A. Prostate-specific antigen (PSA)
PSA is a kallikrein-like serin-protease showing a high degree of
homology with human pancreatic kallikrein (Lundwell and Lilija, 1989). It
represents the most widely used serum marker for diagnosis and monitoring of
prostate cancer and is nearly exclusively expressed by epithelial cells of the
prostate (Balk et al, 2003). Furthermore, it is found in the majority of
prostate cancer tissues and can be detected in the cytoplasmic portion of these
cells by immunoperoxidase staining (Oesterling, 1991).
Among prostate
differentiation antigens, the T cell-mediated immune response to PSA has been
studied most thoroughly to date. Xue et al, 1997 identified an
HLA-A2-compatible peptide corresponding to amino acid (aa) residues 146-154 of
PSA that was successfully used for the in
vitro-stimulation of peptide-specific CTLs from a healthy donor by
autologous peptide-pulsed peripheral blood mononuclear cells (PBMCs). In a
complementary study, CTLs recognizing PSA peptide 146-154 were shown to
specifically lyse HLA-A2-positive tumor cells endogenously expressing the PSA
protein (Perambakam et al, 2002). Applying a similar stimulation protocol, two
other HLA-A2-binding PSA-derived peptides consisting of aa 141-150 and 154-163
were defined as CD8+ T cell epitopes capable of inducing CTLs that
were reactive against an HLA-A2- and PSA-positive prostate cancer cell line
(Correale et al, 1997). PSA peptide 154-163 was additionally verified as a
target structure of PSA-reactive CD8+ T effector cells from
HLA-A2-positive donors that were generated by stimulation with PSA
RNA-transfected autologous DCs (Heiser et al, 2000). In another study,
modification of this PSA peptide by replacing the valine residue in the first
position by a tyrosine led to a strong agonist peptide which markedly increased
the efficiency to induce prostate cancer-reactive CTLs (Terasawa et al, 2002).
Correale et al, 1998 developed a strategy to simultaneously induce
PSA-restricted CTL activities to multiple epitopes. The authors constructed a
30-mer oligopeptide corresponding to aa 141-171 of the PSA protein that
contained two immunogenic HLA-A2-binding peptides described previously (aa
141-150 and 154-163) and an additional HLA-A3-fitting peptide (aa 162-170). CD8+
T cell lines from HLA-A2- and HLA-A3-positive donors that were generated by
stimulation with autologous PBMCs loaded with the oligopeptide reacted against
target cells pulsed with the nonamer or decamer peptides and expressing the
respective HLA molecule.
Two HLA-A24-binding
PSA peptides were reported to generate peptide-specific CTLs. Gotoh et al, 2002
revealed that the PSA peptide spanning the aa 152-160 is immunogenic in
HLA-A*2402/Kb-transgenic mice. Immunization with this peptide
resulted in the induction of peptide-specific and HLA-A*2402-restricted CTLs.
The same peptide as well as another one (aa 248-257) were demonstrated to
function as HLA-A24-restricted CD8+ T cell epitopes by in vitro-activation of specific CTLs
from HLA-A24-positive prostate cancer patients after stimulation with
peptide-loaded PBMCs (Harada et al, 2003). Corman et al, 1998 described an
HLA-A1-binding PSA-derived peptide (aa 68-77) with the capacity to induce CTLs
specifically recognizing peptide-pulsed target cells. However, the endogenous
generation and presentation of these motifs by prostate cancer cells was not
analyzed by the authors.
T helper cell
epitopes were defined by Corman et al, 1998 who identified HLA-DR4-binding
peptides within the PSA protein (aa 49-63 with modifications in two positions
and 64-78). Recently, two immunogenic HLA-DRB1*1501-restricted 20-mer peptides
(corresponding to aa 171-190 and 221-240) were found by immunization of
HLA-DRB1*1501-transgenic mice with human PSA and subsequent screening a library
of overlapping 20-mer peptides spanning the entire PSA protein for
peptide-specific in vitro-proliferation
(Klyushnenkova et al, 2005). These peptides led to the in vitro-generation of specific CD4+ T cell lines from
HLA-DRB1*1501-positive patients with granulomatous prostatitis or prostate
cancer when presented by autologous antigen-presenting cells (APCs). In
addition, the peptide-specific CD4+ T cells responded to APCs pulsed
with the whole PSA protein.
