADP was comparable to that of the first-generation virus Ad5-CD/TKrep. On the basis of the observation that the number of tumor-positive posttreatment biopsies in both trials was less than expected, specifically in patients with intermediate-risk prostate cancer, the investigators postulated that this form of oncolytic adenovirus therapy may add to the clinical efficacy of radiotherapy.

Small and collaborators have published data on the safety of the prostate-specific oncolytic adenovirus CG7870 that expresses E1A under the control of the rat probasin promoter and E1B under the control of the PSA promoter-enhancer, and also expresses the adenoviral E3 gene. In a dose-escalating trial, 23 patients with hormone-refractory metastasized prostate cancer received an intravenous injection of CG7870 (Small et al., 2006). Although dose-limiting toxicity as defined by the clinical protocol was not observed, dose escalation was halted at 6 × 10¹² viral particles (VP) because of the occurrence of asymptomatic grade 1 to 2 transaminase increases and/or isolated D-dimer elevations, indicative of liver toxicity, in patients treated with more than 1 × 10¹² VP. Partial or complete responses defined as a 50 or 100% decline of the PSA level, respectively, were not observed, but five patients did show a dose-dependent PSA decrease between 25 and 49%.

Taken together, these data demonstrate that oncolytic adenovirus therapy for prostate cancer is safe and shows promising clinical effects. The first observations on efficacy will now need to be confirmed in phase III trials with appropriate clinical follow-up in order to have gene therapy recognized as an effective treatment modality for prostate cancer. The first randomized controlled phase III trial was initiated by the Henry Ford Health System (Detroit, MI) to study whether Ad5-yCD/mutTK_SR39 rep-ADP gene therapy in combination with intensity-modulated radiotherapy will improve freedom from failure compared with intensity-modulated radiotherapy alone in patients with newly diagnosed intermediate-risk prostate cancer. This trial will be completed by the end of 2013, according to the information provided in the ClinicalTrials.gov registry.

The GIANT Trial: A Novel Prostate-Specific Oncolytic Adenovirus as a Neoadjuvant Treatment for Radical Prostatectomy

Oncolytic adenovirus therapy as an adjuvant for primary treatment with curative intent has, until now, been studied only in combination with radiotherapy, as described previously. Taking the observed promising complementary effects into consideration, oncolytic adenovirus therapy in combination with radical prostatectomy, which is commonly used as the primary treatment of localized prostate cancer, may also be an attractive treatment modality. Within the GIANT project, a European gene therapy initiative funded by the European Commission Sixth Framework Programme (www.giant.eu.com), a phase I trial will be conducted to test a novel prostate-specific oncolytic adenovirus called Ad[I/PPT-E1A] as a neoadjuvant treatment for radical prostatectomy. Ad[I/PPT-E1A] has been developed by M. Essand (Uppsala University, Uppsala, Sweden). Replication of this virus is restricted to prostate cells because of controlled E1A expression by a regulatory sequence comprising the PSA enhancer, the prostate-specific membrane antigen (PSMA) enhancer, and the T cell receptor γ-chain alternative reading frame protein (TARP) promoter (Cheng et al., 2003, 2004, 2006). It has been demonstrated both in in vitro studies using prostate cancer cells and nonprostate cells, and in mouse studies using subcutaneous xenografts derived from the LNCaP prostate cancer cell line, that Ad[I/PPT-E1A] can specifically kill prostate tumor cells (Cheng et al., 2006). These observations have been confirmed in an orthotopic xenograft mouse model as well as in prostate cancer spheroids (our unpublished data). In addition, in the experimental models replication of Ad[I/PPT-E1A] was found to be active also in the absence of testosterone (Cheng et al., 2006). Ad[I/PPT-E1A] may therefore be attractive for patients receiving androgen ablation therapy or who have hormone-refractory prostate cancer. The promising preclinical results with Ad[I/PPT-E1A] will now be translated into the clinic in a phase I dose-escalating trial that will be conducted according to a standardized protocol at Erasmus Medical Center (Rotterdam, The Netherlands) and Uppsala University. Patients with localized prostate cancer will be treated with an intraprostatic injection of this novel oncolytic adenovirus 3 weeks before surgery. The primary objective will be to assess the safety of Ad[I/PPT-E1A] gene therapy. In addition, the immunological effects will be monitored and characterized at both systemic and local levels, including analysis of the induction of an antiadenovirus and antitumor immune response. In this way, the trial will add to a better understanding of the working mechanism of oncolytic adenovirus therapy. In the long term, the clinical response to neoadjuvant Ad[I/PPT-E1A] gene therapy will be established by combining the data from the two clinical centers. To the best of our knowledge, this trial will be the first to study whether oncolytic adenovirus therapy can increase the efficacy of curative radical prostatectomy.

Conclusion and Future Considerations

The clinical experiences described in this review clearly show that adenoviral gene therapy for prostate cancer can be effective, but that further improvement of the efficacy while maintaining a favorable safety profile is required before this treatment modality will be acceptable for implementation in routine urological practice. The challenges that now need to be addressed are described in the following sections.

