Review

Combining Immunotherapy and Radiation

for Prostate Cancer*
Steven E. Finkelstein,1 Sharon Salenius,2 Constantine A. Mantz,2 Neal D. Shore,3
Eduardo B. Fernandez,2 Jesse Shulman,1 Francisco A. Myslicki,1 Andre M. Agassi,1
Yosef Rotterman,1 Todd DeVries,4 Robert Sims4
Abstract
Radiotherapy has conventionally been viewed as immunosuppressive, which has precluded its use in combination with
immunotherapy for prostate and other cancers. However, the relationship between ionizing radiation and immune
reactivity is now known to be more complex than was previously thought, and data on the use of radiotherapy and
immunotherapy are accumulating. Herein, we review this topic in the light of recently available data in the prostate cancer
setting. Recent research has shown no signicant lymphopenia in patients undergoing radiotherapy for high-risk
adenocarcinoma of the prostate. In addition, emerging evidence suggests that radiotherapy can have immunostimulatory effects, and that tumor cell death, coupled with related changes in antigen availability and inammatory signals, can
affect lymphocyte and dendritic cell activation. Initial studies have focused on combinations of tumor irradiation and
immunotherapy, such as the autologous cellular immunotherapy sipuleucel-T and the monoclonal antibody ipilimumab,
in metastatic castration-resistant prostate cancer. These combinations appear to have clinical promise, and further
investigation of the potentially synergistic combination of radiotherapy and immunotherapy is continuing in clinical trials.
Clinical Genitourinary Cancer, Vol. 13, No. 1, 1-9 2015 The Authors. Published by Elsevier Inc.
All rights reserved.
Keywords: Cancer vaccine, Prostatic neoplasm, Radiation effects, Radiotherapy

Introduction
Radiotherapy has historically been thought of as immunosuppressive and therefore not appropriate for combination with treatments that act on the immune system. However, this view of
radiotherapy might be overly simplistic, and a growing body of
evidence suggests that ionizing radiation can be immunostimulatory. This opens up opportunities for combining radiotherapy with
cancer immunotherapies, which are approved or under investigation
for various malignancies including prostate cancer. Clinical data
on the use of radiotherapy with immunotherapy, both together and
sequentially, are accumulating. In this review we consider recent
*This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/3.0/).
1

21st Century Oncology Translational Research Consortium, Scottsdale, AZ

21st Century Oncology Translational Research Consortium, Fort Myers, FL
Carolina Urologic Research Center, 21st Century Oncology, Myrtle Beach, SC
4
Dendreon Corporation, Seattle, WA
2
3

Submitted: May 30, 2014; Revised: Aug 29, 2014; Accepted: Sep 17, 2014; Epub:
Sep 28, 2014
Address for correspondence: Steven E. Finkelstein, MD, 21st Century Oncology
Translational Research Consortium (TRC), 7340 E Thomas Rd, Scottsdale,
AZ 85251
Fax: 480-945-7287; e-mail contact: snkels@rtsx.com

1558-7673/$ - see frontmatter 2015 The Authors. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.clgc.2014.09.001

advances that challenge widely held views, not only on the effects of
radiotherapy but also the potential synergy between radio- and
immunotherapeutic approaches.

Effects of Radiotherapy on the

Immune System
The accepted rationale for using radiotherapy in cancer is underpinned by tumor cell death and effects on tumor-associated stroma
caused by DNA damage.1 The conventional view is that rapidly
dividing cancer cells are more sensitive to ionizing radiation than
normal tissue, and therapeutic radiation is therefore applied to induce
apoptosis and other forms of cell death within a dened area while
minimizing toxic effects on normal tissue around the treatment eld.1,2
Inevitably, irradiation of living tissue involves damage to that
tissue, whether it is tumor tissue, normal host stroma, normal
host parenchyma, or leukocytes.1 The attenuation of lymphocyte
numbers by radiotherapy, as previously reported in patients undergoing treatment for gynecologic3 or prostate4 malignancies,
might therefore be viewed as an adverse effect. The ultimate
manifestation of this is seen in patients who undergo total body
irradiation (as widely used in conditioning regimens for hematologic malignancies), who experience prolonged pancytopenia.5
Studies have described reductions in numbers of T, B, and

