Inmunopatología del cáncer de próstata. Sistema inmunológico/inflamatorio y cáncer de próstata...

Inmunopatología del

cáncer de próstata

Sistema inmunológico/inflamatorio y cáncer de próstata

¿Participa el sistema inmunológico/ inflamatorio en la etiopatogenia de la enfermedad?

¿Existen alteraciones del sistema inmunológico/inflamatorio en los pacientes? ¿son reversibles?

Se puede modular terapéuticamente el sistema inmunológico/ inflamatorio?

Etiopatogenia del cáncer de próstata

Factores de riesgo

Historia familiar

Edad avanzada

La dieta, de forma

emergente

HU

PA

ETIOPATOGENIA CÁNCER DE PRÓSTATA

HETEROGENEI DAD PATOGENI CA

I NDI VI DUAL Y TEMPORAL

BASE GENÉTICA BASE GENÉTICA INTERACCIÓN INTERACCIÓN CON EL MEDIO CON EL MEDIO

INTERNO Y EXTERNOINTERNO Y EXTERNO

Etiopatogenia del cáncer de próstata Implicaciones del sistema

inmune/inflamatorio

La etiología (el por qué)

La patogenia (el como)Alteraciones intrínsecas de lás

células tumorales (acumulación de alteraciones genéticas y epigenéticas)

Interacciones con el huésped

Enigmas de la etiopatogenia del cáncer de próstata

Etiología desconocida Alta incidencia en países

occidentales y baja en los del extremo oriente

Incidencia nivelada tras la primera generación en emigrantes asiáticos

Marcada alta incidencia con respecto a otros tumores genitourinarios (vesículas seminales)

Localización preferente en área periférica de la glándula

Enigmas de la etiopatogenia del cáncer de próstata

En las autopsias la incidencia de

prostatitis es los hombres

caucasianos y afroamericanos es

alta y muy baja o inexistente en

asiáticos en la primera generación

Borowsky A Neoplasia 8,709-715, 2006

Sistema inmunológico/inflamatorio y

patogenia del cáncer de próstata

En la patogenia de un 20% de

los tumores de los adultos se

implica un entorno inflamatorio

crónico (estómago, intestino

grueso, hígado, árbol biliar, vejiga

urinaria )

Inflamación y cáncer de próstata

Inflamación crónica Alteración epitelial

Atrofia focal o difusa del epitelio

Áreas de proliferación epitelial

“Proliferative inflammatory atrophy” (PIA)

Lesiones transicionales entre epitelio atrófico y

adenocarcinoma McNeal J in Histology for Pathologists Lippincott-Raven, Philadelphia, 1997

De Marzo, A Am J Pathol. 155, 1985, 1999

McNeal, J Am J Surg Pathol 12, 619, 1998

Nakayama, M Am J Pathol 163, 923, 2003

Inflamación y cáncer de próstata

Las lesiones del epitelio atrófico proliferante

(PIA) comparten alteraciones moleculares con

el cáncer de próstata

Disminución de la expresión de genes

supresores NKX3.1

CDKN1B (p27)

PTEN Bethel, Cancer Res. 66, 10683, 2006

Atypical proliferations arise in an inflamed prostate

Epithelial proliferation with

cellular loss of polarity and

cytologic atypia

Segmental area of inflammation (Infl) and another area of

atrophy (Atr)

Inflammation and Atrophy Precede Prostatic Neoplasiain a 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine

(PhIP)-Induced Rat ModelA Borowsky et al 2006

Etiopatogenia del cáncer de próstata Implicaciones del sistema

inmune/inflamatorio

La etiología (el por qué)

La patogenia (el como)Alteraciones intrínsecas de lás

células tumorales (acumulación de alteraciones genéticas y epigenéticas)

