World J Urol (2008) 26:147–154 DOI 10.1007/s00345-008-0246-3

TOPIC PAPER

Tumor vaccines in renal cell carcinoma Hirotsugu Uemura · Marco A. De Velasco

Received: 4 December 2007 / Accepted: 19 February 2008 / Published online: 12 March 2008 © Springer-Verlag 2008

Abstract Introduction Although most vaccines target foreign infectious agents, therapeutic cancer vaccines target both wellestablished and metastatic tumor cells expressing tumor antigens. Active immunotherapy is intended to enhance or activate the immunosurveillance of an individual through a therapeutic vaccine. Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans, which in turn makes it an ideal candidate for immune based therapies. Method Several types of therapeutic vaccines have been tested and applied in the clinical setting and can be divided into cell-based vaccines including direct application of inactivated autologous tumor cells, gene modiWed tumor cell-based, dendritic cell-based (expressing RCC derived tumor antigens), and non-cell-based vaccines. This review will examine the current status of cell-based vaccine immunotherapy and focuses on non-cell-based vaccine strategies. Conclusion Recent advances in molecular targeting therapy have introduced a battery receptor tyrosine kinase (RTK) and mTOR inhibitors that provide promising treatment options, however, the tolerability of tumor vaccines and the success of clinical eVectiveness in selected populations combined with recent advances in cellular therapies warrant the continued exploration of novel methods of tumor vaccine therapies in the clinical setting. Keywords Renal cell carcinoma · Tumor vaccine · Active speciWc immunotherapy

H. Uemura (&) · M. A. De Velasco Department of Urology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan e-mail: [email protected]

Introduction It is well known that renal cell carcinoma (RCC) has unique biological behaviors, for example, spontaneous tumor regression and long dormancy in metastatic lesions is occasionally observed [1]. Investigations regarding such evidences suggest that the host immune system plays an important role for tumor rejecting cell-mediated immune responses. Therefore, immunotherapy, active and passive, as well as speciWc and non-speciWc, seems to be a suitable therapeutic alternative for RCC. Recently developed molecular targeting agents particularly anti-angiogenesis agents, such as sunitinib and sorafenib, have been proven worldwide as Wrst and second line standard treatments for metastatic RCC [2, 3]. Despite their signiWcantly powerful anti-tumor eVects, most of the patients with metastatic disease cannot be cured. To date, combination therapy as well as sequential therapy of sorafenib or sunitinib with interferon-alpha is under investigation. Because of completely diVerent anti-tumor mechanism, clearly, immunotherapy still remains a basis of promising treatment strategies for metastatic RCC. Tumor vaccines, one striking option of active speciWc immunotherapy, seem to be a promising approach that stimulates host immune system to induce speciWc T cell response. To our knowledge, Tykkä et al. [4, 5] reported a clinical study as an initial attempt of tumor vaccine therapy for RCC . Advanced RCC patients were treated with polymerized autologous tumor cell vaccines after palliative nephrectomy and a signiWcantly longer survival was observed compared to non-treated patients. However, subsequent clinical studies revealed no eYcacy of autologous tumor vaccination in RCC patients [6–8]. In the last two decades, a number of clinical studies of tumor vaccines have been carried out in RCC patients (Table 1). There are

123

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some encouraging clinical responses, such as complete responses and partial responses, found in several reports [9, 10]. In this context, we provide a brief out line of tumor vaccine strategy for urologic physicians and discuss current information of clinical trials in metastatic RCC. We also focused on non-cell-based vaccines especially peptide vaccines, as several excellent reviews are focused on cellbased tumor vaccines.

