Download Immunotherapy for prostate cancer: the next step?

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Immunotherapy for prostate
cancer: the next step?
HANNAH RUSH, CLARE GILSON AND SIMON CHOWDHURY
Immunotherapy is showing
great promise in the
treatment of a wide
range of cancers. Using
the body’s own immune
system to attack tumours
is an attractive proposition
that has the advantage
of being selective with
reduced toxicity. In this
article the authors provide a
comprehensive overview of
the current approaches being
tested in the treatment of
prostate cancer.
Immunotherapy involves stimulating the body’s adaptive immune response against tumour
cells. It has the potential to be more targeted and less toxic than cytotoxic chemotherapy
(© Steve Gschmeissner/Science Photo Library)
P
rostate cancer is the most common
cancer among men worldwide and one
of the leading causes of cancer-related
mortality. When diagnosed early, it can
be treated effectively with surgery or
radiotherapy. However, 5% of patients
present with metastatic disease. Despite
recent advances in treatment, the average
life expectancy for these patients is only
3.5 years.
Hannah Rush, Clinical Fellow in Medical
Oncology; Clare Gilson, Clinical Fellow
in Medical Oncology; Simon Chowdhury,
Consultant Medical Oncologist;
Department of Medical Oncology,
Guy’s Hospital, London
www.trendsinmenshealth.com
Androgen deprivation therapy (ADT)
has traditionally been the lynchpin of
first-line management of metastatic
disease. Eventually, all patients treated for
metastatic disease will develop castrationresistant prostate cancer (CRPC). Over the
last five years, a range of new agents have
been found to improve survival in patients
with CRPC, including the cytotoxic agent
cabazitaxel (Jevtana), anti-androgen drugs
abiraterone (Zytiga) and enzalutamide
(Xtandi), and sipuleucel-T, the first cellular
immunotherapy to receive a licence
for solid tumour oncology.1 Although
sipuleucel-T was approved by the American
Food and Drug Administration (FDA) in
2010, following an appraisal in 2015, the
National Institute for Health and Care
Excellence (NICE) has not recommended its
use within the NHS in the UK, largely on
the grounds of cost.2
Recent advances in immunotherapy have
been practice-changing in the treatment of
melanoma, renal cell carcinoma and lung
cancer. It is an exciting therapeutic option,
offering the potential for significant
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improvement in patient outcomes, coupled
with a more favourable side-effect profile
than traditional cytotoxic agents. This
review will outline some of the immunotherapeutic approaches currently being
evaluated in trials.
WHAT IS IMMUNOTHERAPY?
Preclinical data support the role of
immunotherapy in the treatment of prostate
cancer. Studies show that prostate cancer
stimulates an immune response and that
infiltration of certain immune cells within
a tumour correlates with patient survival,3
suggesting the immune system’s key role in
controlling cancer growth (Table 1).
Immunotherapy involves stimulating the
body’s adaptive immune response against
tumour cells, a slower process than the
effect of cytotoxic agents. As prostate
cancer is relatively slow-growing, there
is sufficient time for immunotherapy to
produce a response. One advantage in
harnessing the immune system in prostate
cancer is that the prostate is not a vital
organ. Well described tumour-associated
antigens (TAAs) have been studied, including
prostate-specific antigen (PSA), prostatespecific membrane antigen (PSMA), prostate
acid phosphatase (PAP) and prostate stem
cell antigen (PSCA). No perfect prostate
cancer TAA has yet been discovered.
In addition to the understood mechanism
of their therapeutic effect, some established
prostate cancer treatments also activate
the immune system. ADT enhances immune
response against tumour cells, improving
T-cell activation and homing to sites of
disease.5 Chemotherapy has traditionally
been thought of as impairing immune
response due to lysis of leucocytes; however,
there is some suggestion that it may facilitate
induction of anti-tumour immunity. For
example, docetaxel has been reported to
increase the production of pro-inflammatory
cytokines6 and doxorubicin to enhance
cytotoxic T-cell anti-tumour immunity.7
These data suggest that immune activation
may play a part in the effectiveness
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Immune markers
Prognosis
Protective immune response
Presence of effector T cells specific to TAAs,
including epitopes on the androgen receptor
Presence of antibodies against NY-ESO-1, a TAA
NK cell tumour infiltration
Poor prognosis
Increased level of circulating and tumourinfiltrating immunosuppressive Tregs
Mutations of TGF-β
Increased risk of recurrence
Infiltration of macrophages after ADT
TAA, tumour-associated antigens; NK cell, natural killer cell; Tregs, T regulating cells;
TGF-β, transforming growth factor beta.
