1. health and fitness
2. disease
3. cancer

Sipuleucel-T has a developing role
in prostate cancer therapy.
Nick Patten. 3 Bottles in Light. Oil on panel, 24ʺ × 36ʺ.
Building on Sipuleucel-T for Immunologic Treatment of
Castration-Resistant Prostate Cancer
Neal D. Shore, MD, FACS, Constantine A. Mantz, MD, Daniel E. Dosoretz, MD,
Eduardo Fernandez, MD, PhD, Francisco A. Myslicki, BA, Candice McCoy, MD,
Steven Eric Finkelstein, MD, and Mayer N. Fishman, MD, PhD
Background: Sipuleucel-T is an autologous cellular immunotherapy approved by the US Food and Drug
Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant
prostate cancer. Its mechanism of action is based on stimulation of the patient’s own immune system to target
prostate cancer. Peripheral blood mononuclear cells, including antigen-presenting cells and T cells, are obtained
from patients via leukapheresis and treated ex vivo with PA2024, a fusion protein consisting of prostatic acid
phosphatase/granulocyte-macrophage colony-stimulating factor antigen.
Methods: Data relating to the potential pharmacodynamic biomarkers associated with sipuleucel-T activity
are reviewed, as well as considerations for patient selection and for sequencing sipuleucel-T with other prostate
cancer treatments. Possible directions for future development are also discussed, including treatment of less
advanced prostate cancer populations, combination treatment, and immune modulation.
Results: Data from three randomized, double-blind, placebo-controlled phase III clinical trials of sipuleucel-T
in patients with metastatic castration-rresistant prostate cancer have shown improvement in overall survival vs
control. Here, we review its developing role in prostate cancer therapy and future directions for development.
Conclusions: There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer.
Introduction
Although mortality from prostate cancer is declining
within the United States, the rate remains high, with
an estimated 28,170 deaths occurring in 2012.1 Local-
ized therapies for newly diagnosed prostate cancer
have been successful in curing upward of 75% of
patients, but novel therapies for advanced prostate
cancer are needed to reduce prostate cancer mortality.
From the Carolina Urologic Research Center/Atlantic Urology
Clinics, Myrtle Beach, South Carolina (NDS), 21st Century Oncology Translational Research Consortium, Fort Myers/Cape Coral
(CAM, DED), Plantation, Florida (EF), and Scottsdale, Arizona
(FAM, SEF), Dendreon Corporation, Seattle, Washington (CM),
and the Genitourinary Oncology Program at the H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Florida (MNF).
Submitted June 22, 2012; accepted September 21, 2012.
Address correspondence to either Neal D. Shore, MD, FACS, Carolina Urologic Research Center, 823 82nd Parkway, Myrtle Beach, SC
29572 (e-mail: nshore@gsuro.com) or to Mayer N. Fishman, MD,
PhD, Genitourinary Oncology Program, Moffitt Cancer Center,
12902 Magnolia Drive, WCB-GU PROG,Tampa, FL 33612 (e-mail:
Mayer.Fishman@Moffitt.org).
Dr Shore is a consultant for Dendreon Corp. Dr McCoy is an employee of Dendreon Corp. Dr McCoy is also a stock/shareholder
of Dendreon Corp. Dr Finkelstein is a consultant for Bayer Corp,
Dendreon Corp, Medivation Inc, and Spectrum Inc. No significant
relationship exists between the remaining authors and the companies/organizations whose products or services may be referenced
in this article. None of the authors received financial support or
compensation related to the development of the manuscript.
This article discusses off-label usage of sipuleucel-T combined
with hormonal therapies and other combinations in patients who
have asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. Health professionals should consult the official, complete prescribing information for approved
indications of this drug before making any treatment decisions
regarding its use.
January 2013, Vol. 20, No. 1
Cancer Control 7
Sipuleucel-T was approved by the US Food and
Drug Administration (FDA) in 2010 for asymptomatic
and minimally symptomatic patients with metastatic
castration-resistant prostate cancer (CRPC). Since
then, a number of other treatments have been approved for metastatic CRPC. In 2010 and 2011, both
abiraterone acetate2 and cabazitaxel3 were approved
by the FDA for therapy after prior docetaxel treatment,
and denosumab4 was approved for the prevention of
skeletal-related events in patients with bone metastases. More recently, an overall survival (OS) benefit
was shown with both radium-223 and enzalutamide
in metastatic CRPC,5,6 and the latter was approved
in 2012. Phase III trials of cabozantinib were initiated after phase II results showed evidence of antitumor activity.7 Other promising immunotherapies in
late-phase development for prostate cancer include
prostate-specific antigen (PSA)-TRICOM vaccine (a
poxviral-based vaccine directed against PSA)8 and
ipilimumab (an anticytotoxic T-lymphocyte antigen
[CTLA-4] monoclonal antibody currently approved for
the treatment of metastatic melanoma).9
Among these emerging novel therapies, sipuleucel-T is the only immunotherapy with a demonstrated OS benefit for asymptomatic or minimally
symptomatic metastatic CRPC. Here, we review the
clinical data leading to FDA approval of sipuleucel-T
and the practical aspects of treatment. We also
discuss potential pharmacodynamic biomarkers associated with sipuleucel-T activity, patient selection
and drug-sequencing strategies, and future directions for development.