Mechanisms of tumor vaccine strategy The action of tumor vaccines is schematically shown in Fig. 1. After immunization of tumor vaccines including irradiated or gene modiWed tumor cells, tumor-associated antigen loaded dendritic cells (DCs), and non-cell-based such as cell lysates and peptides derived from tumor-associated antigens (TAAs), the Wrst step of active speciWc immunotherapy is antigen presentation on the cell surface of an antigen presenting cell (APC) such as DCs in combination with major histocompatibility complex (MHC) molecules. Dentric Cells have the unique ability to present

antigens to both CD4+ and CD8+ T cells with MHC classes-I and -II molecules, respectively [10, 11]. Thus, DCs are potentially important APCs with powerful stimulatory capacity. MHC class-I restricted antigen peptide consists 8– 10 amino acids (8–10-mer peptide) and MHC class-II restricted antigen peptide consists 10–34 amino acids. The interaction between CD8+ T cells and antigen-presenting DCs is the most critical step for the induction of antigenspeciWc killer cells eradicating tumor cells in certain circumstances. Actually, T cell–APC interaction leads to stimulation and proliferation of cytotoxic T lymphocyte (CTL) precursors and Wnally establishes antigen-speciWc CTL populations with ability to combat RCC cells expressing the same antigen-peptide on the cell surface. A major focus of active speciWc immunotherapy is what antigen should be targeted. Although many investigators have been searching RCC-associated antigens, only a limited number of tumor antigens have been identiWed. Due to the lack of RCC-associated antigens, cell-based tumor vaccines, including genemodiWed tumor cells, DC-based tumor vaccines such as tumor–DC cell fusion and antigen-loaded DCs, have been widely developed and used for clinical studies. This

Table 1 Selected clinical trials using therapeutic tumor vaccines Vaccine type

Vaccine

Adjuvant

Stage

Phase

N

Reference

tc

Autologous irradiated/allogenic irradiated

C. parvum

mRCC

I

33

[21]

tc

Autologous irradiated

C. parvum

mRCC

I

14

[22]

tc

Aggregated autologous/aggregated allogenic

C. albicans

mRCC

I

16

[7]

tc

Autologous irradiated

None

stage IV

II

119

[23]

tc

Autologous irradiated

BCG

I-III

II

120

[24]

tc

Combination-autologous irradiated/ IFN-
, IFN-

BCG

mRCC

II

14

[25]

tc

Autologous cryo-killed

None

pT2-3b, pN0-3

III

379

[26]

tc

Autologous irradiated

None

II-IV

II

25

[52]

gm

Autologous irradiated-GM-CSF

None

III-IV, mRCC

I

16

[29]

gm

Autologous irradiated-GM-CSF

None

IV

I

6

[53]

gm

Autologous irradiated-tag7/PGRPS

None

mRCC

I/II

4

[54]

gm

Autologous irradiated-GM-CSF and IL-7

oligo-nucleotides

mRCC

I/II

5

[55]

gm

Autologous irradiated-B7-1 gene

IL-2

mRCC

I

13

[30]

gm

Allogenic irraWated-IL-2/ autologous formalin treated

None

mRCC

II

30

[31]

DC

rcc rna transfected DC

None

mRCC

I

10

[34]

DC

Irradiated allogenic DC fused with autologous or allogenic tumor cells

None

mRCC

I/II

12

[56]

DC

Autologous DC pulsed with MUC-1 (M1.1, M1.2)

None

mRCC

I

20

[35]

DC

Autologous DC pulsed with CA-9

KLH

mRCC

I

8

[37]

DC

Autologous DC pulsed with autologous tumor cells

KLH

mRCC

I

3

[38]

DC

Autologous DC pulsed with autologous tumor cells

KLH

mRCC

I/II

9

[36]

DC

Allogenic DC electrofused with autologous tumor cells

None

IV

I/II

20

[39]

Peptide

CA9-derived peptide

Inc. Freund’s adjuvant

mRCC

I

23

[17]

Peptide

HLA-A*2402-restricted 9-mer WT1 peptide

Montanide ISA51

mRCC

I/II

3

[18]

tc tumor cell-based; gm genetically modiWed tumor cell-based; DC dendritic cell-based; mRCC metastatic renal cell carcinoma; GM-CSF granulocyte–macrophage colony stimulating factor; CA9 carbonic anhydrase IX; BCG bacillus Calmette–Guerin; KLH keyhole limpet hemocyanin