Interacciones con el huésped

The molecular mechanisms that underlie the pathogenesis of

inflammation-associated cancer are complex, and involve

both the innate and adaptive immune systems

Highly reactive chemical compounds, including superoxide, hydrogen peroxide, singlet oxygen and nitric oxide are released from activated phagocytic inflammatory cells of the innate immune system

These molcelules can cause oxidative or nitrosative damage to DNA in the epithelial cells, or react with other cellular components such as phospholipids, initiating a free-radical chain reaction

Condeelis Cell 124, 263–266 (2006) Lewis Cancer Res. 66, 605–612 (2006) de Visser Nature Rev. Cancer 6, 24–37 (2006)

LinfocitoCD4+

IFN

NO

TNF

Fagocitosis/Pinocitosis

FagolisosomaLisosoma

ACTIVACIÓN

Exocitosis

PRODUCTOS SECRETADOS• Enzimas que afectan al tejido conectivo y proteínas séricas:Elastasa, activador del plasminógeno, colagenasa, enzimaslisosomales,enzima convertidora de angiotensina, procuagulantes tisulares, arginasa.• Proteínas relacionadas con la defensa y la inflamación:Proteínas del complemento (C2, C3, C4, C5), factores (B, D, H e I), lisozimas, IFN y , fibronectina (FN).• Factores reguladores del crecimiento:G-CSF, GM-CSF, M-CSF.• Citocinas que promueven la inflamación aguda y regulan la respuesta linfocitaria: IL-1, IL-6, TNF y , IL-8, IL-12.• Citocinas inhibidoras:IL-10, TGF1, 2, 3, IL-1ra.• Factores que promueven la reparación tisular:Factor de crecimiento derivado de plaquetas, factor de crecimiento de fibroblástos.• Otros:Apolipoproteína E, derivados del ácido araquidónico, PAF, timidina.

A) Productosmicrobianos

B) Citocinas

FASL

FASR

B) CitocinasROI

CD14+hi CD16+low

CD14+hi CD16-

CD14+hi CD16+hi

CD14+low CD16+hi

Monocitos proinflamatorios

Monocitos

clásicos

MacrófagoMacrófagoTNF-TNF-IL-1IL-1

IL-2IL-2IFN-IFN-

THTH

IL-13IL-13

IL-4IL-4

IL-2IL-2

IFN-IFN-

IL-8, groIL-8, groIFN-IFN-

PMNPMN

IL-1IL-1TNFTNF

LLinfocitos T citotóxicos y NKinfocitos T citotóxicos y NK

Células PlasmáticasCélulas Plasmáticas

IgG1IgG1IgEIgE

Célula TroncalCélula Troncal

PAFPAFLTC4LTC4

Respuesta inflamatoria conlleva Respuesta inflamatoria conlleva aacctivación de ltivación de las célulasas células

sistema inmune y secreción sistema inmune y secreción de citoquinas y factores de de citoquinas y factores de

crecimiento crecimiento

OO22--

proteasaproteasaPGEPGE22

OO22--

proteasaproteasa

Participación patogénica del sistema inmunitario/inflamatorio en el cáncer de

próstata

Infiltración de células inmunológicas/ inflamatorias Secretan citoquinas y quimioquinas que

promueven: el crecimiento epitelial angiogénesis

Secretan enzimas proteolíticas de la matriz extracelular que favorecen:

Invasión tumoral del estroma Invasión vascular

CÁNCER DE PROSTATA. INFLAMACIÓNCITOQUINAS Y FACTORES DE CRECIMIENTO

CÁNCER DE PROSTATA. INFLAMACIÓNCITOQUINAS Y FACTORES DE CRECIMIENTO

MULTIPLESRELACIONESAUTOCRINA

SY

PARACRINAS

MULTIPLESRELACIONESAUTOCRINA

SY

PARACRINAS

ESTROMA,EPITELIO

/LINFOCITOS YMONOCITOS

ESTROMA,EPITELIO

/LINFOCITOS YMONOCITOS

Interleukin-6 It is implicated in the development and

progression of prostate cancer (Keller et al., 1996; Trikha et al., 2003, Cavarretta et

al., 2007)