B. Prostate-specific membrane antigen (PSMA)
PSMA, an integral
membrane glycoprotein that functions as protease and folate hydrolase, was
identified using the monoclonal antibody 7E11.C5 (Israeli et al, 1993; Carter
et al, 1996). Immunhistochemical findings indicate that PSMA is a marker of
normal epithelial cells of the prostate (Murphy et al, 1998). In addition, its
expression is increased in most prostate tumors, particularly in
undifferentiated, metastatic and hormone-resistant cancer (Kawakami and
Nakayama, 1997).
A number of studies
has demonstrated the suitability of PSMA for T cell-based immunotherapy by the
identification of immunogenic peptide epitopes. Tjoa et al, 1996 described an
HLA-A2-binding peptide spanning the aa 4-12 that induced peptide-specific CTLs
when PBMCs of prostate cancer patients were stimulated with peptide-pulsed DCs.
Furthermore, Murphy and co-workers revealed that the HLA-A2-binding peptide
comprising aa 711-719 had the potential to decrease the levels of PSA in
prostate cancer patients following administration of peptide-pulsed DCs (Murphy
et al, 1996). An additional HLA-A*0201-restricted PSMA peptide (aa 27-35)
proved to be effective in triggering antitumoral CTL responses as demonstrated
by the capacity of peptide-induced CTLs to lyse an HLA-A*0201-positive prostate
cancer cell line (Lu and Celis, 2002). Recently, the HLA-A2-restricted peptide
comprising the aa 441-450 of PSMA protein has not only been shown to induce
HLA-A2-restricted and prostate cancer-reactive CTLs but was described to serve
as target of humoral immune responses in prostate cancer patients (Harada et
al, 2004). By the same stategy, Kobayashi et al, 2003a identified an
immunogenic HLA-A24-restricted PSMA peptide (aa 624-632). Furthermore, the in vitro-stimulation of CD8+
T cells from a healthy HLA-A24-positive donor using DCs loaded with predicted
HLA-A24-matching peptides revealed two additional peptides (aa 178-186 and
227-235) which originate from intracellular processing of PSMA protein in tumor
cells (Horiguchi et al, 2002).
Recent approaches
to identify PSMA-derived CD4+ T cell epitopes demonstrated that the
peptide sequences comprising the aa positions 334-348, 687-701 and 730-744 were
restricted to HLA-DR4, HLA-DR9 or HLA-DR53 and HLA-DR53, respectively and
induced antigen-specific T cells which were capable of reacting with naturally
processed antigen (Kobayashi et al, 2003b).
C. Prostatic acid phosphatase (PAP)
PAP was described as an isoenzyme of
the heterogenous group of acid phosphatases specifically secreted by prostate
cells (Gutman et al, 1936). The cDNA isolated by screening cDNA libraries with
polyclonal antisera encodes a 386 aa protein which includes a 32 aa signal
sequence (Yeh et al, 1987; Vihko et al, 1988). PAP expression was shown to be
restricted to the prostate by RNA dot blot analysis (Solin et al, 1990) and by
immunohistochemical staining with monoclonal antibodies (Kuciel et al, 1988;
Lam et al, 1989).
Peshwa et al, 1998
identified an HLA-A2-restricted CTL epitope (aa position 299-307) within the
PAP protein by stimulation of T cells from healthy donors with peptide-pulsed
autologous DCs. Recently, an additional immunogenic HLA-A2-binding peptide (aa
112-120) activating peptide-specific and tumor-lysing CTLs from prostate cancer
patients in vitro was defined (Harada
et al, 2004). Inoue et al, 2001 revealed a PAP-derived, HLA-A*2402-binding
peptide (aa position 213-221) that induced tumor-reactive CTLs from prostate
cancer patients and healthy donors. In addition, two peptides (aa positions
199-213 and 228-242) were described as potential CD4+ T cell
epitopes, although the HLA class II restriction elements were not determined
(McNeel et al, 2001).
