Immunotherapy of Prostate Cancer - Urosource

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Editorial and Rebuttal from Authors

referring to the article published on pp. 694–708 of this issue

Immunotherapy of Prostate Cancer

Christian Doehn *

Department of Urology, University of Lübeck Medical School, Ratzeburger Allee 160, 23538 Lübeck, Germany

Systemic treatment of advanced prostate cancer

comprises of antihormonal and cytostatic agents.

Unfortunately, a survival benefit from these agents is

either doubtful or small [1]. Therefore, development

of other treatment strategies such as immunotherapy

is mandatory. In 2006, it was demonstrated for

the first time that a tumor vaccine can prolong life

compared to placebo in patients with hormonerefractory

prostate cancer [2]. However, that tumor

vaccine was not approved by the Food and Drug

Administration (FDA) for various reasons.

In the current issue of European Urology a review on

‘‘Advances in Specific Immunotherapy for Prostate

Cancer’’ is presented by Kiessling and colleagues [3].

The authors primarily describe vaccination therapy

and antibody therapy of prostate cancer. The tumorassociated,

yet they are not tumor-specific, antigens

(such as prostate-specific antigen [PSA], prostatic

acid phosphatase [PAP], prostate-specific membrane

antigen [PSMA], and many others) that are used for

immunotherapy (ie, vaccine therapy) are well

described. Having defined the antigens used for

immunotherapy the reactions of the immune system

are crucial to understand the principles of immunotherapy.

In fact, the known mechanisms of an

antigen-specific immune response (either peptides,

proteins, RNA, or DNA) are postulated by most groups

to be the main effector mechanism of a vaccine

approach. This comprises CD8 + cytotoxic T lymphocytes

(CTLs) that destroy tumor cells and CD4 + T

lymphocytes that improve the antigen-presenting

capacity of dendritic cells and support the stimulation

of tumor-reactive CTLs. The role of B lympho-

DOI of original article: 10.1016/j.eururo.2007.11.043

* Tel. +49 451 500 6113; Fax: +49 451 500 4666.

E-mail address: doehn@medinf.mu-luebeck.de.

european urology 53 (2008) 681–685

cytes, natural killer cells, and granulocytes is,

however, less clear. Monoclonal antibodies, on the

other hand, are believed to exhibit their antitumor

effects via antibody-dependent cellular cytotoxicity

and complement activation.

Predominantly phase 1 and phase 2 trials have

been performed in the past. The results show some

activation of the immune system, limited clinical

success, and few side effects. Some reasons for

these results are patient selection, immune escape

and immune monitoring, and problems with surrogate

end points in prostate cancer trials.

There are different disease stages in which

immunotherapy can be applied. This is especially

important in patients with prostate cancer because

the clinical course of these patients, even in those

with PSA relapse following surgery or radiotherapy

with curative intention or those with metastatic

disease, can vary significantly. In patients with

organ-confined prostate cancer the most promising

immunotherapeutic approach would be an adjuvant

therapy following surgery or radiotherapy. Patients

with PSA relapse following surgery or radiotherapy

could also benefit from immunotherapy because

tumor burden is usually low. However, as presented

in the review, most patients who underwent

immunotherapy had metastatic hormone-refractory

prostate cancer. High tumor burden correlates

with immune escape phenomena.

Indeed, tumor cells have developed various

mechanisms to escape from immune responses

[4,5]. These mechanisms include loss of expression

of tumor-associated antigens as well as down-

0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.


682

regulation of major histocompatibility molecules,

especially in tumor cells at metastatic sites. Also,

costimulatory molecules can be down-regulated.

Moreover, tumor cells release immunosuppressive

cytokines such as transforming growth factor b,

interleukin 10, prostaglandins, and others [4,5]. Also,

defects of the T-lymphocyte receptor have also been

described [6]. Thus, function of local immune cells

such as T lymphocytes is impaired. Also, tumor cells

up-regulate antiapoptotic cells or express surface

Fas ligand, which induces apoptosis of attacking

CTLs. Therefore, at least in theory an immune

response toward tumor cells might be achieved by

enhancing expression of the tumor-associated

antigens or by transfection or infection of tumor

cells or immune cells with cytokines that stimulate

the antitumor function of immune cells such as

interleukin 2 or granulocyte-macrophage colonystimulating

factor (GM-CSF) [7].

Today, monitoring of cellular immunity is essential

for the assessment of immunotherapeutic

approaches and should be included in trials.

T-lymphocyte function, serologic and proliferation

assays to assess B-lymphocyte and T-helper lymphocyte

activity, and enzyme-linked immunospot

assay (ELISPOT), tetramer, cytokine flow cytometry,

and reverse transcription polymerase chain reaction

assays of T-lymphocyte immunity are generally

used to demonstrate activation of the immune

system [8]. Immune monitoring is important in

phase 1 and phase 2 trials to support a specific

treatment approach. Incorporating immune monitoring

into larger phase 3 trials could be a logistical

problem. Otherwise, in the majority of trials there is

no or poor correlation between activation of the

immune system and clinical outcome.