Clinical Genitourinary Cancer February 2015

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Immunotherapy and Radiotherapy for Prostate Cancer

natural killer (NK) cells, apoptosis or alteration of antigenpresenting cells (APCs), including dendritic cells (DCs) and macrophages, apoptosis of lymphocytes, and changes to antigen
expression on tumor cells after radiotherapy with doses from
approximately 50 to 70 Gy.3,4,6,7 Localized radiotherapy has
reportedly resulted in signicant reductions in lymphocyte levels in
stage I to II prostate cancer or locally advanced gynecologic neoplasms.3,4 Similarly, studies on radiotherapy in patients with stage I
to III breast cancer have shown lymphopenia, low functional activity of NK cells, decreased monocyte phagocytosis, and decreased
tumor necrosis factor (TNF)-a production.7
Observations such as these have contributed to the conventional view of radiation therapy as immunosuppressive, and it has
therefore not been used with cancer immunotherapy. However,
emerging data suggest that standard radiotherapy in high-risk
prostate adenocarcinoma might not be as immunosuppressive as
previously thought, nor the relationship between radiation and
immune responses as straightforward.1,8 The relative contributions and reactions of systemic and locoregional cell populations
and the differing effects of dose and delivery methods might inuence immune responses via a range of cellular mechanisms
(Figure 1).9

Radiotherapy can cause tumor cell apoptosis by inducing DNA

damage, upregulating the p53 tumor suppressor gene, and
through damage to the cellular lipid membrane. This in turn can
lead to ceramide formation and activation of the stress-activated
protein kinases/Jun amino-terminal kinases (SAPK/JNK) signaling pathway. The resultant damage-associated molecular
patterns (apoptotic and necrotic cellular debris) can generate
antigen-specic immunity through DC maturation and presentation of DC-processed antigen to T cells.9
Activation of the SAPK/JNK signaling pathway and the presence of damage-associated molecular patterns might also be partly
responsible for other immunological effects seen after radiotherapy.9 Studies in a variety of tumors have shown that radiation
induces chemokines Chemokine (C-X-C motif) ligand, CXCL10,
and CXCL16, which in turn promote recruitment of effector CD8
and T-helper 1 CD4 T cells.10 Radiation has also been shown to
induce a number of different proinammatory cytokines,
including interleukin (IL) 1b, TNF-a and type 1 and 2 interferons.10 Additionally, in several cancer models, tumor cells
exposed to radiation have been shown to have enhanced expression
of major histocompatibility complex (MHC) class 1 molecules, costimulatory molecules, adhesion molecules (such as intercellular

Figure 1 Radiation Effects on Immune Cells and Consequent Modulation by Radiotherapy.9 Apoptosis Can Be Initiated by RadiationInduced DNA Damage and Upregulation of the p53 Tumor Suppressor Gene, and by Damage to the Cellular Lipid Membrane,
Which Can Induce Ceramide Formation and Activate the SAPK/JNK Signaling Pathway. SAPK/JNK Can Upregulate PKR
Expression, Which in Turn Induces MHC and Cytokines via NF-kB. Radiation Treatment Induces Cellular Expression of MHC
Class I, Adhesion Molecules, Co-Stimulatory Molecules, Heat Shock Proteins, Inammatory Mediators, Immunomodulatory
Cytokines, and Death Receptors

Abbreviations: ATM Ataxia Telangiectasia Mutated; CD Cluster of Differentiation; DNA-PK DNA-Dependent Protein Kinase; MHC Major Histocompatibility Complex; NF-kB Nuclear Factor
Kappa Light Chain Enhancer of Activated B Cells; PKR Protein Kinase R; SAPK/JNK Stress-Activated Protein Kinases/Jun Amino-Terminal Kinases.

Clinical Genitourinary Cancer February 2015

Steven E. Finkelstein et al
Table 1 White Blood Cell Count (WBC) and Absolute Lymphocyte Counts (ALC) at Baseline and After Radiotherapy in 26 Patients With
Adenocarcinoma of the Prostate13
Days After Radiotherapy
Parameter
WBC, Cells/mL

ALC, Cells/mL

Statistic
n

Baseline

1-90

91-180

181-360

>360

26

18

13

21

20

Mean

6527

5806

6362

6038

6085

Median

6050

5350

6000

5800

5200

Minimum

4000

3500

3500

3400

4400

Maximum
n

10,100
21

13,100
11

11,000
9

13,100
10

10,000
8

Mean

1680

1054

1059

1246

1275

Median

1700

970

1100

1250

1350

Minimum

700

700

500

590

1000

Maximum

3100

1700

1500

2100

1400

Normal reference ranges were 3800 to 10,700 cells/mL for WBC and 910 to 4280 cells/mL for ALC.
Abbreviation: n number of observations in an interval.