D. Prostate stem cell antigen (PSCA)
PSCA was identified
by a PCR-based subtractive hybridization strategy as a gene specifically
expressed in the prostate (Reiter et al, 1998). The encoded protein belongs to
the Thy-1/Ly-6 family of glycosylphosphatidylinositol-anchored cell surface
glycoproteins and its aa sequence shares 30% identity with stem cell antigen 2.
By mRNA in situ-hybridization and
immunohistochemistry, PSCA expression was detected in more than 80% of primary
prostate carcinomas and in all bone metastases analyzed (Reiter el al, 1998; Gu
et al, 2000). Its increased expression level in both androgen-dependent and
-independent prostate tumors when compared to the corresponding normal prostate
tissues and its upregulation in carcinomas of high stages und Gleason Scores
make PSCA a promising target structure for the immunotherapy of
hormone-refractory tumors. In addition, PSCA may also provide a candidate for
the immunotherapy of tumors with different histological origin, as PSCA
expression has also been found in transitional cell carcinomas of the bladder
(Amara et al, 2001) and pancreatic cancer (Argani et al, 2001).
Different studies
have pointed out the suitability of PSCA as a target antigen of CTL-mediated
immunotherapy. An HLA-A*0201-restricted PSCA peptide comprising the aa 14-22
was reported to be capable of generating a peptide-specific and tumor-reactive
CTL response from a patient with metastatic prostate cancer by an in vitro-stimulation protocol employing
irradiated peptide-loaded PBMCs as APCs (Dannull et al, 2000). By enzyme-linked
immunospot (ELISPOT) analyses, we detected increased frequencies of CD8+
T cells in the blood of HLA-A*0201-positive prostate cancer patients that
recognize the PSCA-derived HLA-A*0201-restricted peptides with the aa positions
14-22 and 105-113 (Kiessling et al, 2002). Moreover, these peptides had the
capacity to induce peptide-specific and tumor-reactive CTLs from prostate
cancer patients when loaded on autologous DCs for repetitive stimulations of
CD8+ T cell cultures. Matsueda and colleagues identified two
additional HLA-A2-restricted peptides (aa positions 7-15 and 21-30) and an
HLA-A24-presented peptide (aa position 76-78) that effectively stimulated CTLs
from prostate cancer patients (Matsueda et al, 2004a and 2004b).
E. Prostein
Prostein was
identified by a combination of cDNA substraction and microarray screening as a
novel protein with a unique specificity for malignant and normal prostate
tissues (Xu et al, 2001). Prostein is a protein of 553 aa that is predicted to
contain eleven transmembrane domains and a cleavable signal sequence at the
amino terminus. Xu et al, 2001 demonstrated the highly prostate-restricted
expression pattern in normal human tissues by quantitative
reverse-transcription PCR, Northern blot and cDNA microarray analyses as well
as by immunhistochemical analysis. Determining the prostein mRNA level in
paired samples of malignant and non-malignant prostate tissue from prostate
cancer patients by real-time PCR our group found abundant expression in all
tested samples (Kiessling et al, 2004). In addition, the transcript levels were
maintained or even elevated in 87% of the primary tumors when compared to
prostein expression in the autologous non-malignant tissue samples. In a recent
study, a prostein-specific monoclonal antibody was used to determine prostein
expression at the protein level in a high number of tumorous and non-tumorous
human tissues of diverse histological origin (Kalos et al, 2004). In this
study, prostein was detected in 94% of all non-malignant and maligant prostate
samples including metastases, but in none of 4635 non-prostatic normal and
tumor tissues. The tissue-specific expression profile of this molecule and the
abundant expression in the great majority of prostate tumors are promising
prerequisites for the use of this protein as target structure for specific
immunotherapeutic strategies in prostate cancer.
To identify
immunogenic CD8+ T cell epitopes from prostein, we selected six
nonamer and decamer peptides from the aa sequence of prostein that were
predicted to bind to HLA-A*0201 by a computer-based algorithm and verified the
binding affinity to HLA-A*0201 by a competition assay (Kiessling et al, 2004).