How is clinical treatment success defined? In

prostate cancer, PSA (eg decrease/increase and

velocity) is a surrogate end point that shows only

a weak correlation to classical end points such as

time to progression, progression-free survival, and

overall survival. Pain from bone metastases can also

be regarded as a clinical end point, probably more in

therapeutic approaches that are ‘‘bone-specific’’

(eg, radiotherapy, bisphosphonates). However, from

the regulatory viewpoint classic end points such as

overall survival, progression-free survival, and

quality of life remain the most import ones. In

addition, most future markers will be ‘‘molecular

markers’’ from the following pathways: proliferation,

apoptosis, signal transduction, androgen

receptor signaling, cellular adhesion, and angiogenesis.

Today, markers such as p53, Bcl-2, p16 INK4A ,

p27 KIP1 , c-Myc, androgen receptor, E-cadherin, and

vascular endothelial growth factor and others are

european urology 53 (2008) 681–685

already used for prediction of outcome [9]. They

may, however, be also used for the monitoring of

disease progression.

Presently, the most advanced vaccine approaches

are made from whole tumor cells or use dendritic

cells loaded with antigens. For instance, whole

tumor cells are used in the GVAX 1 approach (PC-3

from a prostate cancer bone metastasis and LNCaP

from a prostate cancer lymph node metastasis,

genetically modified to secrete human GM-CSF).

GVAX is presently being studied in phase 3 trials

against docetaxel or in combination with docetaxel

[10]. The results from these trials should be quite

interesting.

Ragde et al reviewed seven vaccine trials using

dendritic cells in 164 patients with advanced prostate

cancer [11]. Antigen sources included peptides,

recombinant protein, and mRNA. The number of

cells injected ranged from 10 5 to 10 10 . Vaccination

was performed intravenously, subcutaneously, intradermally,

and through intralymphatic injections. The

number of vaccinations ranged between 2 and 6. A

total of 45 responders (27.4%) were identified in these

studies. Clinical response ranged from complete

remission to disease stabilization as measured by

PSA decline, reduction in PSA velocity, and changes

monitored by imaging studies such as computed

tomography or bone scans [11].

Provenge 1 is a mixture of cells obtained from the

patient’s peripheral blood by leukapheresis followed

by density centrifugation and exposition. In 2006,

the results of a placebo-controlled phase 3 study

comparing Provenge 1 and placebo were published

[2]. There were 127 men with asymptomatic hormone-refractory

prostate cancer who received

intravenous Provenge 1 or placebo once every 2

wk, for a total of three doses. The primary end point

was time to progression defined as progressive

disease on serial radiographic imaging tests

(increase of at least 50% in measurable disease),

the appearance of at least two new lesions on a bone

scan, and new cancer-related pain events consistent

with progression such as spinal cord compression,

nerve root compression, or pathologic fracture.

Patients were enrolled at 19 US centers between

January 2000 and October 2001. The primary end

point was missed (11.7 vs. 10 wk, hazard ratio, 1.45,

95% confidence interval, 0.99–2.11, p = 0.052). However,

follow-up survival data showed that the

median overall survival was 25.9 mo for patients

in the vaccine group versus 21.4 mo for patients in

the placebo group ( p = 0.02) [2]. The biologic license

application (BLA) was, however, denied by the FDA

earlier in 2007 because the trial had failed to reach

the primary end point, that is, time to tumor


progression. Prior to that decision the 17-member

Oncology Drugs Advisory Committee voted 17 to 0

that the vaccine is safe and 13 to 4 that the vaccine is

effective. With additional data from an ongoing trial

named IMPACT (Immunotherapy for Prostate AdenoCarcinoma

Treatment), it is likely that the

company will resubmit the BLA to the FDA within

the next 2 or 3 yr.

Immunotherapy for prostate cancer shows some

clinical success. It is, moreover, a clear advantage of

vaccine techniques that they are usually associated

with few side effects. Some side effects are even

related to adjuvant therapy or the other partner of a

treatment combination therapy rather than the

vaccine itself. In future trials it will be important

to define the disease status of patients with prostate

cancer as precisely as possible. Also, combinations

of immunotherapy with radiotherapy, chemotherapy,

or hormonal therapy look promising. For

instance, infiltration of the prostate by T lymphocytes

and macrophages is negatively correlated to

cancer recurrence and tumor grade [12]. Interestingly,

antihormonal therapy is followed by an

infiltration of the prostate by activated T lymphocytes.

Thus, it could be beneficial to combine a

vaccine with antihormonal therapy [13]. The combination

of immunotherapy and radiotherapy also

has several potential advantages. Tumor cells

escaping the immune system could be eradicated

by radiotherapy. Radiotherapy also stimulates

expression of major histocompatibility molecules

as well as intercellular adhesion molecule 1 and

others on the tumor cell surface [14]. Radiotherapy

induces necrosis and apoptosis of tumor cells and

may enhance the spectrum of tumor-specific antigens

and tumor-associated antigens (and promote

immune response against them) [14].

Ultimately, better vaccine compositions including

strategies to overcome immune escape, more

effective immune monitoring, and the better clinical

(surrogate) end points are required.

Conflicts of interest

The author has nothing to disclose.

european urology 53 (2008) 681–685 683

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[9] Quinn DI, Henshall SM, Sutherland RL. Molecular markers

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[11] Ragde H, Cavanagh WA, Tjoa BA. Dendritic cell based

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doi:10.1016/j.eururo.2007.12.038

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