(as measured by CD54 upregulation) and presentation of antigen in association with the patient’s own
particular HLA class 1 and HLA class 2 cell-surface
proteins. Following incubation, the now-activated
PBMCs are reinfused.15 In vivo, the activated cells
comprising sipuleucel-T are thought to stimulate naive CD4+ and CD8+ T cells, stimulating an immune
response against prostate cancer cells.16
Although sipuleucel-T is often described as a “vaccine,” the integration of ex vivo and in vivo leukocyte
activation contrasts with a classic vaccine. In the latter, an antigen, or an adjuvant/antigen combination, is
administered directly to the patient. Here, the antigen
presentation and expansion of effector cells physically occur entirely within the host. Alternatively,
sipuleucel-T can be characterized as an “autologous
cellular immunotherapy”; however, this description
does not incorporate the significant ex vivo processing of the cells, which provides an environment apart
from the presumably immunosuppressive cytokine17,18
and cellular milieu19-21 existing within a patient with
ongoing disease progression.
Sipuleucel-T is a cellular product with proportions
of immune cells that vary depending on the original
apheresis product.15,22 The number of APCs, defined
as large cells expressing CD54, must be at least 50
million per infusion dose.23 In addition to APCs, B
and T lymphocytes are also present in the product
and are activated ex vivo during the manufacturing
process, which can further activate APCs.24 The relative importance of lymphocytes activated ex vivo vs
those activated in vivo following infusion is unknown.
Sipuleucel-T: Manufacture, Composition, and
Mechanism of Action
Sipuleucel-T is unique among marketed anticancer
products for its administration and composition: It
is an individually tailored treatment manufactured
from immune cells specific to each patient.10 A standard course of sipuleucel-T treatment consists of three
doses. Each dose is manufactured from a standard
leukapheresis procedure conducted approximately 3
days prior to infusion of the sipuleucel-T dose, from
which a patient’s peripheral blood mononuclear cells
(PBMCs) are isolated. Those cells, including antigenpresenting cells (APCs), are then cultured ex vivo with
PA2024, a fusion protein consisting of prostatic acid
phosphatase (PAP, a protein present on the majority of
prostate cancers)11 linked to granulocyte-macrophage
colony-stimulating factor (GM-CSF). PAP is an ideal
antigen for targeting prostate cancer because of its tissue specificity — expression of this protein is primarily restricted to prostate tissue12 — and the rationale
for using PA2024 stems from preclinical data showing
that a similar fusion protein was effective in breaking
immunotolerance to the PAP self-antigen and inducing
prostatitis in rat models.13
During a 36- to 44-hour incubation at 37° C, the
APCs internalize PA2024,14 resulting in their activation
Phase III Trials With Sipuleucel-T:
Efficacy and Safety Data
Three randomized, double-blind, placebo-controlled
phase III clinical trials of sipuleucel-T in patients
with metastatic CRPC have been completed to date.
The first two trials, designated D9901 and D9902A,10
were identical in design. Patients with asymptomatic metastatic CRPC were randomized 2:1 to receive
sipuleucel-T or control infusions at weeks 0, 2, and
4. In all patients, a standard 1.5–2.0 blood volume
leukapheresis was performed approximately 3 days
prior to infusion. For the control group, one-third of
the leukapheresis product was cultured at 2° C to 8° C
without PA2024 and then infused, and the remaining
two-thirds was cryopreserved for potential crossover
treatment following disease progression.10,25 The primary endpoint of both studies was time to disease
progression (TTP), and an analysis of OS after all
subjects were followed for 36 months or until death
was prespecified in both study protocols.10
The first study, D9901, included 127 patients and
showed a statistically nonsignificant trend toward delayed TTP (hazard rate [HR] for disease progression
= 0.69; 95% confidence interval [CI], 0.47–1.01; P
= .05). At 36-month follow-up, however, there was
a statistically significant 4.5-month prolongation in
8 Cancer Control
January 2013, Vol. 20, No. 1
median OS with sipuleucel-T (25.9 vs 21.4 months;
HR for death = 0.59; 95% CI, 0.39–0.88; P = .01).25,26
The second trial, D9902A,10 enrolled 98 patients; the
study was discontinued early based on the primary
analysis of D9901. This trial demonstrated a similar
trend of improved OS with sipuleucel-T, with a median OS of 19.0 vs 15.7 months (HR for death = 0.79;
95% CI, 0.48–1.28; P = .33).10,26
The FDA approval of sipuleucel-T was largely
based on the results from the pivotal phase III IMPACT
trial (D9902B),15 which included men with asymptomatic or minimally symptomatic metastatic CRPC.
