Clinical

Cancer
CCR Drug Updates Research

PROVENGE (Sipuleucel-T) in Prostate Cancer: The First FDA-Approved

Therapeutic Cancer Vaccine

Martin A. Cheever and Celestia S. Higano

Abstract
Sipuleucel-T (PROVENGE; Dendreon) is the first therapeutic cancer vaccine to be approved by the U.S.
Food and Drug Administration. In men who have metastatic castration-resistant prostate cancer with no or
minimal symptoms, sipuleucel-T prolongs median survival by 4.1 months compared with results in those
treated with placebo. At 3 years, the proportion of patients in the vaccine group who were alive was 50%
higher than that in the control group (31.7% versus 21.7%, respectively). Sipuleucel-T, which is designed to
elicit an immune response to prostatic acid phosphatase, uses the patient’s own immune system to
recognize and combat his cancer. Currently, no other agents are available that offer a survival benefit for

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this population of asymptomatic patients who have not been treated with chemotherapy, except for
docetaxel (whose inherent toxicities often lead patients and physicians to delay administration until
symptoms develop). Straightforward strategies to increase the efficacy of sipuleucel-T are likely to provide
even greater benefit. The preclinical and clinical development of sipuleucel-T is reviewed, and approaches
to enhance efficacy are considered herein. Clin Cancer Res; 17(11); 3520–6.
2011 AACR.

Introduction immune T cells with the capacity to recognize and kill

PAP-positive prostate cancer cells. Three days after leuka-
In April 2010, the U.S. Food and Drug Administration pheresis and after
40 hours of incubation, the cells are
(FDA) approved PROVENGE (sipuleucel-T; Dendreon), an washed to remove the fusion protein, shipped to the
autologous cellular immunotherapy, for the treatment of patient care site, and infused into the patient as the sipu-
patients with asymptomatic or minimally symptomatic leucel-T product.
metastatic castration-resistant prostate cancer (mCRPC).
Sipuleucel-T is a therapeutic vaccine that is formulated Preclinical Data
to stimulate an immune response to prostate cancer cells
by targeting prostate acid phosphatase (PAP), a tissue The prostate gland varies greatly among species (6) and
antigen expressed by prostate cancer cells (1). The thera- immune systems; thus, the results from animal models
peutic intent is to generate PAP-specific T cells capable of cannot be directly extrapolated to prostate vaccine trial
recognizing and killing prostate cancer cells that express designs in humans. However, previous studies showed that
PAP. After radical prostatectomy, the major remaining immunization of rats with rat prostate tissue antigens could
source of PAP in the body is the cancerous prostate tissue. induce destructive prostatitis (7), and a formulation using
The PAP vaccine immunogen is formulated as PA2024, a rat APCs loaded with rat PAP plus GM-CSF could induce rat
fusion protein that combines recombinant PAP with prostatitis (8) without apparent toxicity to normal non-
recombinant granulocyte-macrophage colony-stimulating prostate tissues. Both of these studies showed that it is
factor (GM-CSF). The PAP-GM-CSF fusion protein is incu- possible to overcome normal immune tolerance and
bated with autologous peripheral blood mononuclear cells induction of autoimmunity to prostate tissue (7, 8).
(PBMC) obtained by leukapheresis. GM-CSF is used to Although the prostate gland in rats was not totally
activate antigen-presenting cells (APC) within the autolo- destroyed by the PAP vaccine, despite induction of auto-
gous PBMC product (2–5). The activated APCs are capable immune prostatitis, vaccine induction of prostatitis in rats
of activating and inducing replication of PAP-specific laid the groundwork for clinical trials of similar vaccines
against prostate cancer.