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World J Urol (2008) 26:147–154 Fig. 1 Diagrammatical representation of events involved in the process of tumor vaccine therapy. Antigens derived from the tumor cells are recognized by antigen presenting cells which in turn present these to CD4+ and CD8+ T cells by the way of major histocompatibility complexes class-I and -II molecules, respectively. This interaction leads to the induction and proliferation of cytotoxic T lymphocyte precursors, which will then establish an antigen-speciWc population aimed at destroying cancer cells

149

MHC class I

peptide

tumor cell cell lysate protein

MHC class II

proliferation

Class I peptide CTL

Class II peptide

CTL

CTL CTL CTL

DC

CTL

APC CTL

CD8+

CTL

CTL

Tcell TCR activate CD4+

killing

Tcell Ab Th1

Th2 Cancer cell Bcell

approach allows the targeting of tumor-speciWc antigens that have not yet been identiWed. On the other hand, several investigators recently have identiWed MHC class-I restricted T cell epitopes recognized by CTLs derived from RCC patients [12–16]. However, few data from clinical trials with peptide vaccines is available to date [17–18].

Autologous tumor cell vaccines Historically, cell-based vaccines were comprised of nonviable autologous tumor cells or some form of preparation that would alone provide a source of antigens necessary to elicit an immune response. This is based on the notion that RCCs themselves express TAAs that will in turn initiate a cytotoxic T cell response. This system has the potential advantage in that unknown TAAs are presented, however it was determined early that stronger immune response is necessitated for a strong therapeutic eVect. Thus, the use of traditional adjuvants like incomplete Freund’s adjuvant, alum, QS-21, as well as newer molecules such as IL-2, IL12, granulocytemacrophage colony stimulated factor (GMCSF), bacillus Calmette–Guerin (BCG), and highly puriWed heat shock proteins have also been employed to enhance immune responses [19, 20]. Initial studies of this type of vaccine showed mixed results, although toxicities were relatively mild [21–26]. A study conducted by Kurth et al. on 33 patients with metastatic disease reported that 8 patients had objective responses with a median survival of 32 months compared to the overall survival of 17 months. Although the results were not statistically signiWcant, a

favorable trend was observed and toxicity was reported to be minimal [21]. A multi-center unblinded phase III study was conducted in Germany to determine the long-term eYcacy of tumor progression in pT2–3b pN0-3 M0 RCC patients (n = 379) with an autologous tumor vaccine [26]. Since the objective of the study was to reduce the progression of disease, the primary endpoint was deWned as tumor progression or death and patients were evaluated every 6 months for a minimum of 4 to 5 years. Five-year and 70month progression-free survival rates were 77.4 and 72 and 67.8 and 59.3%, respectively, for the vaccine and control groups. More striking was the 60-month progression free survival in the T3 group that demonstrated a 67.5% survival over 49.7% in the control group. Although this study demonstrated promising results, there were questions regarding the study design [27]. Although devitalized tumor cell vaccines have proven to be safe, there has been a lack of data to support any signiWcant clinical beneWt from this type of treatment. Collectively, these studies established the fact that although an immune response is established, a clinical beneWt is not achieved which prompted a shift towards modiWcations of cell-derived vaccines.

Genetically modiWed tumor cell vaccines A concerted eVort has been directed towards genetically modifying either autologous or allogenic tumor cells in order to increase the immunogenic respose [28]. Genes encoding immunostimulatory cytokines or positive stimulatory