Eligibility criteria included demonstrable metastatic
disease on bone scan or CT scan, no visceral metastases, no corticosteroid use, and no pain requiring
opioid analgesia. The primary endpoint was OS, and
the secondary endpoint was time to objective disease
progression. Additional endpoints included immune
responses, PSA changes, and safety. A total of 512 patients were randomized 2:1 to receive sipuleucel-T (n
= 341) or control (n = 171). The primary endpoint was
met, with a 22% reduction in the risk of death with
sipuleucel-T vs control (HR for death = 0.78; 95% CI,
0.61–0.98; P = .03) and a 4.1-month prolongation of
median OS (25.8 vs 21.7 months). At 36 months, the
probability of survival was 31.7% in the sipuleucel-T
group compared with 23.0% in the control group.
Subjects in the control groups of all three trials
were allowed to cross over at disease progression to
receive treatment with a similar autologous product,
APC8015F. This treatment was not randomized and was
given at investigator discretion with patient consent.
The manufacturing process for APC8015F was identical
to that for sipuleucel-T, but APC8015F was produced
using the frozen PBMCs obtained from the original
leukapheresis rather than a fresh leukapheresis.
For the IMPACT trial,15 64% of control subjects (n
= 109) crossed over to receive APC8015F. The median
OS for control subjects who crossed over compared
with those who did not was 23.8 months vs 11.6
months. Of note, subjects who received APC8015F
had more favorable prognostic features than did those
not receiving APC8015F. Subsequent analyses adjusting for prognostic factors around the time of disease
progression still revealed a positive treatment effect
for APC8015F.27 Thus, it is possible that the true
magnitude of OS difference was underestimated in
the primary analysis of the phase III trial results.
The safety evaluation of sipuleucel-T included a
total of 601 and 303 patients treated with sipuleucel-T
and control, respectively, in four randomized phase
III studies; three included patients with metastatic
CRPC (IMPACT, D9901, and D9902A) and one included patients with androgen-dependent prostate
cancer (PROTECT). Adverse events (AEs) reported
in > 15% of patients who received sipuleucel-T were
chills, fatigue, pyrexia, back pain, nausea, arthralgia,
and headache. Those reported by ≥ 5% of subjects
with at least twice the frequency in the sipuleucel-T
January 2013, Vol. 20, No. 1
group compared with the control group were chills,
pyrexia, headache, myalgia, influenza-like illness, and
hyperhidrosis. Most AEs developed ≤ 1 day following
infusion, were mild to moderate (grade 1 to 2), and
resolved quickly (within 2 days).28
The incidence of serious adverse events (SAEs)
was comparable between treatment groups: 24% (144
of 601) of patients who received sipuleucel-T and
25.1% (76 of 303) of control patients. There has been
no evidence of autoimmune complications following
sipuleucel-T treatment. SAEs that occurred within 1
day of infusion were reported in 3.5% (21 of 601) of
patients who received sipuleucel-T and 2.6% (8 of
303) of control subjects. SAEs that occurred within
1 day of infusion reported for 2 or more patients
who received sipuleucel-T were pyrexia, chills, atrial
fibrillation, catheter sepsis, hematuria, hypertension,
hypoxia, infusion-related reaction, and nausea.
The incidence of cerebrovascular events was 3.5%
in the sipuleucel-T group and 2.6% in the control
group. As required by the FDA review team, Dendreon Corp is conducting a phase IV registry design,
prospective study (PROCEED, trial NCT01306890)29
to further assess the risk of cerebrovascular events as
well as the efficacy and treatment patterns of sipuleucel-T in real-world treatment settings. The PROCEED
study is currently enrolling patients.
Potential issues have been raised regarding the
sipuleucel-T phase III trials. In particular, it was hypothesized that the observed difference in OS could
have been due to a harmful effect of the control intervention in the ≥ 65-year-old control patients resulting
from leukapheresis-induced immunodepletion.30 This
hypothesis has been refuted by experts in the field of
cancer immunotherapy31,32 and the IMPACT authors.33
The issue hinges on the assertion that the OS
benefit seen in the IMPACT trial was limited to the ≥
65-year-old patients. This suggestion is based on the
fact that the treatment effect in the IMPACT trial was
consistent across all 64 individual subgroups (derived
from 27 baseline covariates) assessed,33 with the exception of patients younger than age 65. However,
only a small number of control patients (approximately 13%) were < 65 years of age, which increased
the likelihood for error in this analysis.
