Any thoughts on this critical review. One thing that strikes me as odd, is how there is no information regarding efficacy since 2012. That's 10 years. If something works well, then why isn't there new data showing that? Some people say, it can't hurt, so just do it. That makes sense if it is true but this review below says that it could shorten lifespan in many, who have weak immune systems. Explains why 90 year olds getting vaccines, frequently don't benefit. I'd like to know that provenge will help with OS but it's odd that there is no conclusive data, if you believe what this review says below. Maybe it's better to just start Nubeqa and skip the provenge?
Any opinions or hard data/facts are welcome.
George
DOI: 10.1093/jnci/djr514 © The Author(s) 2012. Published by Oxford University Press.
Advance Access publication on January 9, 2012. This is an Open Access article distributed under the terms of the Creative Commons Attribution
Non-Commercial License (creativecommons.org/license..., which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sipuleucel-T, an autologous cellular immunotherapy, was approved
in April 2010 by the US Food and Drug Administration (FDA) for
the treatment of patients with castration-resistant prostate cancer.
In July 2010, Kantoff et al. (1) reported the results of the phase III
trial (IMPACT), which was central to the FDA’s approval, and also
underpins the pending application for approval with the European
Medicines Agency. Both the accompanying editorial (2) and the
FDA reviewers noted the lack of supportive evidence for the mechanism proposed by sipuleucel-T’s manufacturer (Figure 1 and
Table 1). The absence of such supportive data has raised the concern that the 4.1-month survival benefit could be the result of a flaw
in the trial design or from the chance imbalance of unmeasured
prognostic variables.
We have reconsidered these trial results in light of unpublished
data obtained from internal FDA documents that became available
only after the approval of sipuleucel-T. We believe that analysis of
the data in their totality challenges the published interpretation of
the trial results and suggests a different conclusion about the efficacy, and potentially safety, of sipuleucel-T. Because these data
have not been debated publicly, we hope that this commentary will
stimulate consideration of their implications.
New Observations From Previously
Unpublished Data
Observation 1: Two Unexpected Interactions Between
Patient Age and Survival
The most striking observation from the new data was an unexpected
11-month difference in median survival between placebo patients
younger than age 65 years and patients older than age 65 years
(28.2 vs 17.2 months, respectively) (Table 2). Age is not normally
prognostic for survival in castration-resistant prostate cancer patients
receiving chemotherapy (7–9), as illustrated by the 17.6-month
median survival for the 504 patients younger than 68 years vs the
18.1-month survival for the 502 patients aged 69 years or older in
the pivotal TAX 327 trial (10). Although post hoc subgroup analyses
should be interpreted with caution, it is still noteworthy that the
age dependence of overall survival (OS) in the placebo arm
(two-sided P < .001) is stronger than the treatment effect itself
(Table 2).
Also, it could be observed for the first time in the unpublished
data from the FDA that among the IMPACT patients younger than
65 years, sipuleucel-T treatment appeared to have no effect on
survival (hazard ratio of death = 1.41, 95% confidence interval = 0.87
to 2.29), in contrast with patients 65 years or older (hazard ratio of
death = 0.58, 95% confidence interval = 0.43 to 0.76) (11). This
observation suggests that the overall results were driven entirely by
the differential survival in older patients. This is counterintuitive
given that standard vaccination strategies (12,13), and immunotherapies in particular (14,15), are consistently less effective in the elderly
and therefore raises further questions concerning the immune
enhancement mechanism proposed for sipuleucel-T. In addition, it
appears remarkable that the younger patients for whom the intervention did not appear to be effective lived longer (median = 29.0
months) than the older patients for whom the intervention did
appear to be effective (median = 23.4 months).
These observations from the unpublished data from the
sipuleucel-T studies generated the hypothesis that the placebo
intervention might have had a clinically significant age-related
impact on OS and should be further investigated to assess whether
COMMENTARY
Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in
Castration-Resistant Prostate Cancer
Marie L. Huber, Laura Haynes, Chris Parker, Peter Iversen
Manuscript received July 11, 2011; revised November 7, 2011; accepted November 16, 2011.
Correspondence to: Marie L. Huber, MPhil, PO Box 925, New York, NY 10009 (e-mail: marie.huber@cantab.net).
Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic
acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated
by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor
responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the
placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer
patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T
arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival “benefit.” Patient safety depends on adequately addressing this alternative explanation for the trial results.