Clinical Studies
Authors' Affiliations: Clinical Research Division, Fred Hutchinson Cancer
Research Center, and Division of Medical Oncology, University of
Washington, Seattle, Washington Early-phase trials
Corresponding Author: Martin A. Cheever, Seattle Cancer Care Alliance, Sequential phase I and II studies evaluated the safety of
825 Eastlake Ave. E., Seattle, WA 98109. Phone: 206–288-6370; Fax: 206- the PAP vaccine and the ability to circumvent immune
288-6681; E-mail: mcheever@[Link] tolerance to PAP (9, 10). Patients in the phase I trial received
doi: 10.1158/[Link]-10-3126 increasing doses of sipuleucel-T. Those on the phase II

2011 American Association for Cancer Research. protocol received doses totaling their entire leukapheresis

3520 Clin Cancer Res; 17(11) June 1, 2011

 Therapeutic Prostate Cancer Vaccine

product prepared as sipuleucel-T. Fever was the most com- immune response to occur or be operative until the third
mon adverse event (AE) and was experienced by 14.7% of vaccination (i.e., after 4 weeks of therapy). With a median
the patients. All 31 patients tested (100%) showed an time to progression of 10 to 11 weeks, the optimum
immune response to the fusion protein, PA2024, and immune response would have only 6 to 7 weeks to operate
38% showed an immune response to PAP. Time to progres- before the observed progression. The time might be too
sion was correlated with both dose and immune response to short to expect a prolongation in time to progression,
PAP. With tumor response measured as decreased levels of despite the ultimate demonstration of a vaccine-induced
prostate-specific antigen (PSA; 25%) from baseline, tumor prolongation in median survival. In addition, it is difficult
response was seen in only 20% of patients. Of note, the to precisely determine the time to progression in prostate
fusion protein contains a joining region segment that is not cancer. New lesions on bone scans may be interpreted as
expressed by normal PAP or GM-CSF and can therefore be progression even when the disease is responding (i.e., the
recognized as foreign by the patient’s immune system. flare phenomenon), and the combination of rising PSA
Elicitation of an immune response to this foreign joining and supposed bone scan progression could erroneously
region segment is expected and is a sign of immune com- lead to a designation of progression. On the basis of results
petence but is most likely irrelevant to the therapeutic from this and other immunotherapy trials, the Prostate