Using these peptides, exogenously loaded on DCs, for repetitive in vitro-stimulations of autologous CD8+
T lymphocytes from prostate cancer patients and healthy donors, we were able to
activate cytotoxic T effector cells specifically recognizing a peptide
comprising the aa positions 31-39 in the prostein protein. The peptide-specific
CTLs that were raised from all T cell cultures stimulated with this peptide
also efficiently lysed prostate tumor cells expressing both HLA-A*0201 und
prostein. Recently, another group identified prostein-derived peptides, one of
them presented by HLA-B*5101 (aa position 464-472) and two presented by
HLA-Cw*0501 (aa positions 292-300 and 464-473), that are recognized by
tumor-reactive CTLs (Friedman et al, 2004). The authors used APCs infected with
a prostein-expressing adenovirus for the stimulation of CD8+ T
lymphocytes from two healthy donors and identified immunogenic peptides by the
use of target cells expressing truncated prostein constructs or pulsed with
synthetic prostein-derived peptides.
F. Transient receptor potential (trp)-p8
The gene trp-p8 was recently identified by
screening a prostate-specific substracted cDNA library (Tsavaler et al, 2001).
It encodes a protein of 1104 aa with seven putative transmembrane domains that
shows significant homology to a family of Ca2+ channel proteins. By
dot blot and Northern blot analyses as well as reverse transcription PCR, it
has been demonstrated that trp-p8-mRNA expression in non-malignant human
tissues is mainly restricted to the prostate (Tsavaler et al, 2001; Cunha et
al, 2005). In addition, trp-p8 transcipts were detected in all 16 analyzed
prostate cancer specimens by in situ-hybridization
(Tsavaler et al, 2001). Quantitative RT-PCR analyses of matched samples of
malignant and non-malignant prostate tissues derived from prostatectomized
patients revealed an abundant expression of the trp-p8 mRNA in all specimens
and a marked level of overexpression in tumors of early stages and low grades
when compared to the corresponding normal prostate tissue (Kiessling et al,
2003).
In an approach to
determine the potential of trp-p8 as a target structure of specific CTLs, we
used DCs pulsed with five HLA-A*0201-binding, trp-p8-specific peptides for the
stimulation of autologous CD8+ T cells from prostate cancer patients
(Kiessling et al, 2003). A peptide comprising the aa 187-195 was found to
effectively induce CTLs and was demonstrated to be autochthonously presented on
the surface of prostate cancer cells.
G. Parathyroid hormone-related protein (PTH-rp)
PTH-rp is an
autocrine or paracrine factor that binds to receptors on osteoblasts and
induces bone formation and reabsorption. It is highly overexpressed in prostate
cancer and other cancers of epithelial origin and is considered to be involved
in the development of bone metastases (Guise, 1997; Francini et al, 2002).
Therefore, it might represent a promising immunotherapeutical target for
prostate cancer patients with bone metastases.
Two
HLA-A*0201-restricted peptides (aa 59-68 and 165-173) have been identified by in vitro-stimulation protocols using
autologous peptide-pulsed PBMCs from healthy donors as APCs (Francini et al,
2002). The induced peptide-specific CTLs were able to kill PTH-rp- und
HLA-A*0201-positive tumor cells. Recently, two other HLA-A2-fitting epitopes
(aa 59-67 and 42-51) were defined inducing peptide-specific CTL responses in
prostate cancer patients (Yao et al, 2005).
Furthermore,
HLA-A24-binding peptides comprising the aa positions 36-44 and 102-111 were
proved to be immunogenic in the activation of peptide-specific and
tumor-reactive CTLs when loaded on PBMCs from prostate cancer patients (Yao et
al, 2004).
H. Human telomerase reverse transcriptase (hTERT)
Whereas hTERT
cannot be detected in most nontransformed somatic cells it is expressed in the
majority of tumors of different histological origins including prostate cancer,
(Kim et al, 1994) and is responsible for the protection of tumor cells from
telomere erosion (Blasco and Hahn, 2003). Consequently, hTERT provides an
attractive candidate for T cell-based immunotherapies of many tumors.