J Natl Cancer Inst 2012;104:273–279
274 Commentary | JNCI Vol. 104, Issue 4 | February 22, 2012
it might have unintentionally introduced this active non-placebo
effect. In the sipuleucel-T arm, the 5.6-month longer survival of
the younger group, although less statistically significant, is also
unexpected and should be tested against alternative interpretations
of the trial results.
Observation 2: Older Patients in the Placebo Group
Appear to Have Shorter OS Than Might Be Expected From
Other Studies
To test the hypothesis that the placebo intervention had an agedependent effect on OS, we sought placebo groups from other
trials with which their survival might be compared. In the original
publication of the IMPACT trial results, Kantoff et al. (1) state,
“The 21.7-month median survival of patients in the placebo group
compares favorably with that in control groups in other randomized trials involving similar patient populations (range, 15.5 to
21.7 months) (9,16–21), indicating that the treatment effect cannot
be attributed to a poor outcome in the placebo group.” However,
the control groups in the seven cited trials were not appropriate
comparators for the IMPACT placebo group (Table 3). The initial
IMPACT enrollment criteria selected asymptomatic patients with
an Eastern Cooperative Oncology Group performance status of
0 or 1, Gleason score of 7 or lower, and no visceral metastases.
Each of these restrictions is associated with improved OS in multivariable predictive models developed by both Halabi et al. (7) and
Armstrong et al. (8). After 40% of patients had already been
enrolled, the Gleason restriction was removed and minimally
symptomatic patients were accepted. The placebo groups cited by
Kantoff et al. (1) did not share these restrictions and might therefore have been anticipated to have a shorter survival than that of
the IMPACT placebo group. An illustration of how the multiple
enrollment restrictions in IMPACT selected for a favorable prognosis is seen in the 21.2-month Halabi-predicted survival of its
placebo group vs 16 months for the placebo group in the cited
Figure 1. The manufacturing process and proposed mechanism for
sipuleucel-T (3). A) The manufacturing process for sipuleucel-T is
depicted. Mononuclear cells are harvested from the patient and shipped
to the manufacturing facility (approximately 46% T cells, 7% B cells, 13%
natural killer cells, and 25% monocytes) (4) on day 1. On days 2–3, cells
are put through two buoyant density centrifugation steps before incubation for 36–48 hours with a chimeric antigen (PA2024), consisting of
granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate
antigen presentation, which is linked to the prostatic acid phosphatase
(PAP) tumor-associated antigen. Cells are given a final wash on days 3–4
before shipment back to the clinic for reinfusion into the patient. This
process is repeated every 2 weeks for a complete course of three cycles.
B) The proposed mechanism for sipuleucel-T antitumor activity is given.
The manufacturer proposes that during incubation on days 2–3, antigenpresenting cells (APCs) process and present the synthetic antigen
PA2024 on their surface, thereby becoming activated. Upon reinfusion,
these cells are hypothesized to activate endogenous T-cells, thereby
stimulating them to attack PAP-bearing prostate cancer cells.
jnci.oxfordjournals.org JNCI | Commentary 275
Table 1. Areas of concern regarding support for observed survival benefit of sipuleucel-T for castration-resistant prostate cancer*
Concern Public expressions of concern Source
Improvement in overall survival came without
evidence of a measurable antitumor effect
“Study group assignment had no significant effect on the time to tumor
progression.”
(2)
“1 of 341 patients in the sipuleucel-T group had a partial tumor response, and
3% had a reduction of at least 50% in PSA . . .Thus, the improvement in
survival came without evidence of a measurable antitumor effect.”
(2)
“It is hard to understand how the natural history of a cancer can be affected without
some apparent measurable change in the tumor, either evidence of tumor
shrinkage or at least disease stabilization reflected in a delay in tumor progression.”
(2)
Observations predicted by the proposed
mechanism of sipuleucel-T have not been
made. The absence of alternative
mechanisms leaves the 4.1-month survival
benefit without mechanistic underpinning
“It is not clear that Dendreon has put a high priority on measuring the immune
response in patients in their trials. Considering that there appears to be very
little tumor- and antigen-specific immune response in the vaccinated patient,
one would think that this would be a high priority.”
(5)
T-cell proliferative responses to the chimeric
antigen (PA2024) did not translate to
responses to physiologic, human PAP
“The fact that they are able to get a response to PA2024 but consistently
not to PAP tumor antigen is troubling.”
“It was asked if they had any evidence of a specific response to human PAP.
They stated that, no, they do not yet have any evidence.”
(5)
T-cell proliferative response to the
chimeric antigen (PA2024) or human PAP
did not correlate with improved survival
“No survival difference could be detected between patients in the
sipuleucel-T group who had T-cell proliferation responses to PA2024 or
prostatic acid phosphatase at week 6 and those who did not.”