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outcome. Detection of immunity to PAP is a more impor- Cancer Working Group 2 recently devised progression
tant potential marker of therapeutic immune response. An guidelines to prevent this situation (15).
additional efficacy trial that tested a vaccine containing In the second randomized phase III study, D9902A, time
autologous CD54-positive PA2024-loaded APCs provided to progression was also not statistically different (10.9
similar results (11). CD54, also referred to as intercellular weeks versus 9.9 weeks). The median survival was again
adhesion molecule-1 (ICAM-1), is an activation marker for prolonged in the sipuleucel-T arm compared with the
APCs and other leukocytes (12). control arm (15.7 months versus 9.0 months, respectively)
and survival at 3 years was 50% higher (32.3% versus
Phase III studies 21.2%, respectively). Despite the clear benefit in overall
Two phase III studies (D9901 and D9902A) set the stage survival at 3 years, prolongation of median survival was not
for the Immunotherapy Prostate Adenocarcinoma Treat- statistically significant (P ¼ 0.331; refs. 3, 13, and 14). The
ment (IMPACT) trial, the pivotal study that led to FDA median time to progression occurred on average only
approval (13, 14). Both were randomized, double-blind, 6 weeks after the third vaccination,
1 year before the
placebo-controlled trials of patients with asymptomatic median survival time.
mCRPC. The designated primary endpoint was median The third randomized phase III trial, D9902B (also
time to observed disease progression, and a secondary called the IMPACT trial), led to FDA approval (16). The
endpoint was a planned analysis of overall survival. primary endpoint was overall survival. IMPACT was a
The control was autologous PBMCs obtained by leuka- double-blind, placebo-controlled study involving 512
pheresis, but the PBMCs were cultured without the PAP- asymptomatic or minimally symptomatic patients with
GM-CSF fusion protein (i.e., without either antigen or the mCRPC randomly assigned 2:1 to sipuleucel-T (n ¼
activating effect of GM-CSF). Only one third of the leuka- 341) or control (n ¼ 171). Sipuleucel-T was administered
pheresis sample was processed for each dose of the control every 2 weeks for 3 total doses. Of the 330 patients who
formulation. The remaining PBMCs were cryopreserved received sipuleucel-T, 92% received all 3 infusions, versus
and held in reserve for possible use in a planned salvage 93% in the control arm. A comparison of the treatment and
vaccine study. The control product was denoted as control arms shows that the median overall survival was
APC8015F. 25.8 months versus 21.7 months, respectively (P ¼ 0.032),
For D9901, the median time to disease progression was with a median survival benefit of 4.1 months. The adjusted
11.7 weeks for the sipuleucel-T arm versus 10.0 weeks for hazard ratio (HR) for death was 0.78 [95% confidence
the control arm. The curves separated at 8 weeks and interval (CI), 0.61–0.98]. The Kaplan-Meier estimate for
showed a persistent separation throughout the rest of overall survival for both groups at 36 months was 31.7%
the study. However, the difference favoring sipuleucel-T versus 23.0%, respectively, indicating a 38% increase in
was just short of statistical significance (P ¼ 0.052). The survival at 3 years (ref. 16; Fig. 1).
median overall survival was 112 weeks for sipuleucel-T The Halabi prognostic model can be used to predict
compared with 93 weeks for the control arm. The increase individual survival probabilities of patients with metastatic
in overall survival favoring sipuleucel-T of 4.5 months was hormone-refractory prostate cancer (17). This model is
statistically significant (P ¼ 0.01; refs. 3 and 13). predicated on factors linked to outcome, including lactate
The positive effect on overall survival appeared to be dehydrogenase, PSA, alkaline phosphatase, Gleason sum,
inconsistent with the lack of a detectable effect on median Eastern Cooperative Oncology Group performance status,
time to disease progression, suggesting that median time to hemoglobin, and the presence of visceral disease. The
disease progression might not be appropriate for measur- median overall survival predicted by the Halabi prognostic
ing vaccine effects in patients with very short times to model was 20.3 months for the treatment arm versus 21.2
disease progression. Considering that the regimen involved months for the control arm (3), providing additional
3 vaccinations, one would not expect the optimum support for the efficacy of sipuleucel-T. Among the 3 phase

[Link] Clin Cancer Res; 17(11) June 1, 2011 3521

 Cheever and Higano

gression (defined as PSA reaching 3.0 ng/mL). However,

100% the rate of the PSA increase was slower in patients who
HR = 0.775 (95% CI, 0.614, 0.979) received the vaccine. These results support the assumption
P = 0.032 (Cox model)
80% Median survival benefit = 4.1 months that the vaccine-induced therapeutic response continues to
function after the median time to progression. Changes in
Percent survival

60%
PSA doubling times were not reported in the IMPACT trial.
Sipuleucel-T (n = 341)
Median survival: 25.8 months
36-mo. survival: 31.7%
Open-label vaccine in control patients
40%
When progression was determined by central review, it
was found that these pivotal trials permitted crossover of
20% Control (n = 171) placebo patients. This design may have decreased the
Median survival: 21.7 months
36-mo. survival: 23.0% investigators’ ability to measure the true positive magni-
0% tude of the therapeutic effect of sipuleucel-T. The vaccine
0 12 24 36 48 60 72
Time from randomization (months)
used to treat placebo patients who crossed over to the open-
label vaccine protocol (16) differed in formulation from
No. at risk