123

150

molecules such as GM-CSF, CD80, IL-2, IL-12 and IFN- have been incorporated into either autologous or allogenic tumor cells to elicit an enhanced immune response [29–31]. There are two basic strategies in using genetically modiWed tumor cell vaccines, one uses autologous tumor cells transfected with one of several possible immunostimulatory genes. This entails culturing and tranfecting patients’ cells, however, the limitation that exists with this method is that there is a limited amount of cells available and lifelong immunizations may be required [28]. The second strategy uses genetically modiWed tumor cells from well-established RCC lines. This method circumvents the autologous tumor cell supply limitations and is the system that has the best promise for large-scale production. An initial phase I study by Simons et al. [29] demonstrated the safety of using a replication-defective retroviral vector to transfer the GM-CSF gene into irradiated autologous tumor cells in patients with advanced RCC. Additionally, the group demonstrated the increased inWltration of macrophage, DA, eosinophil, neutrophil and T cell inWltrates in the intradermal injection site in the GM-CSF-transduced vaccine group. Systemic immune response was measured by delayed-type hypersensitivity (DTH) and although signiWcant diVerences were not noted in clinical response between the two groups, probably due to the small sample size, a trend towards increased DTH reactions was observed. Further development of this vaccine entails the use of combination therapy. A combination treatment study of genetically modiWed autologous tumor cells transfected with B7–1 (CD80) gene and IL-2 was approached with the rationale that activated but not resting T cells express IL-2 receptors, therefore the addition of exogenous IL-2 would enhance proliferation of T cells activated by the vaccine [30]. Two out of 9 patients with measurable disease demonstrated partial responses while 2 patients maintained stable disease. Pizza et al. [31] investigated using irradiated genetically modiWed allogenic tumor cells mixed with autologous tumor cells devitalized by formalin treatment on patients that previously failed to respond to IL-2 treatment. ACHN renal cancer cells were used and transfected with the human IL-2 expression vector. Out of 30 patients treated, 1 complete response, 4 partial responses, and 9 stable disease cases were observed. Whether the beneWt was derived from a response elicited by the use of allogenic or autologous tumor antigens is unknown, however the fact remains that there was some beneWt achieved for patients with failed IL-2 therapy.

Dendritic cell-based vaccines The recent trend in cell-based vaccine therapy has been directed towards DC-based vaccines. Dendritic cells are

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World J Urol (2008) 26:147–154

potent antigen presenting cells derived from two precursor populations: CD34+ bone marrow cells and CD14+ monocytes [32]. These cells are naturally found in peripheral tissues where upon tissue damage, they capture loco-regional antigens, process into MHC molecules and migrate into the lymphoid organs where they induce T cell immune responses [33]. InWltration of DCs into primary tumor lesions has been associated with improved survival in a wide range on malignancies. Major steps have been taken towards the development of culture methods to diVerentiate and expand DC populations. DCs pulsed in culture with any TAAs from tumor cells or tumor cell lysate transferred back to the patient play a major role in the presentation of antigens to native T cells and the induction of primary immune responses [9]. As with other cell-based vaccines, initial phase I studies established the safety of this type of therapy [34]. Further investigations with DCs pulsed with HLA-A2-binding peptide MUC1 peptides (M1.1 and M1.2) on metastatic RCC patients in a phase I trial demonstrated an induction in both an immune response as well as clinical response (n = 20) including six patients with regression of metastatic lesions and four patients with stable disease during the duration of the treatment up to 14 months [35]. The induction of an immune response was signiWcantly higher in the group of patients that responded with stabilization of disease or shrinkage of the metastatic lesions (P = 0.0459) and a signiWcant correlation between the vaccine induced immune and clinical responses (r = 0.7906) was observed. Encouraging Wndings were reported in a phase I/II trial (n = 9) administering an autologous tumor lysate-pulsed DC vaccine in mRCC patients [36]. One partial response was noted, however, Wve patients showed stable disease (median follow-up of 17.5 months) suggesting some beneWt from the vaccine. All but one patient demonstrated an antigen-speciWc lymphocyte proliferative response after one cycle beginning mostly after the Wrst cycle, moreover, patients with stable disease or partial response tended to demonstrate higher responses at day 42. Similar Wndings have been recently published suggesting the value of DCbased vaccines [37–39]. These studies show that although immunological responses have been induced, the results have yet to be optimized.