(1)
* PAP = prostatic acid phosphatase; PSA = prostate-specific antigen.
Table 2. Subgroup analysis by age of overall survival of patients
in the phase III trials of sipuleucel-T for castration-resistant
prostate cancer (6)*
Patient
age, y
Sipuleucel-T Placebo
No. of
patients
Median survival
(95% CI), mo
No. of
patients
Median survival
(95% CI), mo
<65 106 29.0 (22.8 to 34.2) 66 28.2 (23.4 to 32.5)
≥65 382 23.4 (22.0 to 27.1) 183 17.3 (13.5 to 21.4)
* CI = confidence interval.
GVAX trial (18). In fact, this predicted 5.2-month survival advantage was not realized because the placebo groups from both of these
two trials lived for a median of 21.7 months.
To find a placebo group with similar baseline characteristics to
those of the IMPACT placebo group, we searched both published
literature and abstracts. We did not find any other castration-resistant
prostate cancer trials with similarly restrictive enrollment criteria.
However, we identified two subanalyses of larger trials that might
provide more appropriate populations to which the IMPACT
placebo group may be compared. 1) In the aforementioned GVAX
trial, Higano et al. (18) reported a subanalysis of the 264 men with
the best baseline prognosis. For men with a Halabi-predicted survival greater than 18 months at enrollment, median survival was
29.7 months on GVAX and 27.1 months in the placebo group.
Because approximately 86% of patients in the IMPACT placebo
group had an Halabi-predicted survival greater than 16 months
(23), the 28.2-month median survival of pooled placebo patients
younger than 65 is in the range that might be anticipated for the
entire IMPACT placebo group. 2) Berthold et al. (24) conducted a
retrospective sub-analysis of the 110 minimally symptomatic patients
from the TAX 327 study; a group similar to, though still not as highly
selected for good prognosis, the IMPACT population. Men with
minimal symptoms had prolonged survival (median = 25.6 months)
compared with symptomatic patients (median = 17.1 months, P = .009).
Furthermore, the median survival for minimally symptomatic
patients in the group given docetaxel every 3 weeks (the chemotherapy regimen received by most of the IMPACT placebo
patients) was 28.4 months. This comparison too suggests that the
28.2-month median survival of the patients younger than 65 years
in the sipuleucel-T trials is in the range of what should have been
expected for all patients, regardless of age.
These comparisons with OS in other CPRC trials support
the hypothesis that the “placebo” intervention might have had a
clinically significant adverse impact on OS in older patients. This
observation too calls for scrutiny of the placebo intervention, to
assess whether it might unintentionally have introduced this effect.
Observation 3: Potential Harm From the IMPACT Study
Interventions
To better understand the potential for harm from the study interventions, we sought data regarding the cellular manipulation in
IMPACT. Kantoff et al. (1) reported no specific cell-level data,
which might be appropriate for a trial investigating the collection
and manipulation of immune cells. Comparison of the cell counts
performed on 526 lots of patient cells received from apheresis centers during an earlier phase III study (9901) (4,25) to the baseline
circulating white blood cell measurements (11) shows that the “standard leukapheresis processing 1.5–2.0 times the patient’s estimated
blood volume” removed more than 90% (median) of the patients’
circulating mononuclear cells. Cells in each lot were counted twice
between steps in the manufacture of sipuleucel-T and underwent a
final count before shipment for reinfusion into patients. Such data
extracted from highly redacted FDA documents revealed that more
276 Commentary | JNCI Vol. 104, Issue 4 | February 22, 2012
Table 3. Comparison of the IMPACT placebo group with placebo groups cited by Kantoff et al. (1)*
Study
No of
patients
Median
OS for
placebo, mo
Reasons why cited placebo group would be
expected to have shorter OS compared with
the IMPACT placebo group Study funding source(s)
Zoledronic acid (16) 208 15.5 The study did not restrict enrollment to minimal or absent
symptomatology. Among patients, 73% had baseline
pain vs 47% in IMPACT. The study conducted before
TAX 327 demonstrated a 2.9-month survival benefit
for docetaxel, leading to its approval by the FDA
in the year 2004
Novartis Pharmaceuticals
Corporation (now Novartis
International AG)
Docetaxel
(TAX 327) (10,17)
335 19.2 The study did not restrict enrollment to minimal or absent
symptomatology, and 45% of patients had clinically
significant baseline pain vs 0% in IMPACT. Baseline
visceral metastases was present in 22% of patients
vs 0% in IMPACT. Clinically significantly worse
baseline performance status and Gleason scores
than IMPACT patients
Aventis (now Sanofi S.A.)