Table 1. Immune markers of prognosis in prostate cancer4
of current therapies and support the
development of novel approaches capable
of exploiting this further.
of progression-free survival (PFS), a
significant 4.3-month median survival
difference favoured treatment.10
IMMUNOTHERAPY AGENTS
Currently, there are two main strategies
for harnessing immunotherapy in prostate
cancer: vaccination and checkpoint
blockade. In the context of treating cancer,
therapeutic vaccines aim to stimulate
immune cells to recognise malignant cells
as foreign, thus initiating an immune
attack. Tumours employ inhibitory
checkpoint signals to prevent stimulating
T-cell activation, thus checkpoint blockade
enables the immune response to proceed
uninterrupted against tumour cells.8
Subsequently, the IMPACT study, a doubleblind, placebo-controlled trial, assessing the
efficacy of sipuleucel-T in 512 patients with
metastatic CRPC, was designed with overall
survival (OS) as the primary endpoint.11 A
significant improvement in median OS of
4.1 months was seen, with a 3-year survival
of 31% versus 23% with placebo. As in the
initial trials, the PFS did not differ between
the two groups. Sipuleucel-T was generally
well tolerated, with 99% of the patients able
to complete the treatment course. The most
common side-effects reported were chills,
fever and headache. A subgroup analysis
demonstrated the greatest effect was seen in
patients with a lower baseline PSA, suggesting
the treatment may be most beneficial in those
with less advanced disease.12
Autologous vaccines
Sipuleucel-T is an autologous dendritic
cell infusion. Following leukophoresis,
the cells are primed with a fusion
protein of the tumour-associated
antigen PAP and granulocyte macrophage
colony-stimulating factor (GM-CSF),
before being infused back into the
patient. The primed dendritic cells activate
antigen-specific cytotoxic T cells, which
target PAP-expressing tumour cells.9
Two phase 3, randomised, placebocontrolled trials were initially conducted
with a total of 225 patients with
metastatic CRPC. Although there was
no difference in the primary endpoint
One criticism of the trial design was that
cells were harvested in both arms of
the trial – approximately 90% of each
patient’s circulating mononuclear cells were
harvested – yet in the control arm these
cells were not re-infused. Cell depletion may
therefore account for poorer survival in the
control arm.13
Viral vector-based vaccines
PROSTVAC-VF comprises two recombinant
viral vectors, each encoding transgenes
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for PSA and three immune co-stimulatory
molecules. A vaccinia-based vector is
used for the initial priming vaccination,
followed by six planned fowlpox-based
vector boosts. This is intended to activate
host dendritic cells, which in turn activate
T cells against PSA-expressing cells.
A phase 2, randomised, double-blind,
placebo-controlled study of 125 patients
with minimally symptomatic CRPC
found a significant 8.5-month (25.1
versus 16.6 months) survival advantage
in patients treated with PROSTVAC-VF.
There was no difference in the primary
endpoint of PFS. Common adverse
events were fever, nausea, fatigue
and injection site reactions.14 It is not
yet clear at which stage of disease
PROSTVAC-VF will be most effective;
the results of studies evaluating its use
in non-metastatic hormone-sensitive
prostate cancer are awaited.
Another viral vaccine in early development
uses adenovirus type 5 vectors to deliver
tumour-associated antigen-coding genes.
In a phase 1 trial including 32 patients
with metastatic CRPC, 48% had an
increase in PSA doubling time and 55%
survived longer than predicted.15
Cell-based vaccines
GVAX is an allogenic, whole-cell vaccine
consisting of two prostate cancer cell
lines transduced with GM-CSF. Two large
phase 2 trials, VITAL-1 and VITAL-2, have
been conducted. VITAL-1, comparing
GVAX with docetaxel and prednisone, was
terminated early due to a futility analysis
that suggested a low probability of the trial
reaching the primary endpoint.16 VITAL-2,
which compared docetaxel and GVAX
with docetaxel alone, was terminated due
to high mortality in the treatment arm.17
The increased death rate in the treatment
group was not clearly related to increased
toxicity. Recent evidence has suggested
that GVAX may have a role when given
in combination with ADT for hormonesensitive prostate cancer.
www.trendsinmenshealth.com
ONY-P1 is another cell-based vaccine
comprising three irradiated prostate cancer
cell lines. In a non-randomised phase 2
trial, 26 patients with metastatic CRPC
received ONY-P1 intradermally, with bacilli
Calmette-Guerin as a vaccine adjuvant
for the first two doses. A significant delay
in PSA velocity was observed in 11 of the
26 patients.18
CTLA-4 targeting agent tremelimumab, a
fully human IgG2 monoclonal antibody,
has undergone testing in a phase 1
trial of 11 patients with PSA recurrence.