Further, in any subgroup analysis, the likelihood
of a type-1 error (false-positive result) is considerable, given that one can anticipate approximately
one significant result (P < .05) by chance alone for
every 20 comparisons performed. In fact, independent FDA review concluded that the results were
false-positive, attributed to the multiplicity of comparisons.34 Data consistent with this finding include
a positive treatment effect in both the older than
and younger than age 65 groups in an analysis of
the first two phase III trials (D9901 and D9902A)
and a consistent treatment effect when the IMPACT trial and the prior phase III trials are dichotomized at the median age in IMPACT of 71 years.33
Cancer Control 9
No data are available to support the assertion that
the control intervention may have had a deleterious
effect on patients’ immune systems. The National
Institutes of Health experience with serial leukapheresis procedures in more than 400 healthy subjects
showed that the decreases in lymphocyte counts after
2 to 9 procedures were not clinically significant, with
no increased susceptibility to infectious diseases or
cancer.33 Across the phase III trials, there was no
evidence that leukapheresis led to immunodepletion.
At 6, 14, and 26 weeks, median white blood cell, absolute neutrophil, lymphocyte, and monocyte counts
remained within the normal range in each treatment
group. It is important to note that an increased rate
of infections would be expected if patients in the placebo group had experienced clinically significant immunosuppression. The incidence of infection-related
AEs was similar between the sipuleucel-T and control
groups (27.5% vs 27.7%), and the majority (83.9%) of
those events were grade 1 to 2. Grade 3 to 5 infections were reported in 5.0% of patients who received
sipuleucel-T and in 3.3% of control patients.28
center, where patients receive leukapheresis to obtain
PBMCs. Although apheresis is a routine procedure at
many centers, it must take place at an approved center
as part of the licensed product specifications.23 The
unprocessed cells from the leukapheresis are then
shipped to one of the three manufacturer’s facilities
for product preparation. During the standard processing, the cells are activated through coculturing with
the PA2024 fusion protein.15,22 The activated cells are
then shipped back for infusion, typically at the physician’s own infusion center. This process is repeated
three times for a standard course of treatment (Figure)
and is coordinated, start to finish, by the Dendreon
Corp ON Call Program.35
The leukapheresis procedure is generally well
tolerated, and premedication is not required. Some
side effects that were reported within 1 day of leukapheresis in controlled clinical trials are described in
the prescribing information.23 Both the leukapheresis and subsequent infusion can be safely administered via peripheral venous catheter in most patients. Clinicians should determine whether a central
venous catheter (CVC) is required; however, routine
placement of CVCs should be avoided. CVCs can
be advantageous, as they provide a ready source of
Practical Aspects With Sipuleucel-T
Production of sipuleucel-T begins at the apheresis
Consultation and eligibility* evaluation:
• CRPC
• Metastasis present
• Minimally symptomatic or asymptomatic
Schedule set by
Dendreon ON Call
• Neither cytotoxic chemotherapy nor
glucocorticoids within 28 days
*Eligibility may be payer-dependent
Apheresis à infusion: ~ 60 hours
Infusion à next apheresis: ~ 2 weeks
Apheresis à
à Infusion
Apheresis à
Apheresis à
à Infusion
à Infusion
Further
treatment
planning
Between collection and infusion:
Cyclophosphamide to clear
regulatory T cells
Pretreatment:
Clearance of MDSCs,
such as all trans retinoic acid
Patient selection options:
Hormone-responsive
prostate cancer
Concurrent with
entire treatment:
Sunitinib to decrease
regulatory T cells
Immediately after:
Checkpoint inhibitors
to enhance response
Other active
anticancer
treatments
Figure. — Examples of hypothetical entry points (red) for additional treatments to overlap with a standard sipuleucel-T administration (blue). CRPC =
castration-resistant prostate cancer, MDSCs = myeloid-derived suppressor cells.
10 Cancer Control
January 2013, Vol. 20, No. 1
access and reduce the need for repeated peripheral
venipunctures. However, they are associated with
an increased risk of complications such as infections,
occlusions, and thrombosis.36 Thus, clinicians should
carefully weigh the risks and benefits of CVC use on
a patient-by-patient basis.
Potential Pharmacodynamic Biomarkers
Based on the results of the phase III trials, classic measures of disease progression have not been reliable
markers of sipuleucel-T activity, which is consistent
with findings from studies of other cancer immunotherapies.8,9 This leaves clinicians and patients in need
of other pharmacodynamic biomarkers or “clinical
feedback” to guide subsequent treatment decisions.
A number of potential pharmacodynamic biomarkers have emerged in recent analyses and may prove
useful in this regard.
To begin, there is evidence from other trials that
sipuleucel-T may prolong PSA doubling time,37 suggesting that the treatment may alter the disease trajectory. Therefore, it seems likely that such measures of
disease kinetics may be useful indicators of sipuleucelT responsiveness.