An immunogenic
HLA-A*0201-restricted peptide comprising the aa 540-548 that is capable of
inducing peptide-specific and tumor-reactive CTLs from healthy donors and
prostate cancer patients was described by several groups (Vonderheide et al,
1999; Minev et al, 2000). Moreover, this peptide and an additional immunogenic
HLA-A*0201-binding peptide (aa 865-873) were shown to induce peptide-specific
CTLs in HLA-A*0201 transgenic mice (Minev et al, 2000). Hernandez et al, 2002
identified a third HLA-A*0201-matching peptide spanning aa 572-580 whose
immunogenicity was markedly increased by substitution of the arginine residue
at position one by tyrosine. Furthermore, an HLA-A3-fitting motif corresponding
to aa 973-981 (Vonderheide et al, 2001), two HLA-A24-binding peptides (aa
324-332 and 461-469) (Arai et al, 2001) and an HLA-A1-restricted peptide (aa
325-333) (Schreurs et al, 2005) effectively inducing peptide-specific and
tumor-lysing CTLs in vitro were
described so far.
Schoers et al, 2002
identified an immunogenic HLA class II-restricted epitope (aa 672-686) by
examining human T cell responses against synthetic peptides that had been
selected by a prediction software. These authors demonstrated that the
identified peptide is presented by HLA-DR7 molecules and derived from natural
processing of hTERT in prostate cancer and other tumor cells. In a further
study, the previously defined peptide comprising the aa 672-686 was
demonstrated to be promiscuous and capable of inducing CD4+ T cell
responses in the context of the HLA class II molecules HLA-DR1, HLA-DR7 and
HLA-DR15 (Schroers et al, 2003). Moreover, these authors identified another CD4+
T cell epitope (aa 766-780) that is efficiently presented by HLA-DR4, HLA-DR11
and HLA-DR15 molecules, naturally generated by tumor cells and elicited
antigen-specific CD4+ T cell responses when used for immunization of
HLA-DR4 transgenic mice.
I. Survivin
Survivin is a
member of the inhibitor of apoptosis protein family and is highly overexpressed
in most human tumors of epithelial and hematopoietic origin including prostate
cancer (Ambrosini et al, 1997; Altieri, 2003). Additionally, survivin
expression correlates with poor prognosis of tumor disease (Swana et al, 1999).
The wide expression in cancer and the almost complete absence of expression in
differentiated adult tissues together with the functional role for the survival
of tumor cells make survivin an interesting target for the development of T
cell-based immunotherapies.
Our group
identified two HLA-A*0201-restricted peptides (aa 5-14 and 95-104) that induced
peptide-specific CTL responses in vitro
when presented by autologous DCs and one of these peptides (aa 95-104) was shown
to evolve from intracellular processing of the protein as the CTLs effectively
recognized Epstein-Barr virus-immortalized B cells transfected with survivin
cDNA (Schmitz et al, 2000). By another group, the peptide spanning aa 5-14 was
verified as target for immunotherapy by the lysis of survivin- and
HLA-A*0201-positive tumor cells by peptide-specific CTLs (Siegel et al, 2004).
Using ELISPOT assay to detect survivin-specific CD8+ T cells in the
blood of tumor patients Anderson et al, 2001a found in vivo reactivities against one of the previously defined peptides
(aa 95-104) and a modified peptide (aa 96-104) in which the native threonine at
position 2 was replaced by the better anchor residue methionine. In an
additional study, multimeric complexes of this modified peptide and HLA-A2
molecules were used to isolate CD8+ T lymphocytes from a
melanoma-infiltrated lymph node that specifically recognized the native peptide
as well as survivin- and HLA-A2-expressing tumor cells (Anderson et al, 2001b).
A number of additional CD8+ T cell epitopes restricted to HLA-A1,
HLA-A2, HLA-A3 and HLA-A11 were defined by Reker et al, 2004 based on
spontaneous peptide-specific CTL responses of tumor-infiltrating lymphocytes
determined by ELISPOT assay. The positions and sequences of these peptides can
be learned from Table 1.
