New therapeutic perspectives in prostate cancer
Irena Manea1, B. Djavan2, C. N. Manea1, V.Cristea1, I. Coman1
1 University of Medicine and Pharmacy „Iuliu Haflieganu” Cluj-Napoca, Romania 2 Minimal Invasive and Prostate Center, New York University (NYU), New York, USA
Along with progresses in understanding the complex interactions between tumor cells and the immune response
of the host and the very dynamic development of genetic engineering techniques, the newer and more efficientimmunotherapeutic techniques which generate less secondary effects are gaining more attention whenapproaching neoplasic pathology. PROVENGE (Sipuleucel-T) falls in this category and it is the first therapeutic cancervaccine to demonstrate effectiveness in patients who suffer from advanced to the late stage of the disease,asymptomatic, hormone-refractory prostate cancer.
immunotherapy, hormone-refractory prostate cancer, therapeutic antineoplastic vaccine
Spitalul Clinic Municipal Cluj-Napoca, Clinica de UrologieStr. Tæbæcarilor Nr. 11, 400139 Cluj-Napoca, Judeflul ClujTel./Fax: 0264406718e-mail: email@example.com
nr. 4 / 2011 • vol 10
Revista Românæ de Urologie
decomposition under the action of an enzyme systemand turn into antigenic peptides (epitopes) on thesurface of the cellular membrane. APC are ex vivotaught to direct the immune response toward PAP .
Once they have been auto-transplanted to the
patient, activated APC generate the immune message
Immunology has in time evolved from theoretical
knowledge to the profoundly skeptical and fact-basedscience we know today. Immunotherapy in its manyapproaches is the highest type of the applicability ofimmunology in medicine.
Along with progresses in understanding the com-
designed in the laboratory through their ability to
plex interactions between tumor cells and the immune
present epitopes (peptide sequences generated
response of the host and the very dynamic develop-
during intracellular decomposition of PAP and T lym-
ment of genetic engineering techniques, the newer and
phocytes). The immunologic consequence is that anti-
more efficient immunotherapeutic techniques which
gen specific activation of corresponding T lympho-
generates less secondary effects are gaining more
cytes takes place. This is the most important moment
attention when approaching neoplasic pathology.
of the PROVENGE strategy against prostate cancer: T
Immunotheraputic strategies in prostate cancer
cells identify and destroy prostate tumor cells that
include: cytokine and anticytokine therapy, activated T
express the target molecule (in this case the human
killer lymphocytes, dendritic cells or other antigen
presenting cells, which are ex-vivo exposed to tumor
Two important aspects deserve recognition: ex vivo
antigens or cells. All these above mentioned are ways
activation of APC eludes immunosuppression in a
to stimulate the specific antitumor immunity and they
tumor context, and using autologous cells excludes
proved to induce a favorable clinical and biological
any incompatibility in the HLA system (Human Leuko-
outcome for patients with prostate cancer .
) because the antigen is expressed in the
PROVENGE (Sipuleucel-T) falls in this category and
context of self CMH molecules (Major Histocompati-
it is the first antineoplasic therapeutic vaccine ap-
proved by FDA (Food and Drug Administration) in the
The final product, Sipuleucel-T, contains APCs and
therapy of metastatic hormone refractory prostate
other cellular types involved in immune response such
as T cells, natural killer cells and very small quantities ofintact PAP-GM-CSF. Each dose of PROVENGE brings tothe host’s immune system hundreds of million of acti-
PROVENGE – action mechanism
vated autologous antigen presenting cells [9, 10].
PROVENGE obeys to the principles of active im-
Among the techniques used to evaluate APC
munotherapy and uses autologous immune cells which
activation, there are the phenotyping techniques (the
are trained to specifically activate one of the most
evaluation of surface expressing of certain markers
efficient anti-tumor immune links: T lymphocytes .
such as the class II histocompatibility antigens) and the
The first step of this revolutionary therapy is to
functional techniques (the evaluation of the ability to
perform a leukapheresis that is meant to isolate
take up, process and stimulate T cells) .
peripheral mononuclear cells („peripheral blood
In PROVENGE therapy, the evaluation of APC acti-
mononuclear cells”, PBMC
) . Among these cells, the
vation is evaluated by flow cytometry studies, which
antigen presenting cells (APC – macrophage, dendritic
detect the CD54 differentiation marker (also known as
cells, B lymphocytes) hold a key role in strategy that
ICAM 1 – intracellular adhesion molecule 1
). This mole-
PROVENGE uses to modulate antitumor immune
cule expresses itself significantly on the surface of the
APC after growing in a culture along with the PAP-GM-
Once isolated, APC are activated in vitro by PAP-
CSF fusion protein. Moreover, in vitro studies showed
GM-CSF. This is a recombinant human protein, which
that CD54 positive cellular types are responsible for
consists of prostatic acid phosphatase („prostatic acid
taking up the antigen. In the same time, ICAM-1 plays
), linked to granulocytes-macro-
an important role in activating the specific immune
phage colony-stimulating factor (GM-CSF
). PAP is an
response as it mediates and amplifies the interactions
antigen intensely expressed in prostate tumor cells,
between APC and T cells. This makes the CD54 mo-le-
while GM-CSF is used as immunostimulant .
