treatment of advanced prostate cancer: the vaccine approach

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Treatment of Advanced Prostate Cancer: the Vaccine Approach P. 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, The Netherlands The role of immunotherapeutic modalities in prostate cancer (PC) has only recently been explored. Adenocarcinoma of the prostate has always been considered a less immunogenic tumour. Routine light microscopy of paraffin-embedded prostate tissue does not show massive infiltration of lympho- cytes in PC. However, recent observations in PC have revealed immunological entities. High intra- tumoral levels of TGF-b mRNA are correlated with poor prognosis in hormone-refractory PC, indicating a local immunosuppressive environment (1). In addition, the finding that cytokine modulation, which is closely associated with tumour invasion and a metastatic phenotype, can alter PC properties, suggests that immunotherapy may have a role in the treatment of hormone-refractory PC (2). Recent observations of single cell suspensions of PC tissue in our laboratory revealed a consistent massive infiltration of tumour-infiltrating lymphocytes with potential tumour-killing capacity. These data suggest that an immune cell environment exists in prostate tumours. However, an interesting observation was made by Troy et al. (3). In order to investigate whether dendritic cells (DC), which as professional antigen-presenting cells have the capacity to stimu- late immune responses against tumour-associated antigens (Fig. 1), are recruited into and activated within PC, they performed phenotypic studies. DC were found to represent a small subset of leucocytes present in both benign and malignant prostatic tissue. Statistically, there was significantly less DC in PC compared with normal prostatic tissue. While only a small subset of DC expressed markers of activation in PC, this was significantly more than the virtual absence of activated DC in normal prostatic tissue. These findings suggest that there is no active recruitment of DC into PC and those DC present are only minimally activated. This is one of the rationales for carrying out in vitro culture of DC in PC treatment (Fig. 2). For PC, several immunogenic peptides have been derived from prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate-specific mem- brane antigen (PSMA) and, in combination with cultured DC, clinical trials have, or will be, performed. Murphy et al. from Seattle, USA completed a phase I trial with a PSMA-derived peptide loaded DC in hormone-refractory PC and showed that these vaccina- tions were well tolerated and a cellular immune response was seen in some patients (4). Data from immunological monitoring studies show an increase in T-cell response to the appropriate PSMA peptides in HLA-A2-positive patients. In these patients a specific in vivo presentation of the PSMA peptides with HLA- A0201-specific motif by autologous DC to circulating T-cells occurs. Seven partial responders were seen based on NPCP criteria PSA. The responses ob- served in the phase I and II clinical trials were significant and of long duration (average 225 days). The partial-responder group included patients who continued to respond from phase I, as well as those who started to respond during the phase II trial. Furthermore, peptides derived from PSA have been shown to be immunogenic. Correale et al. showed that three peptides, PSA-1, PSA-3 and PSA-oligo-epitope peptide, can elicit cytotoxic T-lympocyte (CTL) responses in patients with PC (5). Also DC infected with recombinant PSA-vaccinia viral construct were able to generate CTL response to defined PSA epitopes. PSA, either the whole gene or immunogenic peptides, can be used for the development of cancer vaccine development in patients with PC. Peshoa et al. showed that induction of prostate tumour-specific CD8 cytotoxic T-lymphocytes in 1999 Scandinavian University Press. ISSN 0036–5599 Scand J Urol Nephrol 33 ORIGINAL ARTICLE Scand J Urol Nephrol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 10/29/14 For personal use only.

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Page 1: Treatment of Advanced Prostate Cancer: the Vaccine Approach

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

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Page 2: Treatment of Advanced Prostate Cancer: the Vaccine Approach

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

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Page 3: Treatment of Advanced Prostate Cancer: the Vaccine Approach

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.

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Treatmentof advancedprostatecancer 43

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