III. Vaccination
of prostate cancer patients with TAA-derived peptides, proteins or DNA
Following the
identification of prostate cancer-associated proteins that may be suitable
targets of tumor-reactive T cells several clinical trials were conducted.
Noguchi et al, 2005 performed a clinical phase I/II study to determine the
feasibility, toxicity, immunological and clinical responses to individualized
peptide vaccination in combination with estramustine phosphate for HRPC
patients. The selection of the administered peptides derived from several
prostate cancer-related and epithelial cancer-related antigens was based on the
measurement of peptide-specific CD8+ T cells in the blood of
patients before vaccination. Patients were immunized subcutaneously with only
those peptides to which pre-existing CD8+ T cells could be detected.
Vaccination was well tolerated and augmentation of peptide-specific CD8+
T cells was observed. All 13 patients treated with the combination therapy
showed a decrease of serum PSA levels, including six patients with a decrease
of more than 50%.
Meidenbauer et al, 2000
reported on a clinical trial enrolling 10 prostate cancer patients which was
based on JBT1001, a vaccine consisting of recombinant PSA with lipid A
formulated in liposomes. Patients were vaccinated with JBT1001 either in
combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) or
emulsified in mineral oil. Whereas two patients had PSA-reactive T cells before
vaccination eight of 10 patients showed detectable PSA-reactive T cells after
vaccination. However, the frequency of PSA-reactive T cells in the circulation
of patients was low. In a follow up report, 10 patients treated with JBT1001
plus GM‑CSF and eight additional patients receiving JBT1001 emulsified in
mineral oil were tested for z‑chain
expression in circulating T cells and spontaneous IL-10 secretion by PBMCs
before and after vaccination (Meidenbauer et al, 2002). Prior to therapy,
patients had lower z‑chain
expression in circulating CD3+ T cells, a higher percentage of z‑chain negative CD3+ and CD4+ T cells
and PBMCs producing more IL‑10 than normal subjects. After vaccination,
recovery of z‑chain expression was
observed in 50% of all patients and IL‑10 secretion decreased in patients
treated with JBT1001 and GM‑CSF.
Other clinical
studies were conducted to evaluate the potential of a recombinant vaccinia
virus expressing human PSA. Sanda and colleagues initiated a phase I
clinical trial to determine the safety and biologic effects of recombinant
vaccinia-PSA (rV‑PSA) administered to six patients with recurrence of
prostate cancer after radical prostatectomy (Sanda et al, 1999). Patients were
treated with luteinizing hormone-releasing hormone agonist therapy until an
undetectable PSA nadir was achieved and then vaccinated with rV‑PSA.
Treatment was well tolerated and one of six patients showed undetectable serum
PSA for more than eight months after testosterone restoration. In another
clinical trial, administration of rV‑PSA led to stabilization of serum
PSA levels in 14 of 33 prostate cancer patients for at least six months (Eder
et al, 2000). Increases of at least twofold in the number of PSA-reactive T
cells could be detected in five of seven evaluated patients. More recently,
Gulley and colleagues administered rV‑PSA to patients with metastatic
androgen-independent prostate cancer (Gulley et al, 2002). Six of 42 patients
had stable disease and three of five analyzed patients showed a vaccine-induced
increase of PSA-specific T lymphocytes. Furthermore, in vitro-generated PSA-specific CTL lines of three patients were
able to lyse PSA peptide-loaded APCs and prostate cancer cells.
Kaufman et al, 2004
conducted a clinical phase II study evaluating a heterologous prime/boost
vaccination protocol with vaccinia and fowlpox viruses expressing PSA in
prostate cancer patients with biochemical progression after local therapy. Of
the eligible patients, 45.3% remained free of PSA progression at 19.1 months
and 78.1% demonstrated clinical progression-free survival. An increase in
PSA-specific T cells was found in 46% of patients. Gulley et al, 2005 reported
on another phase II clinical trial administering an admixture of rV‑PSA
plus recombinant vaccinia virus expressing the T cell costimulatory molecule
B7.1/CD80 followed by booster vaccinations with fowlpox virus containing PSA in
combination with standard radiotherapy. Thirteen of 17 evaluated patients with
localized prostate cancer treated by the combination therapy showed an increase
in PSA-specific T cells of at least threefold.