Correlation between IL-6 protein levels and

more advanced stages of the disease and poor

prognosis is now well established (Siegall et al., 1990; Siegsmund et al., 1994; Adler et

al., 1999; Drachenberg et al., 1999; Nakashima et

al., 2000; Giri et al., 2001; Hobisch et al., 2001)

IL-17RC Protein Isoforms Were Differentially Expressed in Prostate Cancers

Four of54 (7%) androgen-dependent prostate

cancers werepositively stained by anti-

ICD, whereas 12 of 55 (22%)

androgen-independent prostate cancers were

positivelystained

La doble cara del sistema inmune y el cáncer

JANO

INDUCEY/O

FAVORECE DEFIENDE

Entorno inflamatorio tisular

inductor de:

Supresión de la respuesta efectora

inmunológica

Apoptosis de las células efectoras

Inmunodeficiencia


próstata

Entorno tisular inductor de:

Supresión de la respuesta efectora inmunológica

Monocitos inflamatorios

Células dendríticas inmaduras

Predomino de subpoblaciones

Treg

Th17

Th1 Miller, J. Immunol. 177, 7398–7405 (2006) Weaver Immunity 24, 677–688 (2006)


próstata






Treg

Th17

Th1

Miller, J. Immunol. 177, 7398–7405 (2006)

Weaver Immunity 24, 677–688 (2006)


próstata

Prevalence and function of CD4CD25high T cells is elevated in peripheral blood and tissue

samples from PC patients

HC BPH PC

FOXP3 expression in prostate tissue

Arrows indicate FOXP3-positive

cells (brown nuclear staining; original magnification, 40)

Representative sections of prostate tissue, showing benign or malignant gland from the same prostate

Miller et al The Journal of Immunology, 2006, 177: 7398 –7405.






Treg

Th17

Th1

Miller, J. Immunol. 177, 7398–7405 (2006)

Weaver Immunity 24, 677–688 (2006)


próstata

In prostate cancer IL-10 prevents the CD40-induced CTL and TNF- and IL-12 production, Th1 skewing, and tumor

regressionThe Journal of Immunology, 2006, 177: 6642–6649

Genes implicados en susceptibilidad a

cáncer de próstata

Pertenecientes a la respuesta

inmunológica innata

Respuesta a virus, RNASEL

Respuesta a patrones microbiológicos, TLR

Respuesta a mediadores inflamatorios, MSR1

Vías inflamatorias Il-1R, MIC1


próstata

La doble cara del sistema inmune y el cáncer

JANO

INDUCEY/O

FAVORECE DEFIENDE

TUMOR DC

New Paradigm – 2 Hit Model

Chronic inflammation

TUMOR DCT/NKCELL

PerforinFasLIFNγTNFα

HMGB1, HSP,Uric AcidHSP, Adenine, ATP

Tumor Necrosis [↓Apoptosis]↓

Release of Factors [HMGB1, others?]↓

Tumor Growth

1

2

- - Immunosuppression mediated by PDC, tumor, other cells

Cáncer de próstata

Causas de la

inflamación crónica

prostática

Possible causes of prostate inflammation

a | Infection Chronic bacterial, viruses, fungi, mycobacteria

and parasites

b | Hormones Hormonal alterations such as oestrogen

exposure at crucial developmental junctures can result in architectural alterations in the prostate that produce an inflammatory response

c | Physical trauma Corpora amylacea can traumatize the prostate

on a microscopic level

De Marzo Nature Reviews Cancer 7. 256-269, 2007

Possible causes of prostate inflammation

d | Urine reflux Urine that travels up back towards the bladder can

penetrate the ducts and acini of the prostate Some compounds, such as crystalline uric acid, can

directly activate innate inflammatory cells Although these compounds would not be expected to

traverse the prostate epithelium, if the epithelium was already damaged this would facilitate the leakage of these compounds into the stromal space where they would readily activate inflammatory cells

e | Dietary habits Ingested carcinogens (for example 2-amino-1-

methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which derives from charred meat) can reach the prostate through the bloodstream or by urine reflux and cause DNA damage and mutations, and result in an influx of inflammatory cells

