treatment of advanced prostate cancer: the vaccine approach
TRANSCRIPT
Treatment of Advanced Prostate Cancer: the VaccineApproachP. F. A. Mulders
From the Department of Urology, University Hospital, Nijmegen, The Netherlands
Scand J Urol Nephrol Suppl 203: 41–43, 1999
Key words:prostate cancer, vaccine treatment of advanced prostate cancer.
Peter F. A. Mulders, MD, PhD, Department of Urology, University Hospital, PO Box 9101, 6500 HB, Nijmegen, TheNetherlands
The role of immunotherapeutic modalities in prostatecancer (PC) has only recently been explored.Adenocarcinoma of the prostate has always beenconsidered a less immunogenic tumour. Routinelight microscopy of paraffin-embedded prostatetissue does not show massive infiltration of lympho-cytes in PC. However, recent observations in PChave revealed immunological entities. High intra-tumoral levels of TGF-b mRNA are correlated withpoor prognosis in hormone-refractory PC, indicatinga local immunosuppressive environment (1). Inaddition, the finding that cytokine modulation, whichis closely associated with tumour invasion and ametastatic phenotype, can alter PC properties,suggests that immunotherapy may have a role inthe treatment of hormone-refractory PC (2). Recentobservations of single cell suspensions of PC tissuein our laboratory revealed a consistent massiveinfiltration of tumour-infiltrating lymphocytes withpotential tumour-killing capacity. These data suggestthat an immune cell environment exists in prostatetumours. However, an interesting observation wasmade by Troy et al. (3). In order to investigatewhether dendritic cells (DC), which as professionalantigen-presenting cells have the capacity to stimu-late immune responses against tumour-associatedantigens (Fig. 1), are recruited into and activatedwithin PC, they performed phenotypic studies. DCwere found to represent a small subset of leucocytespresent in both benign and malignant prostatictissue. Statistically, there was significantly less DCin PC compared with normal prostatic tissue. Whileonly a small subset of DC expressed markers ofactivation in PC, this was significantly more than thevirtual absence of activated DC in normal prostatictissue. These findings suggest that there is no activerecruitment of DC into PC and those DC present are
only minimally activated. This is one of therationales for carrying out in vitro culture of DCin PC treatment (Fig. 2).
For PC, several immunogenic peptides have beenderived from prostate-specific antigen (PSA), prostaticacid phosphatase (PAP) and prostate-specific mem-brane antigen (PSMA) and, in combination withcultured DC, clinical trials have, or will be, performed.Murphy et al. from Seattle, USA completed a phase Itrial with a PSMA-derived peptide loaded DC inhormone-refractory PC and showed that these vaccina-tions were well tolerated and a cellular immuneresponse was seen in some patients (4). Data fromimmunological monitoring studies show an increase inT-cell response to the appropriate PSMA peptides inHLA-A2-positive patients. In these patients a specificin vivo presentation of the PSMA peptides with HLA-A0201-specific motif by autologous DC to circulatingT-cells occurs. Seven partial responders were seenbased on NPCP criteria� PSA. The responses ob-served in the phase I and II clinical trials weresignificant and of long duration (average 225 days).The partial-responder group included patients whocontinued to respond from phase I, as well as those whostarted to respond during the phase II trial.
Furthermore, peptides derived from PSA have beenshown to be immunogenic. Correale et al. showed thatthree peptides, PSA-1, PSA-3 and PSA-oligo-epitopepeptide, can elicit cytotoxic T-lympocyte (CTL)responses in patients with PC (5). Also DC infectedwith recombinant PSA-vaccinia viral construct wereable to generate CTL response to defined PSA epitopes.PSA, either the whole gene or immunogenic peptides,can be used for the development of cancer vaccinedevelopment in patients with PC.
Peshoa et al. showed that induction of prostatetumour-specific CD8� cytotoxic T-lymphocytes in
1999 Scandinavian University Press.ISSN 0036–5599 Scand J Urol Nephrol 33
ORIGINAL ARTICLE
Scan
d J
Uro
l Nep
hrol
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
SUN
Y S
tate
Uni
vers
ity o
f N
ew Y
ork
at S
tony
Bro
ok o
n 10
/29/
14Fo
r pe
rson
al u
se o
nly.
vitro by usingDC pulsedwith aPAPpeptideis possible(6). Selectedpeptidesfrom PAP, a prostatetissue-specificantigen,wereshownto bindHLA-A2. A high-affinity peptidewas usedto generatepeptide-specificCD8� CTLs from the peripheral blood of healthydonors.The obtainedPAP-peptide-specificCTL lysedpeptide-coatedtarget cells, vaccinia-infectedtargetcells, and HLA-A2-positive prostate-tumourcells invitro in anantigen-specificmanner.TheresultsindicatethatCTL precursorsto thePAPgeneproductexistandcould potentially be recruitedto elicit an anti-tumourresponse.PAPmight thereforebeasuitableantigenforinclusionin PCvaccines.