adhesion molecule 1 [ICAM-1]), and stress-induced ligands

(including NK Group 2D ligands on NK cells).10,11 Furthermore,
radiation can upregulate expression of the Fas death receptor on
tumor cells, which induces sensitivity of the tumor cells to T-cell
receptor independent, Fas-mediated killing.11 Finally, a direct effect of radiation on tumors has been reported, in which radiotherapy modies the phenotype of tumor cells to render them
more susceptible to vaccine-mediated T-cell killing.12 As a combined result of these mechanisms, radiotherapy can engage both
the innate and adaptive arms of the immune system,9-11 thereby
converting the irradiated tumor into an in-situ vaccine that
elicits a tumor-specic T-cell response, and the inltration of
leukocytes.
A more detailed summary of the effects of radiotherapy on some
of the components of the immune system is described in the
following sections.

median WBC and then ALC increased gradually to 5800 and 1250
cells/mL, respectively, approximately 6 to 12 months after radiotherapy (Figure 2).13 Thus, median WBC and ALC remained
within normal limits for the full follow-up period. These results
challenge the view that standard radiotherapy in high-risk prostate
adenocarcinoma is immunosuppressive. To be successful, immunotherapy requires an active immune system, and the stability of cell

Figure 2 Median Baseline and Subsequent Cell Counts After

Radiation Therapy.13 (A) White Blood Cell (WBC)
Counts; (B) Absolute Lymphocyte Counts (ALC)

Effects of Radiation Therapy on White Blood Cell Counts

in High-Risk Adenocarcinoma of the Prostate
In contrast to observations discussed previously,3,4,6,7 our group
has demonstrated no signicant lymphopenia in 26 patients aged
62 to 86 years (median 73 years) undergoing radiotherapy for
high-risk prostate adenocarcinoma.13 In this study, complete
blood counts (CBCs) were retrospectively analyzed with differential data on prospectively collected blood samples. CBC data
were collected before radiotherapy and at up to 4 time points
thereafter (1-90 days, 91-180 days, 181-360 days, and > 360
days), and were compared with normal ranges from an outside
laboratory reference (white blood cell [WBC] count, 3800-10,700
cells/mL; absolute lymphocyte count [ALC], 910-4280 cells/mL).
Patients received conventional external beam radiotherapy (EBRT)
from 64.8 to 81.0 Gy in 1.8-Gy fractions, with a small number
receiving brachytherapy. Sixteen patients also received androgen
deprivation therapy.
Baseline cell counts were within normal ranges (Table 1).13
Counts decreased in the 3 months after radiotherapy, although
median values remained within the normal range. Thereafter,

Abbreviation: AUC Area Under the Curve.

Clinical Genitourinary Cancer February 2015

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Immunotherapy and Radiotherapy for Prostate Cancer

counts in these patients therefore underlines the feasibility of
combining radiation and immunotherapy.

Fas- and TNF-related apoptosis-inducing ligand (TRAIL)-induced

apoptosis.20

Radiotherapy and Antitumor Immune Responses

Immunomodulatory Cytokines Such as IL and TNF-a. Expression

of the proinammatory cytokine TNF-a was increased after radiation exposure in a study of human sarcoma cells, with enhancement
of radiation lethality in TNF-aeproducing and enonproducing
cells.21 Radiation exposure has also been linked to expression of
IL-1b (involved in T cell and macrophage activation) and TNF-a
in mouse studies.22,23 Similarly, increased heat shock protein 72
expression has been linked to increases in circulating levels of IL-6
(involved in the acute phase response and antibody responses) and
TNF-a after irradiation in patients with prostate cancer.24