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Sipuleucel-T 341 274 129 49 14 1 sipuleucel-T in that the vaccine (APC8015F) was processed
Control 171 123 55 19 4 1
from frozen PBMCs collected during the original leuka-
pheresis. Patients could be treated at the time of initial
progression or any time thereafter, including after che-
Figure 1. Results of the primary efficacy analysis of treatment with motherapy. APC8015F was manufactured according to
sipuleucel-T as compared with placebo (HR for death in the sipuleucel-T the same specifications as sipuleucel-T using the PAP-
group: 0.78; 95% CI, 0.61–0.98; P ¼ 0.03). Figure derived from Kantoff GM-CSF fusion protein. However, fewer total cells were
et al. (16). Copyright
2010 Massachusetts Medical Society. All rights
injected. On the control arm, 109 of 171 patients (64%)
reserved.
received therapy with the salvage vaccine, APC8015F.
Although those treated with APC8015F had an estimated
III studies, the therapeutic outcome was equivalent for
median survival of 23.8 months versus 11.6 months for
overall survival in the intent-to-treat population (ref. 14;
those who did not, it is difficult to draw any conclusions
Table 1). Despite the demonstrated effect on overall survi-
regarding efficacy, because therapy was not randomly
val, however, only one sipuleucel-T–treated patient showed
assigned. The activity of APC8015F has not been prospec-
evidence of a measurable response with partial remission.
tively studied.
As in the previous smaller phase III trials, the median
Approximately 50% of patients in each arm were treated
time to objective disease progression was short (14.6 weeks
with docetaxel following progression (16); therefore, we
versus 14.4 weeks; P ¼ 0.63). PSA reductions of at least 50%
can conclude that the difference in survival seen in the
compared with baseline were confirmed 4 weeks later in
sipuleucel-T arm is not due to an imbalance of patients who
only 8 of 311 sipuleucel-T–treated patients (2.6%) as
received docetaxel.
opposed to 2 of 153 (1.3%) in the placebo group. In
a double-blind, randomized, placebo-controlled study
(P-11), 176 men with a rising PSA after prostatectomy Acute infusion reactions
received hormonal therapy followed by vaccine or control The majority of patients (71%) experienced acute infu-
(18). Sipuleucel-T did not significantly delay cancer pro- sion reactions. Most events were mild or moderate. The

Table 1. Summary of overall survival results for 3 phase III randomized trials

Overall survival Study D99902B Study D9901 Study D9902A

Sipuleucel-T Placebo Sipuleucel-T Placebo Sipuleucel-T Placebo

(n ¼ 341) (n ¼ 171) (n ¼ 82) (n ¼ 45) (n ¼ 65) (n ¼ 33)

Median, months (95% CI) 25.8 21.7 25.9 21.4 19.0 15.7
(22.8, 27.7) (17.7, 23.8) (20.0, 32.4) (12.3, 25.8) (13.6, 31.9) (12.8, 25.4)
Hazard ratio (95% CI) 0.775 (0.614, 0.979) 0.568 (0.388, 0.884) 0.786 (0.484, 1.278)
P 0.032a 0.010b 0.331b

Abbreviation: LDH, lactate dehydrogenase.

a
Test statistic based on the Cox proportional hazards model adjusted for PSA (1n) and LDH (1n) and stratified by bisphosphonate use,
number of bone metastases, and primary Gleason grade.
b
Hazard ratio based on the unadjusted Cox proportional hazards model and P values based on an unprespecified test (log-rank)
From Biologics License Application SNT125197 (3).

3522 Clin Cancer Res; 17(11) June 1, 2011 Clinical Cancer Research
 Therapeutic Prostate Cancer Vaccine

most common events, which occurred in 20% of patients, to 8.600  109 (3). Dendreon has shown that biological
were chills, pyrexia, and fatigue. These events generally activity is present in the CD54 fraction. Thus, upregulation
occurred within 1 day of an infusion and were managed of CD54 on the monocyte-rich population serves as the
on an outpatient basis, and most resolved within 2 days. potency assay for the product’s manufacture (3) and may
Severe (grade 3) acute infusion reactions were reported in correlate with improved survival.
3.5% of patients and included chills, fever, fatigue, asthe- The final sipuleucel-T product is heterogeneous and varies
nia, dyspnea, hypoxia, bronchospasm, dizziness, head- from dose to dose within each patient. Sipuleucel-T was
ache, hypertension, muscle ache, nausea, and vomiting. designed as a vaccine composed of mature APCs loaded with
No grade 4 or 5 acute infusion reactions were reported PAP; however, the product also contains many other cell
(19). Of note, only 3 of 338 patients (0.9%) in the pivotal types, including T cells, B cells, and natural killer cells. The
trial (16) were unable to receive all 3 infusions because of final mixture of cells depends on the composition of the
infusion-related AEs. individual patient’s leukapheresis product and the outcome
of processing, both of which change with each subsequent
Integrated safety analysis leukapheresis. The product derived from the first leukapher-
Aside from presenting an analysis of acute infusion esis is returned for i.v. administration on day 3. To manu-