Other
immunotherapeutic treatment modalities which were based on so-called ÒnakedÓ
DNA have also been explored. In a phase I/II clinical trial 26 prostate cancer
patients with different stages of disease were immunized intradermally with
varying combinations of separate DNA plasmids encoding either the extracellular
domain of PSMA or the costimulatory molecule B7.2/CD86, a combined PSMA/CD86
plasmid and a replication deficient adenoviral vector expressing PSMA and
GM-CSF (Mincheff et al, 2000). Treatment was well tolerated. Delayed-type
hypersensitivity reactions against the PSMA plasmid were found in several
patients including all patients that were initially vaccinated with the
adenoviral vector expressing PSMA. Six out of 12 patients who received
immunotherapy only were regarded as responders. More recently, a phase I study
investigating the administration of a DNA plasmid encoding PSA in combination
with GM‑CSF and IL‑2 to HRPC patients was conducted (Pavlenko et
al, 2004). Two of three patients who received the highest dose developed a
significant PSA-specific cellular immune response and a decrease in the slope
of serum PSA.
IV. Vaccination of prostate cancer patients with dendritic cells pulsed with prostate cancer-associated antigens
DCs
are professional APCs which display an extraordinary capacity to induce,
sustain and regulate T cell responses (Banchereau and Steinman, 1998;
Banchereau et al, 2000; Steinman, 2003). DCs circulate through the blood and
become resident in peripheral tissues, where they continuously monitor invading
pathogens. These immature DCs are particularly efficient in antigen capture but
are rather ineffective in antigen-processing and in stimulating
antigen-specific T cells. DC maturation is induced by pathogens or
proinflammatory cytokines. Its hallmark is the acquisition of the capacity to
efficiently process and present antigens. During maturation DCs migrate from
the peripheral tissues to the T cell-rich areas of secondary lymphoid organs,
where they initiate antigen-specific T cell responses. Owing to their unique
ability to activate naive T cells DCs evolved as promising candidates for
vaccination protocols in cancer therapy (Fong and Engleman, 2000; Banchereau
and Palucka, 2005; Nestle et al, 2005). The ability of TAA-loaded DCs to induce
both protective and therapeutic antitumor responses has been documented in
animal models (Mayordomo et al, 1995; Celluzzi et al, 1996; Nair et al, 2000).
Also in human, clinical trials revealed promising immunologic and clinical
effects of antigen-loaded DCs administered as a vaccine against cancer (Hsu et
al, 1996; Nestle et al, 1998; Thurner et al, 1999).
In the setting of
prostate cancer, clinical trials have shown that DCs pulsed with TAA-derived
peptide, protein or mRNA were well tolerated, efficiently augmented
antigen-specific T cell responses and exhibited partial or complete clinical
effects. Thus, Murphy and colleagues conducted a phase I trial to determine the
safe administration of DCs and HLA-A*0201-restricted PSMA-derived peptides to
HRPC patients (Murphy et al, 1996; Tjoa et al, 1997). Treatment was well
tolerated by all 51 patients and favourable antigen-specific cellular immune
responses were observed in seven partial responders based on National Prostate
Cancer Project criteria and a 50% reduction of PSA level. Following the phase I
study, the same group initiated a phase II clinical trial to investigate the
therapeutic efficiency of infused DCs loaded with two HLA-A*0201-restricted
PSMA-derived peptides. Nine partial responders were identified in a group of 33
HRPC patients which were already participants in the previous phase I study and
were subsequently enrolled in the phase II trial (Tjoa et al, 1998). In
addition, two complete and six partial responders were observed in a group of
25 evaluated patients with no previous immunotherapy experience (Murphy et al,
1999a). Furthermore, one complete and 10 partial responders were identified
from 37 patients with presumed local recurrence of prostate cancer after
primary treatment failure (Murphy et al, 1999b).