Non-cell-based tumor vaccines Clinical trials of active speciWc immunotherapy have shifted to DC-based tumor vaccines. As described previously, mainly this may be due to the lack of identiWcation of RCC-speciWc antigens. With respect to vaccine design, the use of restricted antigens is more relevant to tumor vaccine therapy rather than the use of tumor cells or cell

World J Urol (2008) 26:147–154

lysates. Tumor cell and tumor lysate vaccines contain unknown antigens including normal self-proteins, however, unpleasant proteins that may result in unexpected host immune responses, for example, inducing autoimmune disease and further malignancy. Other disadvantages of tumor cell or lysate vaccine involve the ex-vivo preparation of cells under good manufacture practice (GMP) and the limitation of tumor materials as source of antigens. Moreover, synthetic peptide vaccines display several advantages, such as, ease of production, stability, safety, and cost eVectiveness. The fundamental goal of vaccination is to elicit tumor-speciWc immune response to eradicate tumor cells, which means the induction of speciWc CTLs carrying capacity to kill tumor cells is needed. Therefore, crucial subject is to identify MHC class-I restricted peptide epitopes capable to induce RCC-speciWc CTL response. In the case of MHC class-I peptide vaccines, HLA-A type must be matched. There are three major known HLA-A types; HLA-A2, -A24, and -A3 super family. HLA-A2 is expressed in 49% of Caucasians and many HLA-A2 restricted peptide vaccines have been developed, however, HLA-A2 molecule is highly heterogeneous and there are more than 17 subtypes, for example HLA-A0201 and A0204 [40]. On the other hand, HLA-A24 is highly expressed in Asians especially Japanese (approximately 60%) and its allele is more homogeneous, 90% have the same subtype, HLA-A2402. Recent progress in immunological techniques allow extensive search for CTL epitopes of tumor-associated antigens. Several tumor antigens and their peptide have been isolated and used for advanced cancer patients, for example, MAGE and gp100 for melanoma, CEA and SART3 for colorectal cancer, cyclophilin B for lung cancer, MUC1 for pancreas and prostate cancer, HER2/new for breast cancer, WT1 for hematopoietic or several types of malignancies. Only a limited number of clinical trials with peptide-based vaccines have been reported to date in RCC. Autologous tumor-derived heat shock protein-peptide (HSPs) vaccines (HSPPC-96) have been widely used in more than 700 patients with therapeutic or prophylactic regimens. After the phase-I trial (n = 29), two phase-II trials were carried out with therapeutic regimen [9]. The phase-III randomized trial was carried out in 644 patients at high risk of recurrence with prophylactic regimen [41]. Peptide-based vaccines corresponding to VHL mutated protein and MUC1 have also been investigated in phase trials [42, 43].

CTL epitope peptide vaccine To our knowledge, few clinical trials with HLA-restricted peptide vaccines, i.e., CTL epitope peptides, have been published to date in RCC. Carbonic anhydrase IX (CA9)