Evidence shows that, in addition to treating a localized tumor,

radiotherapy can inuence immune responses. For example,
tumor-specic immune responses have been reported after
radiotherapy in patients with prostate cancer.14,15 Nesslinger et al
examined serum samples before and after radiotherapy from
men with localized disease and found treatment-associated
autoantibody responses in 4 of 29 (13.8%) who had undergone
radiotherapy and 3 of 10 (30%) who had received brachytherapy,
which included autoantibody responses to serologically dened
colon cancer antigen 1, outer dense ber of sperm tails 2, and
poly [ADP-ribose] polymerase family, member 1.14 In another
study, Schaue et al found the expression of survivin-specic
cluster of differentiation (CD)8-positive (CD8) T cells in peripheral blood to increase with radiotherapy in 7 of 11 (63.6%)
prostate cancer patients.15 Increases in survivin-specic CD8 T
cells were also seen in patients with colorectal cancer in this
study. Signicantly, the observed lack of immune tolerance to
survivin made immunotherapy combined with radiotherapy
feasible in these patients.15

Effects of Radiation Therapy That Might Inuence

Immune Responses
When considering how radiotherapy could stimulate anticancer
immune responses, there is now known to be interplay between
tumor cell death, antigen expression, and inammatory signals that
affect lymphocyte and DC activation.8,9 Indeed, numerous studies
have shown that targeted radiation can induce cellular expression of
a wide variety of immune factors with effects on different cell types,
as discussed in the following sections (see also Figure 1).
Major Histocompatibility Complex Class I. Major histocompatibility complex class I molecules bind cytosol-derived peptides
and present them at the cell surface, allowing CD8 T cells to
recognize and potentially destroy transformed or virus-infected
cells.16 Localized irradiation of a wide variety of human tumor
cell lines can result in increased expression of MHC class I, Fas,
and ICAM-1.17 Upregulation of these cell surface molecules was
accompanied by signicantly enhanced tumor cell killing by
CD8 cytotoxic T lymphocytes (CTLs). Furthermore, in vivo cell
surface expression of MHC class I molecules was shown in murine
adenocarcinoma cells to be dose-dependently increased for several
days after irradiation.18
Death Receptors. Fas is expressed at the cell surface in certain
circumstances and induces apoptosis within the cell when engaged
by the Fas ligand, which is present on activated T cell subsets.16
Therefore induction of Fas expression by tumor cells can facilitate
tumor cell killing by immune effectors. In a murine carcinoembryonic antigen-specic CD8 CTL tumor model, localized irradiation of tumors caused upregulation of Fas and potentiated tumor
rejection.19 In another study, sublethal irradiation of colorectal
carcinoma cell lines resulted in sensitization of tumor cells to

Clinical Genitourinary Cancer February 2015

Adhesion Molecules. Intercellular adhesion molecule 1 (also

known as CD54) is an endothelial membrane protein that contributes to leukocyte adherence to, and migration through, blood
vessel endothelia.16 This process, termed extravasation, is essential
for immune effector cells to exit the blood into the tissues to reach
the site of solid tumors. Irradiation of human dermal microvascular
endothelial cells caused dose-dependent increases in surface
expression and mRNA of ICAM-1.25
Co-Stimulatory Molecules. Expression of co-stimulatory B7
molecules by APCs contributes to T cell activation, and engagement of T cells in the absence of co-stimulation can lead to immune regulation and dampening of immune responses.16
Therefore, B7 expression is particularly relevant in the context
of myeloid leukemias, because key APCs are derived from the
myeloid lineage. Gamma irradiation of human acute myeloid
leukemia (AML) cells has been shown to result in induction of
B7.1 expression, and might therefore be capable of stimulating an
anti-AML immune response.26
The described molecular effects combine with other local effects
to inuence immune responses. For example, radiation can induce
a proinammatory microenvironment within tumors that provide
DCs with maturation-inducing stimuli.9 Cell death caused by
irradiation also results in extensive exposure of the lymphatic system to tumor antigens through necrosis or apoptosis of tumor cells
and the subsequent release of cellular debris.27,28 Furthermore,
irradiation of DCs has been shown to inhibit endogenous antigen
processing while enhancing antigenic peptide presentation.29,30
DCs that had acquired antigen from apoptotic tumor cells were
in turn able to induce MHC class Ierestricted T cells and confer
antitumor immunity in a murine model.27 Molecular pathways
specically activated during irradiation-induced cell death can also
be immunostimulatory.31 For example, dying tumor cells secrete
the high-mobility group box 1 (HMGB1) alarmin protein that acts
on toll-like receptor 4 expressed by DCs, thereby promoting efcient processing and presentation of antigens.32 HMGB1 effects on
DCs also include maturation changes and creation of a chronic
inammatory state.33 In addition, the adhesion molecule effects on
stromal cells described previously increase the permeability of the
local vasculature that allows circulating leukocytes to inltrate the
surrounding tissues.25 Remodeling of the vasculature in a proinammatory environment can permit T lymphocytes to extravasate