De Marzo Nature Reviews Cancer 7. 256-269, 2007

Moléculas ImplicadasMoléculas Implicadasen la en la InteraciónInteraciónLinfocitoLinfocitoTT--Célula AccesoriaCélula Accesoria..

CD80 CD80

óó

CD86CD86MHCMHC

CD4 CD4 CD8CD8

CD54CD54

CD11a/CD11a/CD18CD18

CD58CD58

CD2CD2

CD28 CD28

TCR/CD3 TCR/CD3

AgAg

CD 152CD 152

(CTLA(CTLA--4) 4)

ClaseClaseIIIIClaseClaseII

CELULA CELULA PRESENTADORAPRESENTADORADE ANTIGENODE ANTIGENO

LINFOCITO TLINFOCITO T

Table 2. Proliferative response in stimulated PBMC from PCaD patients.

Stimuli CONTROLS n=30

PCaDnT n=12

PCaDT n=12

PCaDH n=12

Medium

2.9 ± 1.2

2 ± 1.4

2.6 ± 1.4

2.1 ± 1.5

Con A 129 ± 45 48 ± 36 45 ± 24 42 ± 27 PHA 195 ± 64 84 ± 36 78 ± 46 67 ± 42

PHA+IL-2 198 ± 56 198 ± 56 113 ± 47 124 ± 53 PHA+PMA 188 ± 58 110 ± 57 85 ± 53 87 ± 40 PHA+anti-CD28 207 ± 54 95 ± 36 113 ± 46 123 ± 30 PHA+IL-4 211 ± 46 211 ± 46 132 ± 50 139 ± 51

*Peripheral blood mononuclear cells (PBMC) were cultured in the presence of the indicated stimuli and pulsed for 18 h with Ci/well 3H-TdR. The mean ct/min of triplicate samples was determined by liquid scintillation on day 3. Results are indicated as mean ± s.d. in ct/min X 1000. Anti-CD28 and anti-CD2 (CD2.1 + CD2.9) are not mitogenic (data not shown).&.-The degree of statistical significance was calculated by Student´s t test. NS, not significant. Con A, concanavalin A; PHA, phytohaemagglutinin; PMA, phorbol myristate acetate.

DEFECTIVE T LYMPHOCYTE ACTIVATION IN PATIENTS WITH PROSTATE CANCER

Moléculas ImplicadasMoléculas Implicadasen la en la InteraciónInteraciónLinfocitoLinfocitoTT--Célula AccesoriaCélula Accesoria..

CD80 CD80

óó

CD86CD86MHCMHC

CD4 CD4 CD8CD8

CD54CD54

CD11a/CD11a/CD18CD18

CD58CD58

CD2CD2

CD28 CD28

TCR/CD3 TCR/CD3

AgAg

CD 152CD 152

(CTLA(CTLA--4) 4)

ClaseClaseIIIIClaseClaseII

CELULA CELULA PRESENTADORAPRESENTADORADE ANTIGENODE ANTIGENO

LINFOCITO TLINFOCITO T





PCaDnT n=12

PCaDT n=12

PCaDH n=12

Medium

2.9 ± 1.2

2 ± 1.4

2.6 ± 1.4

2.1 ± 1.5

Con A 129 ± 45 48 ± 36 45 ± 24 42 ± 27 PHA 195 ± 64 84 ± 36 78 ± 46 67 ± 42 anti-CD3 65 ± 28 42 ± 27 58 ± 27 40 ± 23 anti-CD2+IL-2 52 ± 22 52 ± 22 51 ± 27 62 ± 25 anti-CD2+PMA 168 ± 80 75 ± 50 85 ± 47 80 ± 42 anti-CD2+anti-CD28 38 ± 20 31 ± 15 36 ± 9 38 ± 14 PMA 26 ± 12 26 ± 12 15 ± 9 15 ± 10