An additional
clinical phase I trial which was based on the administration of peptide-loaded
DCs to patients with metastatic HRPC was performed (Vonderheide et al, 2004).
Five patients were vaccinated with DCs pulsed with an HLA-A*0201-restricted
hTERT-derived peptide and keyhole limpet hemocyanin. No significant side
effects were observed. T cells reactive against the hTERT-derived peptide were
induced in two patients after vaccination. All four evaluable patients had
stabilization of disease. More recently, we conducted a phase I clinical trial to evaluate the
potential of DCs loaded with a cocktail consisting of HLA-A*0201-restricted
peptides derived from PSA, PSMA, survivin, prostein and trp‑p8
(unpublished data). No severe side effects were noted. Four out of eight
patients had a temporary decrease or stabilization of serum PSA level. In
addition, three out of these four PSA responders exhibited antigen-specific T
cell responses against prostein, survivin or PSMA.
Small et al, 2000reported
on a clinical phase I/II trial including 31 patients with HRPC. Patients were
treated with enriched DC precursors preexposed in vitro to PA2024, a fusion protein consisting of human GM-CSF and
PAP. Treatment was well tolerated. All patients developed immune responses to
the fusion protein and 38% displayed immune responses to PAP. Six patients
showed a decline in PSA level. Burch and colleagues also administered
PA2024-loaded DCs to HRPC patients. These infusions were followed by
subcutaneous applications of PAP2024 without cells. Treatment was safe, induced
antigen-specific cellular immunity and resulted in PSA level reduction in three
out of 12 evaluated patiens (Burch et al, 2000). A subsequent phase II study
demonstrated a decline in PSA level in three out of 19 evaluated patients
(Burch et al, 2004).
Another clinical
trial including patients with metastatic prostate cancer was based on the
administration of DCs loaded with recombinant murine PAP. Minimal
treatment-associated side effects were observed. All patients developed T cell
immunity to mouse PAP and 11 of 21 patients to the homologous self antigen. Six
of 21 patients had evidence of clinical stabilization of their previously
progressing prostate cancer as determined by PSA level monitoring, computerized
tomography and bone scans (Fong et al, 2001).
Barrou et al, 2004
performed a clinical trial enrolling prostate cancer patients in biochemical
relapse after radical prostatectomy to assess the feasibility, safety and
immunogenicity of vaccination with DCs pulsed with human recombinant PSA.
Twenty-four patients received nine administrations of PSA-loaded DCs by
combined intravenous, subcutaneous and intradermal routes. No severe side
effects were observed, PSA-specific T cells were detected and 11 patients
exhibited a transient PSA decrease.
Two other clinical
plase I studies were conducted to evaluate the potential of DCs transfected
with mRNA encoding TAAs. In the first trial, 13 patients with metastatic
prostate cancer received PSA mRNA-transfected DCs (Heiser et al, 2002).
Vaccination was well tolerated and PSA-specific T cells were detected in all
patients. Six of seven evaluated patients had a significant decrease of PSA and
three patients exhibited a transient molecular clearance of circulating tumor
cells. In the second trial, hTERT mRNA-transfected DCs were administered to 20
patients with metastatic prostate cancer (Su et al, 2005). Expansion of
hTERT-specific T cells was detected in 19 of 20 patients. Vaccination was
associated with a reduction of PSA velocity and molecular clearance of
circulating tumor cells.
V. Conclusion
Current therapeutic approaches revealed only modest
impact on survival outcomes for patients with metastatic prostate cancer.
Recent advances in the identification of TAA-derived T cell epitopes and in the successful activation of
tumor-reactive CTLs and CD4+ T cells paved the way for new treatment
modalities for prostate cancer. Clinical trials which were based on the in vivo-stimulation of effector T cells
by the administration of peptides, proteins, DNA or TAA-pulsed DCs provide
evidence that these concepts were safe and feasible. In addition, they led to
the induction of antigen-specific T cells as well as clinical responses in
prostate cancer patients. However, further improvement of prostate cancer
therapy is required and may be achieved by combining T cell-based vaccination
strategies with radio-, hormone-, chemo-, antibody- or anti-angiogenic therapy.
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