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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
 Historia
 Edad
 La
de riesgo
familiar
avanzada
dieta, de forma
emergente
ETIOPATOGENIA CÁNCER DE
PRÓSTATA
HUPA
BASE GENÉTICA
INTERACCIÓN
CON EL MEDIO
INTERNO Y EXTERNO
HETEROGENEIDAD PATOGENICA
INDIVIDUAL Y TEMPORAL
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
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
atrófico
y
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
Segmental area of inflammation
(Infl) and another area of
atrophy (Atr)
Epithelial proliferation with
cellular loss of polarity and
cytologic atypia
Inflammation and Atrophy Precede Prostatic Neoplasia
in a 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
(PhIP)-Induced Rat Model
A 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)
Monocitos
proinflamatorios
CD14+low CD16+hi
CD14+hi CD16+hi
CD14+hi CD16+low
CD14+hi CD16-
Monocitos
clásicos
PAF
LTC4
TNF- Macrófago
IL-1
IL-13
Célula Troncal
IL-4
IL-2
IFN-
O2proteasa
PGE2
TH
IgG1
IgE
IL-2
Células Plasmáticas
IFN-
Linfocitos T citotóxicos y NK
IFN-
IL-8, gro
PMN
Respuesta inflamatoria conlleva
activación de las células
sistema inmune y secreción
de citoquinas y factores de
crecimiento
IL-1
TNF
O2proteasa
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
ÁNCER DE PROSTATA. INFLAMACIÓN
CITOQUINAS Y FACTORES DE CRECIMIENTO
MULTIPLES
RELACIONE
S
AUTOCRINA
S
Y
PARACRINA
S
ESTROMA,
EPITELIO
/
LINFOCITOS Y
MONOCITOS
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 of
54 (7%) androgendependent prostate
cancers were
positively stained by antiICD, whereas 12 of 55
(22%)
androgen-independent
prostate cancers were
positively
stained
La doble cara del sistema
inmune y el cáncer
JANO
INDUCE
Y/O
FAVORECE
DEFIENDE
Participación patogénica del sistema
inmunitario/inflamatorio en el cáncer de
próstata

Entorno inflamatorio tisular inductor
de:

Supresión de la respuesta efectora
inmunológica

Apoptosis de las células efectoras

Inmunodeficiencia
Participación patogénica del sistema
inmunitario/inflamatorio en el cáncer de
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)
Participación patogénica del sistema
inmunitario/inflamatorio en el cáncer de
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)
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
Representative sections of prostate tissue, showing benign or malignant
gland from the same prostate
Arrows indicate FOXP3-positive
cells (brown nuclear staining; original magnification, 40)
Miller et al The Journal of Immunology, 2006, 177: 7398 –7405.
Participación patogénica del sistema
inmunitario/inflamatorio en el cáncer de
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)
In prostate cancer IL-10 prevents the CD40-induced CTL and
TNF- and IL-12 production, Th1 skewing, and tumor
regression
The Journal of Immunology, 2006, 177: 6642–6649
Participación patogénica del sistema
inmunitario/inflamatorio en el cáncer de
próstata

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
La doble cara del sistema
inmune y el cáncer
JANO
INDUCE
Y/O
FAVORECE
DEFIENDE
New Paradigm – 2 Hit Model
1
Tumor Necrosis [↓Apoptosis]
↓
Release of Factors [HMGB1, others?]
↓
Tumor Growth
-
2
T/NK
CELL
Perforin
FasL
IFNγ
TNFα TUMOR
-
Immunosuppression
mediated by PDC,
tumor, other cells
DC
DC
HMGB1, HSP,
Uric Acid
HSP, Adenine, ATP
Chronic inflammation
Cáncer de próstata
Causas de la
inflamación crónica
prostática
Possible causes of prostate
inflammation

a | Infection


b | Hormones


Chronic bacterial, viruses, fungi, mycobacteria
and parasites
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-1methyl-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