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reactions, the integrated safety analysis endorsed by the facture the second and third doses of sipuleucel-T, the
FDA and presented in the Biologic License Application (4) patient undergoes leukapheresis again on approximately
and the package insert (19) was summarily unhelpful for days 14 and 28. Although the manufacturing process is
the prescribing physician. The integrated safety analysis identical, the second and third doses are biologically quite
(19) was based on 601 patients who had undergone at least different from the first. Each dose contains progressively
one leukapheresis procedure in 4 randomized controlled more activated APCs as well as more PAP-specific T cells with
trials [D9901, D9902A, D9902B, and P-11 (ref. 3)]. The the capacity to recognize and kill prostate cancer cells (20).
integrated safety analysis showed that AEs occurred during
the entire time of the study. Therefore, a substantial but Mechanism of Therapeutic Efficacy
indeterminate portion of the AEs occurred late after the
vaccine and were equivalent in both the vaccine and con- The designated purpose of sipuleucel-T is to elicit a
trol arms, strongly implying that the AEs described were therapeutic immune response to PAP expressed by cancer
more likely due to the disease than to the vaccine. cells. The first treatment primes the immune system. Sipu-
Cerebrovascular events were observed in 2.4% of the leucel-T activates APCs ex vivo. The activated APCs facilitate
sipuleucel-T–treated patients versus 1.8% of the control both ex vivo priming of T cells during culture and in vivo
patients. Because most of these events occurred >6 months priming after administration. After infusion of the first
after the last infusion, the significance of this finding in dose, there is a detectable increase in APC and T-cell
relation to the vaccine remains unclear. The FDA is requir- activation markers in the PBMCs of treated patients and
ing a postmarketing registry of
1,500 patients to further an increase in the ex vivo production of T-cell activation-
assess cerebrovascular risk. associated cytokines. Studies that examined cytokine secre-
tion from PBMCs during the culture of each leukapheresis
Processing and Character of the Product product showed progressive activation of APCs and T cells.
An analysis of the culture supernatant from PBMC from
Processing of sipuleucel-T involves separating the blood each leukapheresis showed increases in APC activation
mononuclear cells from other blood-borne leukocytes cytokines [interleukin (IL)-1a, MIP1a, MIP1b, and IL-
using proprietary technology and incubation with the 23], T-cell activation-associated cytokines (IL-2, IL-3, IL-
PAP-GM-CSF fusion protein. PBMCs are obtained from 4, IL-5, IL-10, and IL-17), and APC/T-cell activation-asso-
patients via standard leukapheresis and shipped to a Den- ciated cytokines (IL-12p70, IFN-g, and TNFa). Thus,
dreon manufacturing site, where they are then fractionated increasingly activated APCs and T cells are infused into
and incubated with the PAP-GM-CSF fusion protein. the patients (20).
GM-CSF stimulates the growth and activation of APCs, Efforts to detect PAP-specific responses in the patients
including macrophages and dendritic cells (3–5). In turn, and correlate PAP-specific immune responses to outcomes
the APCs activate other cells in the culture, such as T cells. were more problematic. PAP-specific antibody responses
PAP is taken up by activated APCs and processed into a that exceeded the designated low value of 400 at any time
form that is recognizable by T cells (i.e., small peptides after baseline were observed in only 43 of 151 patients
bound to major histocompatibility complex molecules on (28.5%) in the sipuleucel-T arm versus 1 of 70 patients
the cell surface). The activated APCs incubated with PAP are (1.4%) in the placebo arm. At week 6, T-cell proliferation
washed and suspended in Lactated Ringer’s Injection, USP responses (stimulation index >5) to PAP were observed in
(Abbott Laboratories), for infusion back into the patient. only 15 of 55 patients (27.3%) in the sipuleucel-T arm
Specifications for the release of sipuleucel-T for infusion are versus 2 of 25 patients (8.0%) in the placebo group (16).
based on sterility results and cell counts of at least 50 Sipuleucel-T prolonged survival, but without a clear
million CD54þ cells. The median product contains demonstration of detectable PAP-specific immunity in
1.9  109 CD54þ cells, with a range from 0.108  109 the majority of patients. Accordingly, a subset of patients