Steven E. Finkelstein et al
and destroy tumor cells.34 In addition, tumor cells can be phenotypically modulated by radiation, which increases their susceptibility
to cell-killing.35 Taken together, these immunostimulatory effects
of radiation might at least partly explain the abscopal effect, in
which localized treatment with ionizing radiation can result in
reduction of tumor masses distant from the primary site.36 This
effect has been reported in 2 recent cases of metastatic melanoma
treated with radiotherapy and immunotherapy,37,38 demonstrating
that the combination of these 2 therapeutic approaches might
support the host immune response to tumor antigens.
Finally, when reviewing data on this subject it is important to
remember that there is a balance between suppressant and stimulant effects on the immune system that depends on the dose,
fractionation, and targeting of radiotherapy.39,40 In addition to
providing a radiation-induced proinammatory environment that
facilitates antigen presentation and other positive immunologic
effects, radiation can also promote the development of myeloid
cells, which facilitate tumor growth, and regulatory T cells, which
dampen or prevent immune responses.41,42 Thus, radiation can be
an immunoadjuvant in the right circumstances, but the response
reportedly varies with dose and fractionation.40 This offers possibilities for rening radiotherapy techniques so that they favor
stimulant effects.

Combination of Radiotherapy and

Immunotherapy for Prostate
Cancer
Discovery of the variety of immunostimulant effects resulting
from radiation treatment has increased interest in combining
immunotherapy with tumor irradiation to produce synergistic
benet in a range of cancers.1,35,43-46 The preclinical evidence for
synergy between radiotherapy and immunotherapy has been
reviewed recently by Kwilas et al45 and we therefore focus herein on
recent clinical data.

Immunotherapy in Prostate Cancer

New ndings are constantly being made in animal models of
oncology immunotherapy, and these often have important implications for furthering immunotherapy research in humans.47,48
Currently, a variety of immunotherapeutic treatments are available
or in development for use in prostate cancer. These include
sipuleucel-T, an autologous, APC-based immunotherapy that targets the immune response toward a dened prostate antigen
(prostatic acid phosphatase [PAP]).49 Sipuleucel-T was the rst
cancer immunotherapy approved by the United States Food and
Drug Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer
(mCRPC)50 and by the European Medicines Agency for asymptomatic or minimally symptomatic metastatic (nonvisceral)
castration-resistant prostate cancer in male adults in whom
chemotherapy was not yet clinically indicated.51 Approval was primarily based on the phase III IMPACT (IMmunotherapy Prostate
AdenoCarcinoma Treatment) trial, which showed a 4.1-month
improvement in median survival over placebo (25.8 vs. 21.7
months).52 The relative reduction in risk of death was 22% with
sipuleucel-T (hazard ratio, 0.78; 95% condence interval, 0.610.98; P .03). T cell and humoral immune responses to the

prostate antigen were observed in patients receiving sipuleucel-T

and correlated with survival.53 These results and subsequent
approval are reected in recent updates to National Comprehensive
Cancer Network guidelines for prostate cancer treatment, which
include the option of rst-line immunotherapy with sipuleucel-T in
men with mCRPC and good performance status (category 1;
Figure 3). The guidelines also emphasize the importance of radiotherapy for patients with high-risk localized tumors, and clinical
practice has shown the value of EBRT and stereotactic body radiation therapy, also known as stereotactic ablative radiotherapy, for
bone metastases.54-56
Prostate-specic antigen (PSA)-TRICOM (a recombinant viral
vaccine mixture encoding PSA with B7.1, ICAM-1, and leukocyte
functional antigen-3), ipilimumab (a fully human monoclonal
antibody against cytotoxic T-lymphocyte antigen [CTLA]-4), and
various peptides, proteins, and tumor antigens alone or linked to
viruses or co-stimulatory molecules are currently being investigated
in prostate cancer.57