00 2424 4848 7272 9696

250250

500500

750750

10001000

00 2424 4848 7272 9696

00

100100

200200

300300

00 2424 4848 7272 9696

00

150150

300300

450450

600600

CÉ

LU

LA

S V

IVA

S X

10

00

CÉ

LU

LA

S V

IVA

S X

10

00

VIABILIDAD CELULAR TRASVIABILIDAD CELULAR TRASESTIMULAR CON anti-CD3 + PMAESTIMULAR CON anti-CD3 + PMA

CONTROLCONTROLCaPCaP

CÉ

LU

LA

S V

IVA

S X

10

00

CÉ

LU

LA

S V

IVA

S X

10

00

00 2424 4848 7272 9696

00

100100

200200

300300

CD4CD4

CD8CD8

CD45ROCD45RO

CD45RACD45RA

CD4CD4

CD8CD8

CD8CD8++CD45ROCD45RO++




CD4CD4++CD45RACD45RA++

CD8CD8++CD45RACD45RA++




PCaDnT n=12

PCaDT n=12

PCaDH n=12

Medium

2.9 ± 1.2

2 ± 1.4

2.6 ± 1.4

2.1 ± 1.5

anti-CD2+IL-2 52 ± 22 52 ± 22 51 ± 27 62 ± 25 anti-CD2+PMA 168 ± 80 75 ± 50 85 ± 47 80 ± 42 anti-CD2+anti-CD28 38 ± 20 31 ± 15 36 ± 9 38 ± 14

PMA 26 ± 12 26 ± 12 15 ± 9 15 ± 10 PMA+IL-2 80 ± 29 80 ± 29 45 ± 21 49 ± 26 PMA+anti-CD28 116 ± 51 116 ± 51 52 ± 48 62 ± 55 PMA+IL-4 58 ± 34 58 ± 34 26 ± 13 31 ± 20 PMA+Iono 108 ± 38 108 ± 38 79 ± 40 81 ± 50


Proliferación Linfocitaria Testimulada por antígenos bacterianos

Proliferación Linfocitaria TProliferación Linfocitaria Testimulada por antígenos bacterianosestimulada por antígenos bacterianos

T-CD4TT--CD4CD4Monocito

MonoMonocitocito

IL-2ILIL--22

IL-2RILIL--2R2R

T-CD4TT--CD4CD4

T-CD4TT--CD4CD4

T-CD4TT--CD4CD4

T-CD4TT--CD4CD4


Table 4. IL-2 Production after activation.

Stimulus CONTROLS n=12

PCaD n=12

PCaD n=12

PCaD n=12

Medium

30 ± 9.2

7.3 ± 2.7

10 ± 3

19.6 ± 7.5

anti-CD3 296 ± 260 21.3 ± 10 25 ± 15 21.7 ± 9.2 anti-CD3+PMA 2153 ± 717 867 ± 241 985 ± 285 1926 ± 930

PHA 1166 ± 678 160 ± 110 298 ± 168 787 ± 353 PHA+PMA 2920 ± 752 1353 ± 300 1435 ± 364 2238 ± 643

PMA 13.4 ± 6.3 18 ± 6 16 ± 6 25 ± 4.1 PMA+anti-CD28 1049 ± 10 645 ± 85 550 ± 75 260 ± 53 PMA+Iono (PI) 1452 ± 582 980 ± 356 850 ± 300 2465 ± 851 PI+anti-CD28 3392 ± 881 1650 ± 564 2100 ± 650 1230 ± 252

*Cells were cultured for 3 days with the indicated stimuli and stained with anti-CD25-FITC and an irrelevant MoAb of the same subclass (IgG1). , Anti-.&The results are shown as percentage of positive cells for CD25 expression (mean ±s.d.).The degree of statistical significance was calculated with Mann-Whiyney U-test. NS, Not significant.PMA, Phorbol myristate acetate; PCaD, prostate cancer patients; PHA, phytohaemagglutinin.