In our laboratorydifferential display analysishasrevealeda numberof changesin the geneexpressionbetweenbenignand malignanttissueof the prostate.One cDNA, DD3, was selectedthat is highly over-expressedin 47outof 50prostatetumours,whereasnoexpressioncanbe detectedin benignprostatictissuesof thesamepatient.Moreover,no expressioncouldbedetectedin 18normaltissuestested.In contrastto PSAand PSM, the expressionof DD3 is thereforehighlyconfined to prostatic tumours and maintains itsexpressionin poorly differentiatedcarcinomas.DD3,
asthe only prostate-cancer-specific genedescribedsofar, might therefore be an attractive tool for thedevelopmentof a specific immunotherapyapproachagainstPC whenadequatelypresentedto the immunesystem.
DISCUSSION
In summarywe haveapproacheda new eraof cancerresearchwhich focuseson T-cell mediatedspecificimmune responses.Banchereau& Steinmanrecentlysummarizedthat DCs, as potent antigen-presentingcellsaresofar thebestknowncells in thehumanbodythatareableto inducetheseresponses(7). TheirpotentAPC (antigen-presentingcell) function,their ability totake-upand presentantigen for extendedperiodsoftime, andtheir capacityto migrateto lymphoidorgansmake DCs attractive candidatesfor delivery andpresentationof antigenfor theinductionof anti-tumourimmunity. This recommendsthe searchfor new andpotent immunogens in a variety of cancers. Incombinationwith DC, potent tumour vaccinesin PCcanbedeveloped.
Fig. 1. Interactionof thedendriticcell tumourantigenwith theT-cell: thedendriticcell hasthephenotypiccharacteristics(highMHC classIandII complexes,adhesionandco-stimulatorymolecules)to adequatelypresentthe tumourantigento thecellular immunesystemin orderto inducean specificimmuneresponse.
ScandJ Urol Nephrol33
42 P. F. A. Mulders
Scan
d J
Uro
l Nep
hrol
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
SUN
Y S
tate
Uni
vers
ity o
f N
ew Y
ork
at S
tony
Bro
ok o
n 10
/29/
14Fo
r pe
rson
al u
se o
nly.
REFERENCES
1. Kim IY, Ahn HJ, Lang S, Oefelein MG, Oyasu R,Kozlowski JM, et al. Lossof expressionof transforminggrowth factor-beta receptors is associatedwith poorprognosisin prostatecancerpatients.Clin CancerRes1998;4: 1625–30.
2. Sokoloff MH, Tso CL, Kaboo R, Taneja S, Pang S,deKernion JB, et al. In vitro modulation of tumourprogression-associatedpropertiesof hormonerefractoryprostatecarcinomacell lines by cytokines.Cancer1996;77: 1862–72.
3. Troy A, Davidson P, Atkinson C, Hart D. Phenotypiccharacterisationof the dendritic cell infiltrate in prostatecancer.J Urol 1998;160: 214–219.
4. Tjoa BA, SimmonsSJ,BowesVA, RagdeH, RogersM,
ElgamalA, et al. Evaluationof phaseI/II clinical trials inprostatecancerwith dendritic cells andPSMA peptides.Prostate1998;36: 39–44.
5. CorrealeP, WalmsleyK, NierodaC, ZarembaS, Zhu M,SchlomJ, et al. In vitro generationof humancytotoxic Tlymphocytesspecificfor peptidesderivedfrom prostate-specificantigen.J Natl CancerInst 1997;89: 293–300.
6. PeshwaMV, Shi JD, RueggC, Laus R, van SchootenWC. Induction of prostatetumour-specificCD8� cyto-toxic T-lymphocytes in vitro using antigen-presentingcells pulsed with prostatic acid phosphatasepeptide.Prostate1998;36: 129–38.
7. BanchereauJ, SteinmanRM. Dendritic cells and thecontrol of immunity. Nature1998;392: 245–52.
Fig. 2. Monocytes/macrophagesare isolatedform the peripheralblood of patientswith prostatecancer,loadedwith the immunogenicpeptides(PSMA, PSA,PAP) in the laboratoryandsubsequentlyinjectedinto the patient.
ScandJ Urol Nephrol33
Treatmentof advancedprostatecancer 43
Scan
d J
Uro
l Nep
hrol
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
SUN
Y S
tate
Uni
vers
ity o
f N
ew Y
ork
at S
tony
Bro
ok o
n 10
/29/
14Fo
r pe
rson
al u
se o
nly.