151

antigen is a tumor-associated glycoprotein antigen expressed in a variety of malignancies, e.g., cervical cancer, colorectal, esophageal, and lung cancers [44–47]. Approximately, 90% of any types of RCC and 99% of clear cell RCC express CA9, whereas CA9 expression in normal tissues including kidney tissue is limited. Thus, CA9 antigen is a suitable target for active speciWc immunotherapy. HLA-A2402 restricted 9-mer peptides derived from CA9 antigen, CA9p219 (EYRALQLHL), CA9p288 (AYEQLLSRL), CA9p323 (RYFQYEGSL) were identiWed [48]. A phase-I study with a set of three CA9 peptide vaccines was carried out in patients with progressive cytokinerefractory RCC [17]. Approximately 70% of evaluable patients displayed CA9 speciWc CTL as well as IgG responses, resulted in anti-tumor eVects with shrinking of pulmonary metastatic lesions in three patients. However, at least more than 12 vaccinations were needed to elicit speciWc CTLs, suggesting that these CA9 peptides have low immunogenicity. A similar study has been reported by Oosterwijk et al, using HLA-A0201 restricted 9-mer peptide CA9p254 and HLA-DR restricted 20-mer peptide CA9p249 loaded DC vaccine [37]. Unfortunately, Wve intradermal vaccinations did not induce peptide speciWc IgG and CTLs. Although it is diYcult to compare two diVerently designed vaccination therapies, the induction of speciWc immune responses may be related to the number of vaccinations. Another encouraging clinical study in RCC was WT1 peptide immunotherapy recently reported by Iiyama et al. [18]. One modiWed HLA-A2402 restricted WT1 peptide (CYTWNQMNL), in which Y at second position replaced M in the natural epitope, was developed and used in patients with progressive metastatic RCC as part of a multi-centered phase I/II trial for various malignancies. Two patients induced peptide speciWc CTLs and DTH response during 12 weekly vaccinations. These patients showed long stable disease. In both CA9 and WT1 clinical trials in RCC, overall vaccinations were well tolerated and the only remarkable adverse event was grade 1 or 2 local skin reactions at the injection sites. However, WT1 vaccination induced a serious adverse event of grade 3-4 leukocytopenia in two patients with myelodysplastic syndrome, which means the peptide vaccine-induced CTLs perfectly targeted malignant stem cells. This indicates that MHC class-I peptide could induce speciWc CTLs with powerful capacity to combat target cells. Despite of the fact that a majority of tumor vaccine therapy has rapidly shifted to antigen-loaded DC-based strategies, peptide-based vaccination serves as an attractive means due to its technically simple approach. In addition, there is no clear understanding with regards to the functional eYcacy, clinically as well as immunologically, in DC-based vaccines versus peptide-based vaccines. There is continued interest in the prospect of tumor vaccine

123

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Table 2 List of ongoing RCC clinical trials using vaccine therapy NCT IDb

Recruitment statusa

Intervention

Phase

NCT00381173

Recruiting

ZYC300 (a plasmid DNA, encoding CYP1B1 ) administration with cyclophosphamide pre-dosing

I

20

NCT00083941

Recruiting

Viral delivery of tumor-associated antigen, 5T4 (TroVax®) and IL-2

II

25

NCT00272649

Recruiting

RCC RNA transfected DC

I/II

26

NCT00309829

Recruiting

RCC RNA transfected DC

II

26

NCT00258687

Recruiting

Autologous irradiated tumor cell virally transfected with the GM-CSF gene

I

36

NCT00197860

Recruiting

Tumor antigen loaded autologous dendritic cells

I/II

40

NCT00485563

Recruiting

Folate–hapten conjugate therapy (vaccination with EC90 [KLH-FITC] and GPI-0100 adjuvant followed by treatment with EC17 (folate-FITC) in combination with low-dose IL-2 and IFN-


II

47

NCT00458536

Recruiting

DC/tumor fusion and GM-CSF

I/II

51

NCT00523159

Recruiting

Pre-treatment with a single low dose of cyclophosphamide followed by IMA901(peptide-based) vaccination plus GM-CSF as adjuvant