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?
DEFECTIVE T LYMPHOCYTE ACTIVATION IN
PATIENTS WITH PROSTATE CANCER
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
PHA
PHA+IL-2
PHA+PMA
PHA+anti-CD28
PHA+IL-4
129
195
198
188
207
211
48 ± 36
84 ± 36
198 ± 56
110 ± 57
95 ± 36
211 ± 46
45 ± 24
78 ± 46
113 ± 47
85 ± 53
113 ± 46
132 ± 50
42 ± 27
67 ± 42
124 ± 53
87 ± 40
123 ± 30
139 ± 51
±
±
±
±
±
±
45
64
56
58
54
46
*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
Table 2. Proliferative response in stimulated PBMC from PCaD patients.
Stimuli
Medium
Con A
PHA
anti-CD3
anti-CD2+IL-2
anti-CD2+PMA
anti-CD2+anti-CD28
PMA
CONTROLS
n=30
PCaDnT
n=12
2.9 ± 1.2
129 ± 45
195 ± 64
65 ± 28
52 ± 22
168 ± 80
38 ± 20
26 ± 12
2 ± 1.4
48 ± 36
84 ± 36
42 ± 27
52 ± 22
75 ± 50
31 ± 15
26 ± 12
PCaDT
n=12
2.6 ± 1.4
45 ± 24
78 ± 46
58 ± 27
51 ± 27
85 ± 47
36 ± 9
15 ± 9
PCaDH
n=12
2.1 ± 1.5
42 ± 27
67 ± 42
40 ± 23
62 ± 25
80 ± 42
38 ± 14
15 ± 10
*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.
VIABILIDAD CELULAR TRAS
ESTIMULAR CON anti-CD3 + PMA
CONTROL
CaP
300
CD4
200
CD8
CD4
100
CD8
0
0
CÉLULAS VIVAS X 1000
CÉLULAS VIVAS X 1000
1000
750
500
250
0
24
48
72
24
48
72
96
600
450
CD45RO
300
150
CD45RA
0
0
24
48
72
96
300
96
+
+
+
+
+
+
CD8 CD45RO
200
CD4 CD45RO
CD4+CD45RO+
CD8 CD45RO
+
+
CD4+CD45RA+
CD8 CD45RA
100
0
0
24
48
72
96
DEFECTIVE T LYMPHOCYTE ACTIVATION IN
PATIENTS WITH PROSTATE CANCER
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
anti-CD2+IL-2
anti-CD2+PMA
anti-CD2+anti-CD28
52 ± 22
168 ± 80
38 ± 20
52 ± 22
75 ± 50
31 ± 15
51 ± 27
85 ± 47
36 ± 9
62 ± 25
80 ± 42
38 ± 14
PMA
PMA+IL-2
PMA+anti-CD28
PMA+IL-4
PMA+Iono
26
80
116
58
108
26
80
116
58
108
15
45
52
26
79
15
49
62
31
81
±
±
±
±
±
12
29
51
34
38
±
±
±
±
±
12
29
51
34
38
±
±
±
±
±
9
21
48
13
40
±
±
±
±
±
10
26
55
20
50
*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
Table 4. IL-2 Production after activation.
Stimulus
Medium
anti-CD3
anti-CD3+PMA
PHA
PHA+PMA
PMA
PMA+anti-CD28
PMA+Iono (PI)
PI+anti-CD28
CONTROLS
n=12
30 ± 9.2
296 ± 260
2153 ± 717
1166 ± 678
2920 ± 752
13.4 ± 6.3
1049 ± 10
1452 ± 582
3392 ± 881
PCaD
n=12
PCaD
n=12
PCaD
n=12
7.3 ± 2.7
10 ± 3
19.6 ± 7.5
21.3
867
160
1353
18
645
980
1650
±
±
±
±
±
±
±
±
10
241
110
300
6
85
356
564
25
985
298
1435
16
550
850
2100
±
±
±
±
±
±
±
±
15
285
168
364
6
75
300
650
21.7
1926
787
2238
25
260
2465
1230
±
±
±
±
±
±
±
±
9.2
930
353
643
4.1
53
851
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.
HUPA
LAS ALTERACIONES DEL SISTEMA
INMUNE....COMO FACTOR DE RIESGO
M
U
R
P
H
Y
W
A
S
A
N
O
P
T
I
M
I
S
T
MURPHY´S LAW
FRIENDS COME AND GO
BUT
ENEMIES ACCUMULATE
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?
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 3 106
CD8 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-I
cells 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
Twelve-week-old male
TRAMP or nontransgenic,
WT mice received 3 106
CFSE, CD8, and Thy1.1
TCR-I T cells. Eighteen
hours later, mice received
peptide-pulsed DCs
Vaccine DLN were
harvested 3 days after DC
vaccine
Anderson J Immunology, 2007, 178: 1268–1276.
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%)
Standard Treatments Induce Antigen-Specific
Immune Responses in Prostate Cancer
Clin Cancer Res 13,1493 2007
Standard Treatments Induce Antigen-Specific
Immune Responses in Prostate Cancer
Clin Cancer Res 13,1493 2007
 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
Clin Cancer Res 13,1493 2007
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?
Immunotherapy for prostate cancer