[Link] Clin Cancer Res; 17(11) June 1, 2011 3523

 Cheever and Higano

without detectable immune responses appeared to benefit vaccine therapy (24). As with sipuleucel-T, there was no
from the vaccine. The apparent benefit of the vaccine in significant prolongation of median survival.
patients without detectable immune responses hindered
the attempt to correlate outcome to PAP immunity. Chemotherapy
A low incidence of detectable antibody response is To date, chemotherapy has shown only modest benefit in
expected from any activated APC vaccine. The activated patients with mCRPC. In 2 phase III studies [TAX 327 and
APCs in sipuleucel-T are known to process and degrade PAP Southwest Oncology Group 9916], docetaxel-based regi-
for presentation to T cells. As a result of the washing mens showed a survival advantage (25, 26). In TAX 327,
process, very little free PAP in protein form (the configu- the pivotal trial for docetaxel approval, the median survival
ration needed to elicit antibody responses) is injected into was 18.9 months in the every-3-weeks docetaxel arm com-
patients. The dearth of detectable T-cell responses to PAP pared with 16.4 months in the mitoxantrone arm, with an
may be explained by the fact that responses were assayed HR of 0.76 or a 2.5-month improvement in median survival
from peripheral blood. Peripheral blood may not ade- (25). The most significant grade 3 and 4 AEs were neutro-
quately represent T-cell responses at sites of tumor deposi- penia (32%), infection (6%), anemia (5%), sensory neuro-
tion. Alternatively, it is possible (although unlikely) that pathy (2%), motor neuropathy (2%), nausea (3%), diarrhea