Dose-limiting toxicities of diarrhoea
and skin rash were observed; however, a
prolongation of PSA doubling time in three
patients suggests that further investigation
may be warranted.21
Personalised peptide vaccines
This approach screens a patient’s
immune response against a panel of
31 TAA-peptide epitopes known to be
potentially immunogenic in prostate
cancer. A small panel of peptides is
selected and the patient is vaccinated
with them. One phase 2 study involving
42 patients with CRPC, of whom half
were resistant and half sensitive to
docetaxel, found a non-significant trend
towards improved survival amongst the
docetaxel-resistant patients compared
with historical controls (17.8 versus
10.8 months).19
PD-1 checkpoint blockade
The immune regulatory inhibitor
programmed cell death protein 1 (PD-1) is
another suppressive immune checkpoint
receptor. Tumour cells can express
programmed death ligand 1 or 2 (PD-L1
or PD-L2), which interact with PD-1 on
T cells, resulting in inhibition of T-cell
activation against the cancer. In mouse
models, the absence of PD-1 has shown
to dramatically delay tumour growth and
increase cytotoxic T cells within tumour
tissue.22 A study examining the tumour
biopsies of seven patients with prostate
cancer found that 90% of the infiltrating
CD8+ T lymphocytes had upregulated cell
surface expression of PD-1.23
CTLA-4 checkpoint blockade
T-cell responses depend on a balance
between positive and negative co-regulatory
signals that are generated within the
T cell. Cytotoxic T-lymphocyte antigen 4
(CTLA-4) is an immune checkpoint
receptor responsible for suppressing
T-cell activation. Ipilimumab is a fully
human monoclonal antibody that binds
to and inhibits CTLA-4 ligand-driven
activation. By overcoming the CTLA-4
mediated suppression, T cells are activated
with the potential to ‘take them off
the leash’, allowing TAA recognition
and elimination.
A phase 3 trial of 799 patients with
advanced CRPC that had progressed
after docetaxel compared radiotherapy
and ipilimumab with radiotherapy and
placebo. There was no significant survival
difference (11.2 versus 10.0 months).20
Ongoing studies are investigating the
use of ipilimumab in earlier stages of
prostate cancer.
Nivolumab is an anti-PD-1 monoclonal
antibody that has recently been approved
by the FDA for use in metastatic
melanoma. In a phase 1 trial of nivolumab,
including 17 patients with metastatic
CRPC, no objective response was seen
amongst the prostate cancer patients.24
42 patients in the trial, with a mix of solid
tumour types, had biopsies assessed for
PD-L1 expression. Whilst none of the
patients with negative PD-L1 biopsies had
a response, 36% of patients with evidence
of PD-L1 expression had an objective
response to treatment. PD-L1 was the only
biomarker to have a significant correlation
with response to nivolumab.25
CONCLUSION
Immunotherapy is an exciting and
rapidly advancing field that is enjoying
renewed interest and some success in
prostate cancer. Sipuleucel-T continues to
demonstrate durable and well-tolerated
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responses in prostate cancer; studies to
determine if the impressive results seen
with checkpoint inhibitors in other solid
tumours can be replicated in prostate
cancer are ongoing. Questions remain
regarding the efficacy of newer treatments,
what constitute optimum sequencing
and the potential benefits of combination
therapy (see Table 2 for a summary of
ongoing trials).
To date, immunotherapy has been
investigated predominantly in advanced
disease, where the immune system may
have been suppressed and impaired by
previous treatments, disease burden and
associated comorbidities. Immunotherapy
could potentially be more effective when
administered early in the course of the
disease; many current trials are focused on
this possibility (Table 2).