Atrasentan (19) 401 20.3 The study excluded patients requiring opiate analgesia but,
unlike IMPACT, did not enroll 40% of patients under
explicit exclusion of all pain and with favorable Gleason
scores. No eligibility restrictions on patients with visceral
metastases were given. Enrolled from June 2001 to
September 2002, before TAX 327 demonstrated a
2.9-month survival benefit for docetaxel, leading to
its approval by the FDA. The study was conducted
at 180 sites in 21 countries, with variable local
supportive care practices, which could induce bias
in either direction
Abbott Laboratories
ZD4054 phase II (20) 107 17.3 The study excluded patients requiring opiate analgesia,
but unlike IMPACT, did not impose eligibility restrictions
on ECOG status, visceral metastases, pain, and Gleason
score. The study was conducted at 65 centers (of which
only 12 were in North America) across four continents
where placebo patients were given “best supportive
care according to local practice,” which could induce
bias in either direction
Astrazeneca PLC
Mitoxantrone (21) Kantoff et al. (1) chose the arm receiving the low-dose
prednisone (median OS = 19 months) for comparison,
yet the mitoxantrone plus low-dose prednisone
(median OS = 23 months) would represent a more
appropriate comparator for the IMPACT placebo
group in which 50.3% of patients received docetaxel
and 8% received other chemotherapy. The IMPACT
placebo group excluded patients with visceral
metastases [6% of mitoxantrone group in the study
by Berry et al. (21)] and enrolled 75.4% of patients
with favorable Gleason scores. Patients were enrolled
from March 1997 to Jan 1999, and the results were
reported in the year 2001, before docetaxel was granted
FDA approval
Immunex Corporation
Mitoxantrone plus (now Amgen Inc)
prednisone arm
56 23
Prednisone
alone arm
63 19
PROSTVAC
phase II (9)
40 16.6 Post-treatment chemotherapy usage was neither prescribed
nor monitored. Results reported for the 40 placebo
patients are problematic for the many reasons
outlined by Small and Fong (22)
BN Immunotherapeutics
(now Bavarian Nordic)
GVAX (18) ~310† 21.7 Exclusion of opiate pain medication was the only enrollment
criterion used to select for a favorable prognosis
Cell Genesys (now BioSante
Pharmaceuticals Inc)
* FDA = US Food and Drug Administration; OS = overall survival.
† There is an approximate number of participants given for this trial because full results have not been published. The study completed accrual of 626 patients in
the year 2007, randomized 1:1 between study arms, and all patients completed the initial 6-month treatment period.
than 65% (median) of the cells harvested from patients were lost at
the manufacturing facility during the two centrifugation steps
performed on incoming cell lots and during the final cell wash (4).
A more complete description of the sipuleucel-T intervention
would therefore include the extraction of more than 90% of circulating mononuclear cells followed by the return of less than 35%
of these cells 2 days later after incubation with chimeric antigen.
This intervention is repeated three times at 2-week intervals.
Of particular note, the interventions administered to the placebo
group differed from those in the sipuleucel-T group in three
jnci.oxfordjournals.org JNCI | Commentary 277
Box 1. Select aged-related impairments of the immune
system
Decreased thymic production of naive T cells (27,28)
Collapse in diversity of both naïve and memory T cell subcompartments (13,29,30)
Decreased T-cell responsiveness resulting from both decreased
expression of CD28 and proliferative exhaustion (14,31,32)
Increased numbers of circulating natural killer cells with
reduced responsiveness and cytotoxicity per cell (33)
Impaired differentiation of CD34-positive cells into mature
dendritic cells (34)
Decreased frequency of myeloid peripheral blood dendritic
cells (35)
Disruptions in T-cell/B-cell interactions (36)
Alterations in immune cell trafficking as a consequence of widespread changes in cytokine and chemokine signaling (37–39)
important respects. 1) After the two centrifugations that begin the
manufacturing process, two-thirds of the cells in each placebo lot were
removed and frozen for possible later use, leaving only one-third of
the cells for further processing and reinfusion into placebo patients.