Additionally, studies have shown correlations between OS and key parameters measured during the
manufacturing process. In an integrated analysis of
data from the phase III trials of sipuleucel-T, OS positively correlated (P < .001) with the total nucleated cell
count and CD54 upregulation (a marker of APC activation).24 Furthermore, both B-cell activity (humoral
response as measured as antibody production) and
T-cell activity (measured as titers of cells that produce
interferon-γ if stimulated with cells presenting the test
antigen) were observed with sipuleucel-T treatment
in the IMPACT trial.15 For detectable antibody to
PA2024 with a titer > 400 at any point posttreatment,
the frequency in the treatment group was 66.2% vs
2.9% in the control group and 28.5% vs 1.4% for PAP.
Consonant with this finding was the pattern for Tcell proliferation responses (counting those that were
greater than 5-fold at week 6), with a frequency of
73.0% vs 12.1% for PA2024 and 27.3% vs 8.0% for PAP
in treatment groups vs control groups.15 Most important, positive correlations between OS and humoral
and T-cell responses were observed.24 These data
support the immunologic mechanism of sipuleucel-T
and in the future may provide a potential biomarker
for monitoring response to treatment. Other potential
biomarkers with sipuleucel-T that have been shown to
correlate with OS include eosinophilia38 and increased
serum globulin proteins.39
Patient Selection
A natural starting point for patient selection is the
eligibility criterion for the three phase III trials: asymptomatic or minimally symptomatic men with metastatic CRPC. The strength of the randomized trial is
based in part on enrolling a population large enough
January 2013, Vol. 20, No. 1
for population heterogeneities to be well balanced.
In the IMPACT trial, 63 individual subgroups were
assessed34 (47 of which were reported by Kantoff
et al15). There was remarkable consistency of the
treatment effect shown across these subgroups, with
OS favoring sipuleucel-T in all but the subgroup of
patients younger than age 65. As previously noted,
the results in this latter subgroup were considered
most likely to be false-positive,37 and the discrepancy
between age groups was not seen in analyses from
the other phase III trials or when dichotomized by
the median age of 71 years.
However, as with any new therapy, further investigation as to benefit in specific subpopulations may
be warranted, using the results of the large randomized study as a basis. Thus, whether by conventional
clinical features (such as Gleason score or extent of
cancer-related pain), established histologic features,
novel tests on patients’ tumors (looking for expression of particular proteins), or patients’ blood (eg,
addressing the emerging circulating tumor cell quantitation technology), there appear to be opportunities
to define a population for which sipuleucel-T would
be most beneficial.
Other patient attributes/trial inclusion criteria
could potentially be applied more or less strictly
(Figure). Examples include patients who have experienced significant symptoms of cancer pain but for
whom there is good pain control, perhaps with the
use of irradiation of the symptomatic areas. From
an immunologic basis, irradiating some of the tumor
could favor provision of cancer antigens and immunologic stimulation.
The point in the disease course should be a key
consideration for determining whether sipuleucel-T is
appropriate. The phase III trials were restricted to asymptomatic or minimally symptomatic disease to enroll patients who were not thought to require urgent
treatment with chemotherapy and who would survive
long enough to derive benefit from immunotherapy.
As highlighted previously, there is a discordance between traditional measures of disease progression
(eg, TTP, objective and PSA responses) and OS, and
similar findings have been shown in trials of other
immunotherapies, suggesting that such a discordance
may be characteristic of immunotherapies.8,9
It has been proposed that this discrepancy reflects
the time required to mount an immune response following sipuleucel-T treatment.40,41 Indeed, the OS
curves from the IMPACT trial separated after 6 months,
and a recent post hoc analysis of time to diseaserelated pain showed a similar delay.42 Thus, the asymptomatic patient with newly diagnosed metastatic
disease is clearly an appropriate candidate for sipuleucel-T therapy. Nonetheless, data from the phase III
studies showed that the benefit of sipuleucel-T treatment was consistent for patients with asymptomatic
and minimally symptomatic disease, suggesting that
those with minimally symptomatic disease may also
Cancer Control 11
be candidates for sipuleucel-T. It should be noted,
however, that there are potential costs to deferring
treatment: The disease could progress quickly, resulting in the attenuation of host features necessary for
mediating an immune response due to either side
effects of additional required therapies (eg, chemotherapy) or the disease itself.
Thus, the optimal patient population for sipuleucel-T treatment may be those with a low disease
burden and an immune system uncompromised by
disease and/or prior therapy. Data from recent post
hoc analyses subdividing the IMPACT patient population by baseline PSA level support this approach.