cule essential for an efficient cooperation of immune
Antigen presenting cells activated by GM-CSF
cells and is also used as a criterion to measure the
exposure take over PAP, which undergo intracellular
10 Revista Românæ de Urologie
nr. 4 / 2011 • vol 10
The impact of PROVENGE therapy over the immune
response is complex and unpredictable. Along the
PROVENGE immunotherapy has up to now been
designed effect (that of destruction of the positive PAP
used for over 1000 patients diagnosed with hormone
cells), it also elicits humoral immune response. Sipule-
refractory metastatic prostate neoplasm.
cucel-T immunomodulation is associated to measura-
The adverse effects of Sipuleucel-T therapy have
ble serologic levels of specific antibodies (M and G
been investigated in the frame of 3 randomized multi-
isotypes), which are directed against the PAP-GM-CSF
center, double-blind, placebo-controlled clinic studies.
fusion protein and the prostatic acid phosphatase.
The patients included in the study have undergone
However the neutralizing humoral response is tran-
three episodes of leukapherese during weeks 0, 2 and
sitory; it has also been demonstrated that a T cell me-
4. Each leukapherese has been continued with PRO-
diated response against the fusion protein develops
VENGE or placebo administration. Inactive autologous
for patients undergoing PROVENGE therapy. The clinic
immune cells were administered to the witness group.
meaning of activating two sides of the specific
For all patients, the curating doctor had total freedom
immune response (both cellular and humoral) remains
in choosing a therapeutic approach imposed by the
a subject of further studies and interpretation .
evolution of the disease. The exception from this rule
Hypothetically, this therapeutic vaccine can gene-
was the immunosuppressive therapy,which goes
rate a continuous antineoplasic immune response.
against the objective of the PROVENGE therapy to
Further study is needed to confirm the activation of
stimulate antitumor immune response .
All these studies showed an increase in life expec-
tation for patients treated with PROVENGE. In the firstphase III trial, the average life expectation of patients
PROVENGE – adverse reactions
treated with Sipuleucel-T was of 25,9 months com-
This new therapeutic approach of the neoplasic
pared to that of 21,4 months of the placebo treated
patient also has its side effects. The majority of adverse
patients. The second trial also found a bigger survival
reactions is immediate and occurs after the first dose.
period for patients undergoing PROVENGE therapy.
They are usually acute infusion reactions, in relation to
The third trial, IMPACT, included over 500 patients and
the dose, but secondary to the cytokine imbalance,
the average survival rate of patients taking Sipuleucel-
and they usually improve by slowing the perfusion
T was 25,8 months compared to that of 21,7 month of
rate. In the majority of cases, the immediate reactions
patient from the witness group. The results presented
consecutive by PROVENGE administration can be
in March 2010 during the Genitourinary Cancer
prevented by acetaminophen or antihistaminic pre-
Symposium of the American Clinic Oncology Associa-
medication. Clinically, the most frequent immediate
tion showed that Sipuleucel-T increased the survival
reactions are nausea, vomiting, increasing fever, chills,
rate to 3 years (approx. 40% more than the survival rate
back pain, headache, fatigue, dyspnea, and broncho-
of he placebo group: 32,1% vs. 23%) .
spasm. The majority of side effects are mild or mode-
PROVENGE is being currently tested for patients
rate in terms of severity. Data from controlled clinical
with non-metastatic prostate adenocarcinoma and the
trials shows that acute reactions (linked to the dose)
show in small percent of PROVENGE treatmentpatients (3,5%) .
Among late events that occur during Sipuleucel-T
immunomodulatory therapy are eosinophilia, rhabdo-
The last decades have generated and increased
myolysis, myasthenia gravis, and myositis. An impor-
interest of immunology researchers which has resulted
tant complication of PROVENGE administration is the
in new ways of manipulating and controlling the
occurrence of cerebral vascular accidents. No fatal
immune system, aiming to suppress inadequate,
exaggerated or altered response (as it is the case of
Another important aspect is that active antioneo-
auto-immune diseases, allergies and transplant rejec-
plasic immunotherapy isn’t free of the dramatic side
tions), to stimulate protective or corrective immune
effect of the conventional therapy (both chemothe-
response in case they are insufficient or depressed (as
rapy and radiotherapy) that the tumoral stage would
it is the case of immunodeficiency of advanced cancer).