HU

PA

LAS ALTERACIONES DEL SISTEMA INMUNE....COMO FACTOR DE RIESGO

MURPHY´S LAWMURPHY´S LAW

FRIENDS COME AND GO FRIENDS COME AND GO

BUT BUT

ENEMIES ACCUMULATEENEMIES ACCUMULATE

MM

UU

RR

PP

HH

YY

WW

AA

SS

AA

NN

OO

PP

TT

II

MM

II

SS

TT

DC vaccination induces tumor-specific T cells with potent effector function

TCR-I T cells primed with a DC vaccine

were protected from tolerance and

acquired cytolytic function

Twelve-week-old male TRAMP

mice or WT mice received 3 106CD8 and Thy1.1 TCR-I T cells

Eighteen hours later, mice received

peptide-pulsed DCs as previously described.

Prostates were harvested on the

indicated day postvaccine, and TCR-Icells were isolated by magnetic beads

A, T cells were directly used as responder cells in an IFN-ELISPOT assay.

B, T cells were directly used as responder

cells in a granzyme B ELISPOT assay

C, T cells were assayed for their ability to

Degranulate in response to the cognate

TAg epitope, based on CD107a expression

Anderson J Immunology, 2007, 178: 1268–1276.

Priming with a DC vaccine results in upregulation of activation markers and

IFN- production

Anderson J Immunology, 2007, 178: 1268–1276.

Twelve-week-old male TRAMP or nontransgenic, WT mice received 3 106 CFSE, CD8, and Thy1.1TCR-I T cells. Eighteen hours later, mice received peptide-pulsed DCs Vaccine DLN were harvested 3 days after DC vaccine

Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer

Clin Cancer Res 13,1493 2007

Autoantibody responses in patients undergoing Neoadjuvant hormone therapy (7 of 24,

29.2%)

External beam radiation therapy (4 of 29, 13.8%)

Brachytherapy (5 of 20, 25%)

0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%)



Several antigens recognized by treatment associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2

Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups.

PSA values over time for patients who showed a hormone

therapy associated autorreactivity


Immunotherapy for prostate cancer Dendritic cell-based immunotherapeutics

GM-CSF-based approaches Systemic GM-CSF Cellular delivery of GM-CSF Antigen-pulsed dendritic cells

T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy

B Lymphocyte-based immunotherapeutics Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy

PSA vaccines Prostate-specific membrane antigen

Glycoprotein vaccines

DC vaccination trials

Of the about 17 DC vaccination trials reported on in peerreviewed journals

All trials have demonstrated negligible toxicity

Clinical responses or favorable changes in PSA-kinetics in about 45% of the patients

In the first randomized, placebo-controlled vaccination trial, a survival benefit of several months for vaccinated patients could be shown

Immunotherapy for prostate cancer using prostatic acid phosphatase

loaded antigen presenting cells

Loaded dendritic cell therapy using prostatic acid phosphatase (APC8015; Provenge®, Dendreon Corp., Seattle, WA) as an immunogen has shown a survival benefit in patients with metastatic hormone-refractory prostate cancer in a randomized phase III trial

In the intent-to-treat analysis, which included all 127 patients, there was a survival advantage with APC8015, with a median overall survival of 25.9 months versus 21.4 months (representing a 4.5-month difference), hazard ratio 1.43 (P 0.01)

Urologic Oncology, 24 (2006) 434–441

DC vaccination trials

Although from the other (Phase I/II)

trials, a clinical efficacy cannot

formally be concluded, their results

are encouraging and provide a proof

of principle for the immunogenicity

of DC-based immunotherapy in

prostate cancer patients

Which subset ?