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substantial numbers of PAP-specific T cells were not acti- (2%), vomiting (2%), dyspnea (3%), fatigue (5%), and
vated in most patients, and thus the demonstrated ther- arthralgia (1%). Patients reported lower-grade but none-
apeutic effect was not related to or dependent on elicitation theless disturbing side effects of fluid retention (24%) with
of PAP-specific immune responses. Additional studies peripheral edema (18%) and weight gain (8%), and sensory
are needed to determine the proximate mechanisms of neuropathy (30%), motor neuropathy (7%), alopecia
efficacy. (65%), nail changes (41%), diarrhea (32%), stomatitis/
One might speculate that mechanisms other than or in pharyngitis (20%), taste disturbance (18%), nausea
addition to the slowing of tumor growth were responsible (17%), and fatigue (53%). In the supporting phase III SWOG
for the improved outcomes. This raises two questions: Why 9916 trial, the median survival advantage was 1.9 months
do patients with prostate cancer die, and what was the (17.5 months for the docetaxel plus estramustine arm versus
proximal cause of death influenced by sipuleucel-T? In 15.6 months for the mitoxantrone plus prednisone arm)
general, patients with cancer die of some combination of with an HR of 0.80 (26). Given these modest survival data
organ failure, infection, and cachexia. In particular, and the toxicity profile of docetaxel, it is clear why both
patients with prostate cancer commonly have dominant patients and physicians are reluctant to use chemotherapy in
pain and cachexia. The proximal cause of death in the men who have no or few symptoms related to mCRPC.
sipuleucel-T trials was not reported. However, in general,
approximately 60% to 70% of patients with advanced Conclusions
prostate cancer have cachexia (21–23). Several cytokines
(e.g., TNFa, IL-1, IL-6, and IL-8) are elevated in patients At the present time, sipuleucel-T is the only therapy that
with prostate cancer and may be involved in cachexia (21). is specifically approved for men with asymptomatic or
The infusion of activated APCs and T cells, as components minimally symptomatic mCRPC. The very acceptable toxi-
of sipuleucel-T, may have substantially perturbed the char- city profile makes sipuleucel-T an attractive option for such
acter and level of these circulating cytokines without patients, particularly in comparison with docetaxel.
noticeably affecting tumor size or growth. Although a significant proportion of patients taking sipu-
leucel-T will undoubtedly receive docetaxel at a later stage
Advantages over Other Vaccines in in the disease, the availability of a therapy that can improve
Development and Chemotherapy survival at an earlier stage is a welcome addition to treat-
ment options for patients with mCRPC. Guidelines from
Vaccines the National Comprehensive Cancer Network now include
Sipuleucel-T is the first FDA-approved vaccine for cancer. sipuleucel-T in the treatment options for men with mCRPC
Thus, there is no approved direct comparator vaccine. with no or minimal symptoms (27).
However, an alternative, well-tolerated, recombinant Pox- One of the current challenges of sipuleucel-T therapy is
virus-based PSA-targeted vaccine (PROSTVAC-VF; Therion determining when in the course of prostate cancer it should
Biologics) currently in development could prove to have be used. The FDA-approved package insert states that
substantial efficacy. An overall survival analysis of a phase sipuleucel-T "is indicated for the treatment of asympto-
II, randomized, controlled trial in patients with mCRPC matic or minimally symptomatic metastatic castrate resis-
showed a 44% reduction in the death rate and an 8.5- tant (hormone refractory) prostate cancer." The label gives
month improvement in median overall survival (24). The little additional guidance for use. Specifically, patients
data strongly suggest a therapeutic benefit but require treated with chemotherapy are not excluded from receiving
confirmation from a phase III study. On the basis of sipuleucel-T, yet many such patients continue on low-dose
preliminary data, the study investigators hypothesize that prednisone as a component of their prior chemotherapy.
patients with more indolent mCRPC (Halabi predicted Because of its potential detrimental effects on the immune
survival 18 months) may best benefit from PSA-specific system, corticosteroid use was excluded in the clinical trials,

3524 Clin Cancer Res; 17(11) June 1, 2011 Clinical Cancer Research
 Therapeutic Prostate Cancer Vaccine

and hence should be stopped before treating a patient with leucel-T given as a single agent to patients with sympto-
sipuleucel-T. In general, sipuleucel-T should be adminis- matic mCRPC.
tered before chemotherapy, except in cases where the Clinical development of sipuleucel-T for FDA approval
disease remains stable after chemotherapy without the began after the first patient was treated in 1997. Thus, the
use of steroids. formulation and regimen have been "locked" and
It is anticipated that abiraterone, an investigational unchanged for 13 years. In this locked regimen, 3 doses
CYP17 inhibitor, will be approved by the FDA in 2011. of sipuleucel-T are administered over a period of
4 weeks.
Abiraterone has been studied in two phase III trials that are Given the comparative efficacy and limited toxicity of this
fully accrued and maturing [one in asymptomatic patients agent, studies to increase the efficacy of sipuleucel-T are
who have not yet received docetaxel (COU-AA-301) and warranted. Simple methods that are likely to increase effi-
the other in patients previously treated with docetaxel cacy include (i) administering sipuleucel-T >3 times to boost
(COU-AA-302)]. The basis for this phase III program and extend the response; (ii) treating patients earlier in their
was the significant activity seen in early-phase trials (28– disease course, thus extending the immune response time
30). Recently presented interim results for COU-AA-302 against a lower number of cancer cells; and (iii) combining
(31) showed that abiraterone plus prednisone was superior sipuleucel-T with agents that are known to activate, accel-