Although the study was not powered to show significance within each quartile (due to small patient
numbers), it was found that patients in the lowest
quartile (ie, those with ≤ 22.1 ng/mL baseline PSA)
had the greatest magnitude difference in median
OS: a 13.0-month improvement with sipuleucel-T
vs control (41.3 months vs 28.3 months; HR = 0.51;
95% CI, 0.31–0.85). By comparison, patients in the
upper quartile (> 134.1 ng/mL baseline PSA) had a
2.8-month improvement in median OS with sipuleucel-T vs control (HR = 0.84; 95% CI, 0.55–1.29).43
In another analysis, product characteristics of sipuleucel-T were compared across studies of patients
with a range of disease states (neoadjuvant, earlier
asymptomatic or minimally symptomatic metastatic
CRPC, and metastatic CRPC).44 The results showed
that although sipuleucel-T could be successfully produced for patients across all disease settings, those
in earlier treatment settings showed more favorable
product parameters, including CD54 upregulation. As
this latter parameter has been shown to positively correlate with OS, these data further suggest that patients
in early disease settings may derive the greatest benefit from treatment. Thus, treatment with sipuleucel-T
as early as possible following detection of metastatic
disease may yield optimal results.
Drug-Sequencing Strategies
Optimal timing of newer treatments for CRPC, such
as sipuleucel-T, may not be obvious. Clinical decisions regarding drug sequencing become increasingly
complex with the expansion of treatment choices for
metastatic CRPC, as new drugs become commercially
available (eg, abiraterone acetate, enzalutamide, and
radium-223). Although trials are underway to evaluate various drug-sequencing approaches with some of
these newer treatments, no data are currently available
to guide such decisions. Therefore, in the practical setting, drug-sequencing decisions are subject to heuristic
factors and are based on the physician’s interpretation
of the disease setting at which the best medical riskto-benefit ratio could be achieved, the potential susceptibility of the tumor to various treatments, and the
commercial cost vs survival impact for each patient.
Within the context of the current metastatic CRPC
treatment paradigm, points at which sipuleucel-T may
12 Cancer Control
be integrated could be defined as follows: directly
after androgen deprivation therapy (ADT) failure, after
failure of secondary hormonal therapy and prior to
docetaxel therapy, or after docetaxel therapy. As previously highlighted, one might argue that sipuleucel-T
should be used earlier in the treatment paradigm and
temporally separated from corticosteroid use, due to
the immunologic mechanism of action.
In the early setting (eg, soon after ADT failure),
patients are not likely to have received immunosuppressive or cytotoxic chemotherapies and are more
likely to have a lower disease burden than patients
in later settings will have. Thus, in comparison to
patients with later-stage disease, early-stage patients
are likely to have a more robust immune system and
slower disease kinetics, affording the best opportunity
for an immune response to develop prior to exposure
to corticosteroids or chemotherapy.
There is a rationale for concurrent use of sipuleucel-T with agents such as bicalutamide, nilutamide,
estrogen, or low-dose ketoconazole without hydrocortisone. To begin, there may be some desire to
induce PSA responses in early settings, which could
be accomplished with hormone therapies. Additionally, there is evidence suggesting that ADT may
have effects on the immune system, which could
enhance the activity of sipuleucel-T and other immunotherapies.45 Of note, however, immunosuppressive
effects have been suggested to be associated with
ketoconazole.46-48
Currently, no clinical trial data are available on
sipuleucel-T following failure of new-generation secondary hormonal therapies, such as abiraterone acetate and enzalutamide. As highlighted previously,
the presumably higher disease burden of such patients suggests that the effect of sipuleucel-T treatment
would be of a lower magnitude in this setting than
in the post-ADT setting. Data from the IMPACT trial
showed a trend toward greater benefit among patients treated prior to secondary hormone therapy (ie,
castration alone) compared with those who received
combined androgen blockade.15 It is possible that
this difference in treatment effect could be accentuated for newer hormonal agents administered for an
extended period. Thus, sipuleucel-T treatment may
not be optimal in this setting. However, sipuleucel-T
may be appropriate for patients following secondary
hormonal therapy if their disease burden is relatively
low and they are not likely to require chemotherapy
for 3 months or more.
Although sipuleucel-T is likely to be most effective
in the predocetaxel setting, data from the phase III clinical trials have shown that patients who have received
prior docetaxel should not be precluded from sipuleucel-T treatment. In the IMPACT trial, 15.5% of patients
received docetaxel prior to sipuleucel-T.15 Data from
a subanalysis of these patients suggested that those
who received prior docetaxel are capable of generating immune responses and may experience a survival
January 2013, Vol. 20, No. 1
benefit.49 Of note, these patients had received docetaxel
at least 3 months prior to study enrollment. Given the
disease kinetics of most patients following docetaxel
treatment, a 3-month wait period for the next therapy
may not be possible, in which case other treatments
should be considered if the patient is not thought to
be an appropriate candidate for sipuleucel-T therapy.
However, several questions remain unanswered
regarding the drug sequencing of sipuleucel-T within
the CRPC treatment paradigm. What is the appropriate
sequencing of sipuleucel-T with emerging therapies
such as radium-223, which have a direct impact on
bone marrow production of leukocytes? How should
it be sequenced with secondary or later-generation
hormone-axis drugs (eg, estrogens, cytochrome inhibitors, abiraterone acetate, and enzalutamide) or with
drugs that are partnered with daily oral corticosteroids
(eg, abiraterone acetate, docetaxel, cabazitaxel, and
others)? Currently, no data are available that directly
answer these questions, yet ongoing studies may address some of them, and guidance can be gleaned
from available data.