Dose and frequency ?

Which route of injection ?

Which maturation stimulus ?

Which method of antigen preparation and delivery ?

Combination with other therapies ?

How to determine efficacy ?

CD14+ or CD34+ DC precursors in blood

Antigen-loaded DC

Critical parameters for DC-based immunotherapy

InduceCTL and Th1

DC vaccination trials To further improve patients’ outcome, several

strategies involving choice of antigen, optimization of DC maturation, combination with conventional treatment or immune modulation such as removal of Treg are being evaluated.

Furthermore, patients with low tumor burden and better immune competence might profit more from vaccination therapy than heavily pre-treated, advanced-stage cancer patients

Standardization of DC preparation, clinical and immune monitoring are warranted.



T Lymphocyte-based immunotherapeutics Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based

therapy B Lymphocyte-based immunotherapeutics

Antibody-based therapy Antibody to vascular endothelial growth factor Antibody to PSMA Radiolabelled antibody therapy



A PilotTrial of CTLA-4 Blockade with Human Anti CTLA-4 in Patients with Hormone-Refractory

Prostate Cancer

A single dose of 3 mg/kg Ipilimumab, an

anti-CTLA-4a ntibody, given to patients

with prostate cancer is safe and does not

result in significant clinical autoimmunity

PSA-modulating effects observed

warrant further investigation Eric J. Small et al Clin Cancer Res 13, 15, 2007

Anticuerpos monoclonales Anticuerpos monoclonales

Dirigidos frente an antígenos tumorales o específicos de la próstata:

PSA, PSCA

Conjugados a tóxina o agenets radiactivos o no conjugados Lampe MI, et al. Development of new prostate specific monoclonal

antibodies. Prostate 58, 225, 2004 Nanus DM, et al. Clinical use of monoclonal antibody HuJ591 therapy:

targeting prostate specific membrane antigen. J Urol 170, 84, 2004 Milowsky MI, et al. Phase I trial of yttrium-90-labeled anti-prostate-

specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer J Clin Oncol 22, 2522, 2004

Bander NH, et al. Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 23, 4591, 2005

Vaccines

Recently, immunotherapy with tumor vaccines has emerged as an alternative therapeutic approach

However, despite evidence for the induction of tumor-specific T cell responses, significant objective clinical response rates are low

The reasons behind the limited success of these approaches in PC patients are still largely unknown

Investigación etiopatogénica,diagnóstica, terapéutica y

reparativa

SIMILITUDCLÍNICA

DIAGNÓSTICODE

ENFERMEDAD ÚNICA

HETEROGENEIDADEN LOS MECANISMOS

ETIOPATOGÉNICOSCELULARES Y MOLECULARES

EN LAS ENFERMEDADESCONSIDERADAS ÚNICAS

SUPERARLIMITACIONES EN:•LA REALIZACIÓNDE ENSAYOS CLÍNICOS•LA OPTIMIZACIÓN YEL DESARROLLOTERAPÉUTICO Y REPARATIVO

Medicinatraslacional

Medicinaindividualizada

No existen enfermedades sino enfermos

Cervantes, 1605Cervantes, 1605

El mal de quien la causa no se El mal de quien la causa no se sabe, milagro es acertar la medicinasabe, milagro es acertar la medicina

Medicina clínica de calidad fundamentada en hacer investigación biomédica

mutidisciplinaria y traslacional hacia la

enfermedad y el paciente

Joaquín CarballidoHospital Universitario Puerta de Hierro

Belen MartínezJorge Monserrat

AM3 State of the ArtsAM3 State of the Arts

HU

PA

Gracias por su atenciónGracias por su atención

15-11-200715-11-2007

Inmunopatología del cáncer de próstata. Sistema inmunológico/inflamatorio y cáncer de próstata...

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