Dendritic cell-based immunotherapeutics





T Lymphocyte-based immunotherapeutics





Antibody-based therapy
Antibody to vascular endothelial growth factor
Antibody to PSMA
Radiolabelled antibody therapy
PSA vaccines


Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy
B Lymphocyte-based immunotherapeutics


GM-CSF-based approaches
Systemic GM-CSF
Cellular delivery of GM-CSF
Antigen-pulsed dendritic cells
Prostate-specific membrane antigen
Glycoprotein vaccines
Immunotherapy for prostate cancer

Dendritic cell-based immunotherapeutics





T Lymphocyte-based immunotherapeutics





Antibody-based therapy
Antibody to vascular endothelial growth factor
Antibody to PSMA
Radiolabelled antibody therapy
PSA vaccines


Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy
B Lymphocyte-based immunotherapeutics


GM-CSF-based approaches
Systemic GM-CSF
Cellular delivery of GM-CSF
Antigen-pulsed dendritic cells
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, placebocontrolled 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 4.5month 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
CD14+ or CD34+ DC precursors in blood
Which subset ?
Dose and frequency ?
Which route of injection ?
Induce
CTL and Th1
Which method of antigen
preparation and delivery ?
Antigen-loaded DC
Which maturation stimulus ?
Combination with other therapies ?
How to determine efficacy ?
Critical parameters for DC-based immunotherapy
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.
Immunotherapy for prostate cancer

Dendritic cell-based immunotherapeutics





T Lymphocyte-based immunotherapeutics





Antibody-based therapy
Antibody to vascular endothelial growth factor
Antibody to PSMA
Radiolabelled antibody therapy
PSA vaccines


Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based
therapy
B Lymphocyte-based immunotherapeutics


GM-CSF-based approaches
Systemic GM-CSF
Cellular delivery of GM-CSF
Antigen-pulsed dendritic cells
Prostate-specific membrane antigen
Glycoprotein vaccines
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
Immunotherapy for prostate cancer

Dendritic cell-based immunotherapeutics





T Lymphocyte-based immunotherapeutics





Antibody-based therapy
Antibody to vascular endothelial growth factor
Antibody to PSMA
Radiolabelled antibody therapy
PSA vaccines


Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy
B Lymphocyte-based immunotherapeutics


GM-CSF-based approaches
Systemic GM-CSF
Cellular delivery of GM-CSF
Antigen-pulsed dendritic cells
Prostate-specific membrane antigen
Glycoprotein vaccines
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-prostatespecific membrane antigen monoclonal antibody J591 for androgenindependent 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
Immunotherapy for prostate cancer

Dendritic cell-based immunotherapeutics





T Lymphocyte-based immunotherapeutics





Antibody-based therapy
Antibody to vascular endothelial growth factor
Antibody to PSMA
Radiolabelled antibody therapy
PSA vaccines


Cytotoxic T lymphocyte antigen-4 (CTLA-4)-based therapy
B Lymphocyte-based immunotherapeutics


GM-CSF-based approaches
Systemic GM-CSF
Cellular delivery of GM-CSF
Antigen-pulsed dendritic cells
Prostate-specific membrane antigen
Glycoprotein vaccines
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
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?
Investigación etiopatogénica,
diagnóstica, terapéutica y reparativa
SIMILITUD
CLÍNICA
DIAGNÓSTICO
DE
ENFERMEDAD
ÚNICA
Medicina
traslacional
SUPERAR
LIMITACIONES EN:
•LA REALIZACIÓN
DE ENSAYOS CLÍNICOS
•LA OPTIMIZACIÓN Y
EL DESARROLLO
TERAPÉUTICO
Y REPARATIVO
HETEROGENEIDAD
EN LOS MECANISMOS
ETIOPATOGÉNICOS
CELULARES Y MOLECULARES
EN LAS ENFERMEDADES
CONSIDERADAS ÚNICAS
No existen enfermedades sino enfermos
Medicina
individualizada
El mal de quien la causa no se
sabe, milagro es acertar la medicina
Cervantes, 1605
Medicina clínica de calidad fundamentada en
hacer investigación biomédica mutidisciplinaria y
traslacional hacia la enfermedad y el paciente
Belen Martínez
Jorge Monserrat
Joaquín Carballido
Hospital Universitario Puerta de Hierro
Gracias por su atención
HUPA
15-11-2007
AM3 State of the Arts