Combination therapy with sipuleucel-T and abiraterone acetate plus prednisone is currently being
evaluated in a randomized phase II trial of patients
with asymptomatic or minimally symptomatic metastatic CRPC (NCT01487863). In this trial, concurrent
treatment with sipuleucel-T and abiraterone acetate
plus prednisone will be compared with sequential
treatment of sipuleucel-T followed by abiraterone
acetate plus prednisone. Again, along with the
strong scientific rationale for combining these two
treatments is a consistent observation that suppression of testosterone may yield immunostimulatory
effects.45,50-55
Outside this ongoing phase II study, the concurrent use of corticosteroids with leukapheresis or
sipuleucel-T administration has not been assessed.
Thus, for a patient on corticosteroids, it should be
determined whether it is medically appropriate to
reduce or discontinue the corticosteroid prior to treatment with sipuleucel-T.23 Based on the known immunosuppressive effects of corticosteroids, there was
a required washout period of at least 28 days for all
corticosteroids before treatment with sipuleucel-T on
the IMPACT trial. There are no data on the optimal
timing of subsequent steroid-containing regimens following sipuleucel-T treatment.
In the phase III clinical trials, most subjects subsequently received additional therapies following
confirmed disease progression, which occurred at a
median of approximately 3 to 4 months following
treatment. Treatment was at the physician’s discretion
and included docetaxel and other corticosteroid-containing regimens. Notably, the timing of subsequent
chemotherapy on the IMPACT trial did not appear to
alter the treatment effect of sipuleucel-T.15 Thus, the
initiation of subsequent therapy following sipuleucelT should be based on clinical parameters.
January 2013, Vol. 20, No. 1
Future Directions
Other Prostate Cancer Populations
Could patients in the premetastatic setting respond
differently to sipuleucel-T compared with patients
with metastatic disease? Based on the exploratory
analyses described here, it seems possible that such
patients would derive greater benefit than those
whose disease has already progressed to metastatic
CRPC. As highlighted previously, studies of sipuleucel-T in patients with nonmetastatic prostate cancer
and a rising PSA level (PROTECT [NCT00779402] and
P10-2 [NCT01431391]) and in the neoadjuvant setting
(NeoACT [NCT00715104]) are underway.
Beer et al37 reported results from the randomized
phase III PROTECT trial in which postprostatectomy
patients with hormone-responsive prostate cancer and
a rising PSA level were treated with sipuleucel-T (n =
117) or control treatment (n = 59). The primary trial
endpoint was time until PSA reached at least 3.0 ng/
mL. Although it favored the investigational treatment
arm, the difference was not significant (18.0 vs 15.4
months; P = .737). However, PSA doubling time was
significantly longer in the sipuleucel-T arm (155 vs
105 days; P = .038).45
Additionally, data from a trial of sipuleucel-T in
the neoadjuvant setting demonstrated lymphocyte
infiltration at the site of disease in patients treated
with sipuleucel-T compared with controls, supporting
the immunologic mechanism of action.56 Collectively,
these findings suggest that sipuleucel-T is biologically
active in these early settings. OS results from trials in
earlier disease settings are eagerly awaited.
Combination Therapy and Target Modulation
One potential area for development is in evaluating
whether induction treatment with radiotherapy or
with other cytotoxic and hormonal treatments may enhance the activity of sipuleucel-T. As for most pivotal
trials introducing new treatments, the IMPACT trial of
sipuleucel-T had few preparatory requirements except
the inclusion criterion, specifying no recent corticosteroids or chemotherapy, and a minimum white blood
cell count of ≥ 2,500/μL. This approach allowed for
a definitive evaluation of the sipuleucel-T treatment
effect but did not address whether certain treatments
in combination with sipuleucel-T (either concurrently
or sequentially administered) may have additive or
synergistic effects.
As discussed previously, there is a rationale for
combining sipuleucel-T with hormone suppression
based on the potential immunostimulatory properties of the latter, and current studies are testing
such combinations: one with leuprolide acetate
(NCT01431391) and another with abiraterone acetate (NCT01487863). Besides hormone suppression, the palette of drugs with other mechanisms of
action that mediate tumor regression is considerably
broader in 2012 than when the IMPACT trial and
D9902A and D9901 trials were conceptualized a deCancer Control 13
cade ago. Some of these drugs, such as the antiandrogen enzalutamide or other CYP17 inhibitors, have
mechanisms of action that are still related in some
way to the suppression of androgen receptor activity.
The bone-targeted agent radium-223 chloride should
induce production of radiation-response genes and
tumor-cell apoptosis. Other emerging agents, such
as the vascular endothelial growth factor receptor
2/c-MET tyrosine kinase inhibitor cabozantinib, could
have direct cytotoxic effects, theoretically causing the
release of additional tumor antigen and favoring a
more robust immune response.