We need to better understand the natural
history of changes within tumours treated
with immunotherapy. According to current
methods of measuring PFS, most patients
show no response to immunotherapy, yet
there is often significant improvement
in OS. The Prostate Cancer Clinical
Trials Working Group has proposed
new criteria for evaluating cytotoxic and
non-cytotoxic agents, which include
changes in how immune-related responses
are assessed.26,27
Studies have assessed whether genetic
analysis of tumour cells can provide clues as
to who will respond to immunotherapy. New
peripheral biomarkers are also being sought
to aid in the prediction and measurement
of response to treatment, as well as markers
that would enable the prediction of toxicity.
This would allow targeted therapy for
individuals most likely to benefit from
immunotherapy, providing a rationale
for the use of such high cost treatments
and a basis on which truly individualised
treatment plans could be formulated.
Agents
Population
No. of
patients
Phase
Primary outcome
Trial number
Sipuleucel-T and
enzalutamide
Metastatic CRPC
100
2
Evaluate peripheral
immune response
NCT01981122
Sipuleucel-T and ADT
Non-metastatic
prostate cancer with
rising PSA
68
2
Measure change in
immune response
NCT01431391
Sipuleucel-T and
indoximod
Refractory metastatic
prostate cancer
50
2
Immune response to
sipuleucel-T
NCT01560923
PROSTVAC and GM-CSF
Metastatic prostate
cancer
1298
3
Overall survival
NCT01322490
PROSTVAC and
enzalutamide
Non-metastatic
hormone-sensitive
prostate cancer
26
2
Decrease in tumour
regrowth rate
NCT01875250
PROSTVAC and
enzalutamide
Metastatic CRPC
76
2
Progression-free survival
NCT01867333
Adenovirus vaccine
ProstAtak as adjuvant
with radiotherapy
Localised prostate
cancer
711
3
Disease-free survival
NCT01436968
GVAX and ADT with
cyclophosphamide
Localised prostate
cancer
29
1 and 2
Assess CD-8 infiltration
into prostate cells
NCT01696877
Ipilimumab and
sipuleucel-T
Pre-chemotherapy
metastatic CRPC
54
2
Impact of the timing of
ipilimumab on immune
reponse created by
sipuleucel-T
NCT01804465
Pidilizumab and
sipuleucel-T with
cyclophosphamide
Advanced CRPC
57
2
Feasibility and immune
efficacy
NCT01420965
Table 2. Ongoing trials of immunotherapy agents in prostate cancer
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Acknowledgement
Thank you to Dr Sophie Papa for her review
and feedback on this article.
Declaration of interests: none declared.
REFERENCES
1.US Food and Drug Administration.
April 29, 2010 approval letter – Provenge.
(http://www.fda.gov/BiologicsBlood
Vaccines/CellularGeneTherapyProducts/
Approved Products/ucm210215.htm;
accessed 19 January 2016).
2.National Institute for Health and Care
Excellence. Sipuleucel-T for treating
asymptomatic or minimally symptomatic
metastatic hormone-relapsed prostate
cancer. NICE technology appraisal [TA332]
Feb 2015.
3.Galon J, Pagès F, Marincola FM, et al. The
immune score as a new possible approach
for the classification of cancer. J Transl Med
2012;10:1.
4.Quinn DI, Shore ND, Egawa S, et al.
Immunotherapy for castration-resistant
prostate cancer: progress and new
paradigms. Urol Oncol 2015;33:245–60.
5.Mercader M, Bodner BK, Moser MT, et al.
T cell infiltration of the prostate induced
by androgen withdrawal in patients with
prostate cancer. Proc Natl Acad Sci USA
2001;98:14565–70.
6.Chan OT, Yang L. The immunological effects
of taxanes. Canc Immunol Immunother
2000;49;181–5.
7.Mattarollo SR, Loi S, Duret H, et al. Pivotal
role of innate and adaptive immunity in
anthracycline chemotherapy in established
tumours. Cancer Res 2011;71:4809–20.
8.Pazdur MP, Jones JL. Vaccines: an innovative
approach to treating cancer. J Infus Nurs
2007;30:173–8.
9.Wesley JD, Whitmore J, Trager J, Sheikh N.
An overview of sipuleucel-T: autologous
cellular immunotherapy for prostate
cancer. Hum Vaccin Immunother 2012;
8:520–7.
10.Higano CS, Schellhammer PF, Small EJ, et
al. Integrated data from 2 randomized,
double-blind, placebo-controlled, phase III
trials of active cellular immunotherapy with
www.trendsinmenshealth.com
sipuleucel-T in advanced prostate cancer.
Cancer 2009;115:3670–9.