Improvement of adenoviral gene therapy for localized prostate cancer

The stage of the disease, that is, localized prostate cancer or advanced metastasized prostate cancer, dictates the required characteristics of the adenoviral vector. For localized prostate cancer, which is nowadays the most commonly diagnosed stage because of the widespread use of screening, curative treatment aimed at the complete removal of the tumor either by surgery or by radiotherapy is available. Taking the heterogeneity of prostate cancer into consideration, it is highly unlikely that any form of gene therapy will be efficient enough to replace surgery or radiation as a single primary treatment for this malignancy. Nevertheless, adenoviral gene therapy is a promising adjuvant treatment to enhance the cure rate of primary therapy, as shown by the clinical results described in this overview. Local delivery is feasible in these patients, which is attractive with respect to safety and side effects. Still, the effectiveness of adjuvant adenoviral gene therapy needs to be improved by inducing a higher level of activity at the site of the tumor. This can be achieved by targeted delivery and sustained replication of the virus and/or expression of therapeutic genes. In parallel, a high degree of specificity is required to ensure that systemic spreading does not result in serious adverse events. Various strategies for improvement of targeting, prolongation of activity, and enhancement of specificity of adenoviral vectors are currently being explored, as described by de Vrij and colleagues in one of this issue's two other reviews on prostate cancer. The development of sophisticated vectors also imposes challenges on scientists with respect to preclinical testing. For prostate cancer, various preclinical models are available that enable analysis of the efficacy, specificity, toxicity and immunogenicity of a novel adenovirus-based vector. An overview of these models is presented by Maitland and colleagues in the third review of this trilogy.

Improvement of adenoviral gene therapy for advanced prostate cancer

Compared with men with localized disease, the population of patients suffering from advanced metastasized prostate cancer is small; in addition, this stage is incurable and associated with severe pain and poor quality of life. Improvement of the current palliative therapies for advanced prostate cancer, such as chemotherapy, by new treatment modalities, ultimately aiming at the development of a curative therapy, will thus be invaluable for this patient category. The challenges for the development of effective adenoviral gene therapy as well as of other forms of gene therapy for advanced prostate cancer are quite different from those in development for localized disease. First, this stage of the disease cannot be efficiently addressed locally as is the case for localized prostate cancer. Prostate cancer metastasizes primarily to multiple sites in the skeleton. The adenovirus therefore preferentially needs to be delivered systemically, must leave the circulation at the appropriate sites, and then must specifically penetrate the bone and destroy the metastatic lesions. In one trial by Small and colleagues, the tolerability of intravenous administration of a targeted adenoviral vector was demonstrated (Small et al., 2006). For efficient and safe systemic delivery, a high level of shielding to avoid systemic immunotoxicity and rapid neutralization of the virus in the circulation are required, as well as mechanisms to increase vascular permeability to get the virus to the target site and to target prostate cancer-specific antigens to avoid damage to other tissues. Prostate-targeted nonviral or cell-based carriers of (adeno)viral genomes are considered to be alternative promising tools that can fulfill these specific requirements (see the next review in this trilogy, by de Vrij and colleagues, for a description of ongoing research on these topics), but the development of these novel gene therapy devices is still in a preclinical phase. An important point to consider in the selection of the best prostate cancer-specific targets is that in its advanced stage prostate cancer becomes hormone independent. Transcriptional targeting using promoters of androgen-regulated genes such as the PSA gene will therefore most likely not be highly efficient in hormone-refractory disease.

Mechanism of action of adenoviral gene therapy

To design effective strategies for improving the efficacy of adenoviral gene therapy, a proper understanding of the mechanism of action is of pivotal importance. There is a substantial body of evidence from numerous trials that adenoviral gene therapy activates the human immune system, and it has been postulated as the explanation for the long-term clinical effects observed for Ad5-CD/TKrep oncolytic adenovirus therapy. Various questions remain to be addressed. Is the immunological response primarily directed against the adenovirus or does the induction of antitumor immunity occur as well, as demonstrated in a suicide gene therapy trial for locally recurrent prostate cancer using a replication-deficient adenoviral vector (Onion et al., 2009)? Would a boosting-type treatment schedule be more effective? If indeed a response to prostate cancer cells is evoked, knowledge of the primary tumor-associated antigens involved will provide numerous new leads for the development of next-generation targeted adenoviral vectors, immunogene therapy strategies, and combinations thereof. Primary treatment aimed at the destruction of a localized tumor together with gene therapy directed toward the induction of an anti-prostate tumor immune response to combat local and distant metastases may be a powerful combination to enhance the cure rate for an increasing number of men diagnosed with prostate cancer. In addition, boosting of the immune system by immunogene therapy may be a forceful supplement in active surveillance of indolent prostate cancer. This type of asymptomatic cancer represents 30 to 50% of the prostate tumors detected by screening (Schroder et al., 2009). Indolent prostate cancer is nonaggressive, has a low risk of progression, and can best be managed by active surveillance to avoid the severe side effects of primary therapy such as impotence and incontinence (Roemeling et al., 2007). Generating antitumor immunity in patients with indolent prostate cancer might be an interesting therapeutic approach, especially to control tumors that would eventually become progressive.

Altogether, it is evident that extensive preclinical and clinical research, including trials with long-term follow-up, will be required to bring adenoviral gene therapy for prostate cancer toward clinical implementation.

Footnotes

Acknowledgments

This work was supported by the European Union through the Sixth Framework Programme Integrated Project GIANT (contract no. LSHB-CT-2004-512087) and by the Dutch ZonMw Programme Translational Gene Therapy Research.

Author Disclosure Statement

Ellen Schenk, Magnus Essand, and Chris Bangma declare no competing financial interests.

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