After a decade of research and over a thousand
nr. 4 / 2011 • vol 10
Revista Românæ de Urologie
Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survi-val analysis of a phase II randomized controlled trial of a Pox-viral-based PSA-targeted immunotherapy in metastatic cas-tration-resistant prostate cancer.
J Clin Oncol. 2010;28:1099–105.
Attar RM, Takimoto CH, Gottardis MM. Castration-resistant
patients that underwent this revolutionary therapy,
PROVENGE inaugurates a new era in anti-tumortherapy. As of April 2010 it becomes the firstantineoplasic therapeutic vaccine approved by FDA.
Up to now, PROVENGE therapy generated an increasein life expectancy and an improvement in the quality
prostate cancer: locking up the molecular escape routes.
of life for patients with advanced prostate neoplasm.
10. Pal SK, Sartor O. Phase III data for abiraterone in an evolving
landscape for castration-resistant prostate cancer.
11. Vaishampayan UN, Marur S, Heilbrun LK, Cher ML, Dickow B,
1. N. C. Manea, Irena Nedelea, V. Cristea, I. Coman. Molecular
Smith DW, et al. Phase II trial of capecitabine and weekly do-
patterns of metastatic bone disease in prostatic adenocarcino-
cetaxel for metastatic castrate resistant prostate cancer.
Romanian Urology Journal 2009; 3:5-8
2. Small EJ, Fratesi P, Reese DM. et al. Immunotherapy of hor-
12. Sheikh NA, Jones LA. CD54 is a surrogate marker of antigen
mone-refractory prostate cancer with antigen-loaded den-
presenting cell activation.
Cancer Immunol Immunother
J Clin Oncol. 2000 Dec 1;18(23):3894–903.
Higano CS, Schellhammer PF, Small EJ. et al. Integrated data
13. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-con-
from 2 randomized, double-blind, placebo-controlled, Phase 3
trolled phase III trial of immunologic therapy with sipuleucel-T
trials of active cellular immunotherapy with sipuleucel-T in
(APC8015) in patients with metastatic, asymptomatic hormone
advanced prostate cancer.
Cancer. 2009 Aug 15;115(16):
refractory prostate cancer.
J Clin Oncol 2006;24:3089-3094
14. Goldman B, DeFrancesco L. The cancer vaccine roller
Terando A, Roessler B, Mule JJ. Chemokine gene modification
Nat Biotechnol 2009;27:129-139
of human dendritic cell-based tumor vaccines using a recombi-
15. Department of Health and Human Services. Parallel review
nant adenoviral vector.
Cancer Gene Ther. 2004;11:165–73.
of medical products.
Fed Regist 2010;75(180):57045-57045
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immu-
16. Centers for Medicare and Medicaid Services. Proposed deci-
notherapy for castration-resistant prostate cancer.
N Engl J
sion memo for autologous cellular immunotherapy treatment
of metastatic prostate cancer (CAG-00422N).
March 30, 2010.
Di Lorenzo G, Buonerba C, Autorino R, et al. Castration-resis-
17. Sonpavde G, Agarwal N, Choueiri TK, Kantoff PW. Recent
tant prostate cancer current and emerging treatment strate-
advances in immunotherapy for the treatment of prostate
Drake CG. Prostate cancer as a model for tumour immunothe-rapy.
Nat Rev Imm. 2010;10:580–93.
Pe mæsura progreselor în înflelegerea interacfliunilor complexe dintre celulele tumorale øi ræspunsul imun al
gazdei, alæturi de dezvoltarea explozivæ a tehnicilor de inginerie geneticæ, noi modalitæfli imunoterapeutice eficienteøi cu efecte secundare cât mai mici, câøtigæ teren în abordarea patologiei neoplazice. În acest registru se înscriePROVENGE, primul vaccin terapeutic antitumoral, care øi-a dovedit eficienfla la pacienflii cu stadiu tumoral avansat,hormonorezistent.
cancer prostatic hormonorezistent, imunoterapia, vaccin terapeutic antineoplazic
12 Revista Românæ de Urologie
nr. 4 / 2011 • vol 10
MATERIAL SAFETY DATA SHEET CALCIUM HYDROXIDE immediate medical (ophthalmologic) attention. 1 PRODUCT AND COMPANY IDENTIFICATION Speed in treatment can prevent serious eye damage. Clumps of moist material may lodge CALCIUM HYDROXIDE deeply in cul-de-sacs inferiorly and superiorly, and may be difficult to remove by normal irrigation. Ensure adequate flushing by opening eyelids
NCRI Palliative Care Clinical Studies Group 2006-7 The remit of the Group is in line with the existing Clinical Studies Groups and the primary aimis to develop a portfolio of national collaborative studies, which are clinically relevant andlikely to have an impact on day-to-day practice. The full committee is concerned withdeveloping a strategy for the Group and identifying priorities for palli