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to placebo plus prednisone in terms of overall survival erate, and augment immune responses. Multiple strategies
(14.8 months versus 10.9 months, HR ¼ 0.65), the primary involving targeted agents might also have substantial effects
endpoint. On the basis of these results, regulatory approval by facilitating T-cell entry into tumors and thus enhancing
is anticipated for abiraterone in patients who have received efficacy. In one study (33), investigators combined the
docetaxel. Given the survival benefit seen in patients who vaccine with bevacizumab in patients after definitive ther-
have received chemotherapy, it is anticipated that COU- apy, but the study was too small and the single-arm design
AA-301 will also be positive, leading the way for approval precluded insights into how the agents combine.
in the asymptomatic CRPC population for which sipuleu- Immunotherapy agents with known immunologic effi-
cel-T is also approved. cacy that could likely increase the efficacy of sipuleucel-T
Assuming that abiraterone will eventually be approved include T-cell growth factor (IL-7) to increase the number
by the FDA for patients with asymptomatic CRPC either and repertoire of naı̈ve T cells, T-cell growth factor (IL-15) to
before or after docetaxel treatment, it is important to increase the growth and survival of immune T cells,
consider the appropriate timing of sipuleucel-T adminis- growth factors (Flt-3Ligand) to increase the number of
tration with respect to abiraterone. Because abiraterone was APCs, agonists to activate dendritic cells and other APCs
studied in combination with low-dose prednisone, (CD40Ligand), adjuvants (IL-12, cytosine phosphorothio-
approval will include concurrent use of prednisone to ate guanine, and monophosphoryl lipid) to augment
prevent the mineralocorticoid effects of hypertension T-cell responses, agonists to activate and stimulate T cells
and hypokalemia seen in some patients on abiraterone (anti-CD137), inhibitors of T-cell checkpoint blockade
alone. Because abiraterone must be administered with (anti-CTLA4 and anti-PD1), and agents to inhibit,
prednisone, it seems logical to assume that sipuleucel-T block, or neutralize cancer cell– and immune cell–derived
should be administered before abiraterone, and that the immunosuppressive cytokines (anti–IL-10, anti-TGF-b, and
administration of any therapy that includes prednisone 1-methytryptophan). These and similar agents in the same
should be delayed for as long as possible due to the categories have been discovered, invented, or constructed,
immunosuppressive effects of corticosteroids. Although and shown to have immunologic function in both animal
some results in the literature suggest that abiraterone can models and human clinical trials (34). In the past, a variety
be given without prednisone (32), its use as a single agent is of regulatory and legal hurdles have made it extremely
not advised until better data are presented and guidelines challenging, if not impossible, to combine investigational
about this practice are developed. immunotherapeutic agents owned by different sponsors.
A confusing issue for patients and clinicians alike is the With the commercial availability of sipuleucel-T and per-
lack of the usual response indicators after administration of haps other promising vaccines in the future, we can proceed
sipuleucel-T. Neither the PSA level nor the time to progres- to test and develop agents designed to activate, augment,
sion was significantly affected by sipuleucel-T. Therefore, and extend immune responses, with the hope of refining
there should be no expectation that PSA will decline or that and improving immunotherapeutic outcomes in patients
imaging studies will improve after treatment. The lack of with prostate cancer and other solid tumor malignancies.
response indicators also means that physicians cannot
Disclosure of Potential Conflicts of Interest
advise an individual patient as to whether he has benefited
from receiving sipuleucel-T; they can only explain that C.S. Higano is an investigator and consultant for Dendreon.
there is a population benefit in terms of overall survival.
This is similar to the logic used in adjuvant therapy of Grant Support
breast or colon cancers. In addition, sipuleucel-T is not National Cancer Institute, U.S. Department of Health and Human Services
indicated for the treatment of patients who have symptoms (grant CA015704).
of metastatic disease. At this writing, there is no evidence of Received November 23, 2010; revised March 10, 2011; accepted March
survival benefit or indication of palliative benefit of sipu- 14, 2011; published OnlineFirst April 6, 2011.

[Link] Clin Cancer Res; 17(11) June 1, 2011 3525

 Cheever and Higano

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