Thus, given the greater than 65% (median) of cells lost in processing
and the further two-thirds removed for freezing, less than 12% of
the original pheresed cell load was left for reinfusion into the placebo
patients. 2) Also, cells processed into sipuleucel-T were incubated
with the granulocyte-macrophage colony-stimulating factor/prostatic
acid phosphatase (GM-CSF/PAP) chimeric protein, whereas cells
processed into placebo were stored in medium containing no
GM-CSF. GM-CSF is a cytokine that functions as a white blood cell
growth factor, and furthermore, may have antitumor activity as a
single agent in prostate cancer (26). 3) Whereas cells being processed
into sipuleucel-T were incubated at 37°C for 36–44 hours, placebo
cells were stored at 2°C–8°C. In our experience, storage of isolated
mononuclear cells at 2°C–8°C for 36–44 hours can result in the death
of most, if not all, of those cells. Neither the article by Kantoff et al.
(1) nor the FDA review documents for sipuleucel-T specify a determination of the viability of placebo cells before reinfusion into the
patient. Thus, at best, at each of the three interventions, placebo
patients received less than 12% of their harvested cells back; and at
worst, they received an infusion with an equivalent number of dead
cells. These three differences between the placebo and experimental
interventions were assumed to be benign and have no impact on OS
in this population. However, this assumption remains to be proven,
and the term “placebo” is inappropriate. The IMPACT placebo constituted a biologically significantly different intervention that could
have had distinct clinical properties and was therefore an inappropriate control for sipuleucel-T.
Synthesis and Discussion of Observations
The observations above suggest a simple, albeit unproven, alternative explanation of the IMPACT trial outcome. According to this
alternative explanation, the enrollment criteria selected for a patient
population with a favorable prognosis of approximately 28–29
months and the placebo intervention, involving a repeated depletion of circulating mononuclear cells, exerted an age-dependent
adverse impact on OS. There are several possible explanations for
this. Most simply, patients younger than 65 years may have been
able to replace the lost cells (and clear the dead cells) with few or
no negative consequences, as reflected in their 28.2-month survival
(6). However, patients older than 65 years may have been harmed
by the cell loss (or the infusion of dead cells), as reflected in their
17.3-month survival, which is 11 months shorter than might have
been predicted without the placebo intervention. It is noteworthy
that the sipuleucel-T intervention, involving a similar, though
smaller, repeated depletion of circulating lymphocytes, may have
resulted in a similar, but less severe, age-dependent impact on survival. Although the patients younger than age 65 lived 29 months, the
survival time expected of the entire group, the cells lost during sipuleucel-T manufacture may have contributed to the 5.6-month shorter
survival of patients older than 65 years. Such an explanation would not
involve a therapeutic benefit related to the chimeric antigen.
The field of immunosenescence provides support for this
alternative explanation. The age-dependent deterioration of
multiple components of the immune system are widely accepted
and believed to contribute to the increased incidence of cancer in
the elderly (Box 1) (40,41). Each of these affected elements is
believed to be involved in the recognition and suppression of developing malignancies (42–45), and therefore a depletion of cellular elements by apheresis with inadequate replacement could
exacerbate some or all of these age-related immunodeficiencies.
Because T cells are proposed to be enacting the purported
treatment effect of sipuleucel-T, it is of particular note that the
age-related decline in both naive and memory T-cell diversity is
not linear, but that age 65–70 years is associated with a precipitous
contraction (29,46). This collapse in both number and diversity
of circulating naive T-cells is believed to underlie the poor
response to vaccination in elderly humans and primates
(13,14,47) and by similar mechanisms leads to a reduced ability
to respond to new tumor antigens (14,15). Thus, there is a solid
scientific and mechanistic basis for belief that the interventionrelated depletion could have a greater detrimental effect on the
anticancer immune competence of older individuals, with 65
years representing an important threshold age. Homeostatic
proliferation and migration of peripheral T-cells might maintain
the absolute numbers in the circulation (48); yet the resultant
population would differ from the unperturbed population in
important functional ways (49).
Overall, we believe that a detrimental effect of the placebo intervention is at least as plausible as a beneficial effect of sipuleucel-T
as an explanation of the survival difference observed in the
IMPACT trial. We would be interested in other possible explanations for the 11-month survival difference between placebo
patients older and younger than age 65, as well as explanations for
why the patients in whom sipuleucel-T is apparently efficacious
(aged >65 years) live clinically and statistically significantly shorter
lives than the patients in whom it has no apparent efficacy (aged <65
years). The safety of prostate cancer patients as well as the
278 Commentary | JNCI Vol. 104, Issue 4 | February 22, 2012
judicious development of beneficial immunotherapies depends
on addressing the concerns raised and considering all possible
interpretations of the IMPACT trial results.
References
Apalutamide for Metastatic Castration-Sensitive Prostate Cancer
****Provenge Over with****
Metformin: Preliminary Results of Trial in Advanced Prostate Cancer (MANSMED)
Provenge - is it worth it?