II

72

Enrollment

NCT00014131

Recruiting

Autologous DC pulsed with autologous tumor cells

I/II

80

NCT00087984

Active, n/r

RCC RNA transfected DC

I/II

16

NCT00096629

Active, n/r

Human and mouse prostate-speciWc membrane antigen plasmid DNA vaccine

I

18

NCT00325507

Active, n/r

Viral delivery of tumor-associated antigen, 5T4 (TroVax®) and IL-2

II

25

NCT00093522

Active, n/r

Combination-autologous DC pulsed with autologous tumor cells/Xuradabine

II

28 32

®

®

NCT00445523

Active, n/r

TroVax and TroVax in combination with IFN-


II

NCT00085436

Active, n/r

combination-autologous DC pulsed with autologous tumor cells/ IL-2 and IFN-


II

33

NCT00082459

Active, n/r

HSPPC-96

II

40

NCT00203866

Active, n/r

G250 peptide/montanide/GM-CSF plus IL-2

II

40

NCT00019526

Active, n/r

von Hippel-Lindau peptide vaccine

II

60

NCT00091403

Active, n/r

HLA-A2, A3-restricted FGF-5 peptides/montanide ISA-51 vaccine/IL-2

II

210

NCT00004880

Active, n/r

autologous DC pulsed with autologous tumor cells and multiantigen liposome

I

n/a

NCT00005816

Active, n/r

autologous dendritic cells transfected eith autologous total tumor RNA

I

n/a

NCT00006431

Active, n/r

RCC RNA transfected DC

I

n/a

NCT00031564

Active, n/r

B7-1 gene-modiWed autologous tumor cell vaccine and systemic IL-2

II

n/a

NCT00050323

Completed

Allogeneic DCs and autologous RCC Tumor derived cells

I/II

30

NCT00019396

Completed

lt3L alone or in combination with melanoma peptide immunization (MART-1, gp100:209-217, gp100:280-288, and tyrosinase)

II

n/a

NCT00002475

Suspended

Irradiated autologous or allogenic tumor cells treated with IFN-
or IFN- treated and cyclophosphamide

II

40

NCT00004023

Suspended

Irradiated autologous tumor cell vaccine and sargramostim (GM-CSF) followed by monoclonal antibody OKT3- activated T lymphocytes and IL-2

II

n/a

NCT ID: ClinicalTrials.gov IdentiWer. Data compiled from the worlwide clinical trial registry at http://www.ClinicalTrials.gov a Recruitment status legend: recruiting: participants are currently being recruited and enrolled, active, n/r: study is active but not recruiting (i.e., patients are being treated or examined), but enrollment has completed, completed: the study has concluded normally; participants are no longer being examined or treated (i.e., last patient’s last visit has occurred), suspended: recruiting or enrolling participants has halted prematurely but potentially will resume

immunotherapy; in fact, there are several ongoing peptidebased vaccine trials, including terminated, recruiting, and not yet open (Table 2).

Limitations The most important hurdle for RCC as well as most cancer therapeutic vaccines revolves around the complex interac-

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tions involved between immunosurveillance and immunoediting [49]. Established or metastatic tumors will characteristically release immune inactivating factors or the expression of ligands for death receptors. Consequently any stimulation of tumor speciWc T cells is impaired or evaded as a result of the existing immunosuppressive tumor microenvironment. The concept of immunotherapy is theoretically simple yet the practical experiences demonstrate that it is a very complex system. Furthermore, tumor

World J Urol (2008) 26:147–154

surveillance derives from the concept that over 1,000 human tumor antigens could potentiate the adaptive immune response; still, few TAAs from renal cancers have been identiWed; thus, many investigators prefer to opt for DC-based vaccines [50]. It has also been proposed that due to the complex behavior of cancer cells in relation to the their genetic instability, expression of molecules targeted by eVector T cells such as TAAs, MHC molecules and molecules associated with antigen processing and presentation may be reduced or lost [51]. RCC clinical trials have proven that vaccine therapy is safe and less toxic than other present therapies, however, their eYcacy has yet to be maximized.

Future of RCC vaccine therapy As technology evolves, the promise for the development of strategies aimed at circumventing tumor-associated immunosupression will certainly improve the eYcacy of tumor vaccines. Furthermore, as new TAAs or immunostimulatory peptides (endogenous or synthetic) are discovered, the prospect of personalized cancer therapy becomes more imminent especially with peptide-based tumor vaccines. Therapeutic vaccine therapies have been limited to advanced or metastatic disease; future studies should explore their eVectiveness in cases where disease is not as advanced and an individual’s immune system is not compromised. Finally, the eYcacy of combination therapy of tumor vaccines with chemotherapeutic agents needs to be explored. ConXict of interest

There is no conXict of interest.

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