External-beam radiation therapy may cause the
microenvironment to be more conducive to inflammation and an anticancer response,57 with a potential
for influencing the systemic response to sipuleucel-T.
Hypofractionated radiation therapy may cause intratumoral changes that are different from those caused by
conventional fractionation, with more necrotic components and enrichment with available antigenic material. As more experience is gained with these types
of radiation therapy as well as new drugs for treating
CRPC, it may be feasible, empirically and directly, to
address testing of sipuleucel-T in strategic concurrent or sequential trial designs beyond conventional
hormone suppression.
Modulation of the Immune Environment
As noted previously, although the antigen-presentation step in the manufacture of sipuleucel-T is distinctly ex vivo, the ultimate immune response occurs
in vivo, in the patient’s own tumor-influenced immune
context. Thus, the growing awareness of the direct
impact of the tumor cell burden on immune function (eg, through release of inflammatory cytokines,
abundance of regulatory T cells, burden of senescent
T cells, phenotypic dendritic cell modulation favoring
tolerance) defines a variety of possible directions for
improving the sipuleucel-T treatment effect.
Several pharmaceutical approaches, including
some marketed products, can influence the immune
microenvironment and may offer opportunities for
rational combinations with sipuleucel-T. Selected
examples of such agents include those that may decrease the burden of immunosuppressive regulatory
T cells (eg, cyclophosphamide58 and sunitinib59) and
those that promote breakage of immune tolerance by
either modulating the dendritic cell phenotype60 (eg,
all-trans-retinoic acid,61 triterpenoids,62 and Toll-like
receptor ligands63) or blocking immune checkpoints
affecting T-cell deactivation (eg, ipilimumab or antiPD-1 [BMS 965538/MDX1106]64).
Other Antigen Targets
Theoretically, the manufacturer’s active cellular immunotherapy platform is broadly applicable to any tumor
antigen for prostate cancer as well as other tumor
types. DN24-02 is designed to stimulate an immune
response against HER2/neu. This product is manufac14 Cancer Control
tured through a process similar to that of sipuleucel-T
but uses the BA7072 fusion protein, which consists of
HER2/neu linked to GM-CSF. In two phase I studies, a
product similar to DN24-02 showed a good AE profile,
cellular immune responses to BA7072, and evidence
of antitumor activity.65,66 A randomized phase II trial
of adjuvant DN24-02 in HER2/neu-positive urothelial
cancer is ongoing (NCT01353222). Other antigen–
GM-CSF fusion proteins are in development, including
an agent involving carbonic anhydrase 9 for application in kidney cancer.67,68
Conclusions
The landscape of treatment for castration-resistant
prostate cancer (CRPC) integrating hormonal therapy,
chemotherapy, targeted agents, radiopharmaceuticals,
and other immune strategies will continue to evolve
and so may the application of sipuleucel-T. With the
April 2010 approval by the US Food and Drug Administration of sipuleucel-T as a novel treatment of
asymptomatic and minimally symptomatic metastatic
CRPC, immunotherapy has emerged as a standard of
care option with a survival impact. Data from the
phase III randomized IMPACT trial15 spanning a decade showed improved median overall survival (25.8
vs 21.7 months) and hazard ratio for death (0.78).
Although classic measures of disease progression
such as objective response and progression-free survival are not reliable markers of sipuleucel-T activity,
other pharmacodynamic indicators may prove to be
useful in providing treating clinicians with immediate feedback from the treatment. Thus, for patients
with asymptomatic or minimally symptomatic metastatic CRPC, with disease features closely paralleling
those required for participation on the pivotal trial,
sipuleucel-T may be an option.
Many questions remain regarding where sipuleucel-T best fits in the treatment paradigm and how
it should be sequenced with other therapies. Current data seem to indicate that sipuleucel-T may yield
greatest benefit in patients with CRPC who are early in
their disease course. Thus, it could be reasoned that
sipuleucel-T should be administered to patients soon
after androgen deprivation therapy failure. However, other disease management options, including the
newest hormone-related drugs such as abiraterone
and enzalutamide, will be available for physicians
to consider either prior to or following sipuleucel-T
administration. The complexity of treatment decisions will not be directly solved. We hope that the
emergence of sipuleucel-T for prostate cancer will be
a starting point for effective application of other immune treatments building on more antigens as well as
for strategic coordination with nominally nonimmunemediated treatments.69
Johnathan C. Maher, PhD, of Dendreon Corporation contributed to the writing and editing of the submitted work.
The authors were fully responsible for all content and editoJanuary 2013, Vol. 20, No. 1
rial decisions; contributed to the conception and design of
the manuscript, data analysis and interpretation, writing
and editing of the manuscript; and approved the final version for submission.
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