11.Kantoff PW, Higano CS, Shore ND, et al.
Sipuleucel-T immunotherapy for castrationresistant prostate cancer. N Engl J Med
2010;363:411–2.
12.Schellhammer PF, Chodak G, Whitmore
JB, et al. Lower baseline prostate specific
antigen is associated with greater
overall survival benefit from sipuleucel-T
in the Immunotherapy for Prostate
Adenocarcinoma Treatment (IMPACT) trial.
Urology 2013;81:1297–302.
13.Huber ML, Haynes L, Parker C, et al.
Interdisciplinary critique of sipuleucel-T
as immunotherapy in castration-resistant
prostate cancer. J Natl Cancer Inst
2012;104:273–9.
14.Kantoff PW, Schuetz TJ, Blumenstein, et
al. Overall survival analysis of a phase II
trial of a poxviral-based PSA-targeted
immunotherapy in metastatic prostate
cancer. J Clin Oncol 2010;28:1099–105.
15.Lubaroff DM, Konety BR, Link B, et al. Phase
I clinical trial of an adenovirus/prostate
specific antigen vaccine for prostate cancer:
safety and immunologic results. Clin Cancer
Res 2009;15:7375–80.
16.Higano C, Saad F, Somer B, et al. A phase III
trial of GVAX immunotherapy for prostate
cancer vs. docetaxel plus prednisone in
asymptomatic, castration-resistant prostate
cancer (CRPC). Abstract LBA150, Genitourinary
Cancers Symposium 2009 (http://meeting
library.asco.org/content/20543-64; accessed
19 January 2016).
17.Small EJ, Demkow T Gerritsen W, et al.
A phase III trial of GVAX immunotherapy
for prostate cancer in combination
with docetaxel versus docetaxel
plus prednisone in symptomatic,
castration-resistant prostate cancer
(CRPC). Abstract 07, Genitourinary
Cancers Symposium 2009 (http://meeting
library.asco.org/content/20295-64;
accessed 19 January 2016).
18.Michael A, Ball G, Quatan N, et al. Delayed
disease progression after allogeneic cell
vaccination in hormone-resistant prostate
cancer and correlation with immunologic
variables. Clin Cancer Res 2005;11:4469–78.
19.Noguchi M, Moriya F, Suekane S, et al.
Phase II study of personalized peptide
vaccination for castration-resistant
prostate cancer patients who failed in
docetaxel-based chemotherapy. Prostate
2012;72:834–45.
20.Kwon ED, Drake CG, Scher HI, et
al. Ipilimumab versus placebo after
radiotherapy in patients with metastatic
castration-resistant prostate cancer
that had progressed after docetaxel
chemotherapy (CA184-043): a multicentre,
randomized, double-blind, phase III trial.
Lancet Oncol 2014;15:700–12.
21.McNeel DG, Smith HA, Eickhoff JC, et
al. Phase I trial of tremelimumab in
combination with short-term androgen
deprivation in patients with PSA-recurrent
prostate cancer. Cancer Immunol
Immunother 2012;61:1137–47.
22.Ahmadzadeh M, Johnson LA, Heemskerk B,
et al. Tumour antigen-specific CD8 T cells
infiltrating the tumour express high levels
of PD-1 and are functionally impaired.
Blood 2009;114:1537–44.
23.Sfanos KS, Bruno TC, Meeker AK, et al.
Human prostate-infiltrating CD8+ T
lymphocytes are oligoclonal and PD-1+.
Prostate 2009;69:1694–703.
24.Topalian SL, Hodi FS, Brahmer JR, et al.
Safety, activity, and immune correlates of
anti-PD-1 antibody in cancer. N Engl J Med
2012;366:2443–54.
25.Taube JM, Klein A, Brahmer JR, et al.
Association of PD-1, PD-1 ligands,
and other features of the tumour
microenvironment with response to
anti-PD-1 therapy. Clin Cancer Res
2014;20:5064–74.
26.Scher HI, Halabi S, Tannock I, et al.
Design and end points of clinical trials
for patients with progressive prostate
cancer and castrate levels of testosterone:
recommendations of the Prostate Cancer
Clinical Trials Working Group. J Clin Oncol
2008;26:1148–59.
27.Wolchok JD, Hoos A, O’Day S, et al.
Guidelines for the evaluation of immune
activity in solid tumours: immunerelated response criteria. Clin Cancer Res
2009;15:7412–20.
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