Recent Progress with Combination Therapy

Notably, 2 recent studies have combined radiotherapy and
immunotherapy to good effect in patients with prostate cancer.
The rst was a pilot study of intraprostatic injection of autologous
DCs combined with EBRT and brachytherapy in 5 men with
localized tumors without radiologically evident metastases but with
high risk of recurrence (Table 2).58-60 In this study, serial prostate
biopsies consistently showed limited levels of lymphocytic inltration. No temporal inltrate pattern linked to radiation or DC
injection was evident. The theoretically optimal time to inject
DCs into the tumor environment would be when apoptosis is
proceeding maximally, which was assessed in this study. However,
among tumor cores that were examined, there were up to 19%
of cells showing apoptosis. This small proportion reects the difculty in targeting a tumor using biopsies (the organ rather than
the tumor is targeted), and it therefore appears that the identication of time points at which radiation induces high rates of
apoptosis is not straightforward.
Functional T-cell responses before, during, and after treatment
were assessed by stimulating peripheral blood cells with prostate
tumor cell-derived peptides and measuring the number of interferon-g-producing cells by enzyme-linked immunosorbent spot.
Tests showed a detectable increase from baseline in prostatespecic T-cell responses in 2 of the 5 men. However, there was
no clear temporal pattern, baseline responses were detectable in
some men, and in some cases, strong responses to control peptides
were noted.
The technique used was feasible, well tolerated, and specic
immune responses were observed. However, the coordination of
apoptosis-inducing radiotherapy with autologous DC treatment
requires further study. In fact, a randomized phase II trial
(NCT01807065) is under way to assess the efcacy of sipuleucelT in combination with radiotherapy in patients with mCRPC.
It should be noted that the treatment described herein58 differed
from sipuleucel-T therapy in the method of APC administration (intraprostatic injection vs. intravenous infusion), and also
in a lack of a dened antigen (sipuleucel-T therapy directs the
immune response toward PAP). Similar approaches combining

Clinical Genitourinary Cancer February 2015

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Immunotherapy and Radiotherapy for Prostate Cancer

intratumoral DC injection with radiotherapy or chemotherapy for
sarcoma have shown promising preliminary results and warrant
further study.61,62
The second trial was a phase I/II study in men with mCRPC
that compared ipilimumab as monotherapy and in combination
with radiotherapy (Table 2).59 Ipilimumab is a fully human
monoclonal antibody that specically blocks the binding of the
immunoregulatory molecule CTLA-4 to its ligands (CD80/CD86)

and thereby augments T cell activation and proliferation.63 This

combination therapy study was carried out after initial trials
showed ipilimumab to have acceptable tolerability and antitumor
activity in patients with mCRPC.64,65 Of the 41 patients who
received combination therapy, 30, 8, and 3 had 1, 2, and 3 bone
lesions irradiated, respectively. Among patients who received 10
mg/kg with or without EBRT (n 34), 28 had evaluable tumors:
8 had PSA reductions of at least 50% ranging in duration from

Figure 3 Systemic Therapy for mCRPC. Abridged Summary of NCCN Guideline for Patients With Advanced Disease Who Test
Positive for Metastases.56

Sipuleucel-T Is Appropriate for Asymptomatic or Minimally Symptomatic Patients With Eastern Cooperative Oncology Group Performance Status 0 to 1, and Is Not Indicated for Patients With Hepatic
Metastases or Life Expectancy < 6 Months.
Docetaxel Can Be Used To Treat Patients With Rapid Progression or Asymptomatic Hepatic Metastases, Because Asymptomatic and Symptomatic Patients Experience Survival Benet With Docetaxel.
z
Radium-223 Is Not Approved for Use Combined With CT.
x
For Patients Unable to Receive Docetaxel; However, Although Mitoxantrone Is Included in the NCCN Guidelines, Some Physicians No Longer Consider This Agent As Standard First- or Second-Line CT.
Abbreviations: CT Chemotherapy; HT Hormonal Therapy; mCRPC Metastatic Castration-Resistant Prostate Cancer; NCCN National Comprehensive Cancer Network; RT Radiotherapy.
y

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Steven E. Finkelstein et al
Table 2 Overview of Clinical Trials Evaluating Immunotherapy Combined With Radiation for Prostate Cancer
Citation
Finkelstein et al, 201258

Slovin et al, 201359

Kwon et al, 201460

Design

Treatment

Measurements

Activity

Nonrandomized, open-label
pilot study in 5 men with
localized tumors without
radiologically evident
metastases but with
high risk of recurrence

Twenty-eight months of androgen

Interval biopsies and blood Biopsies showed some apoptosis
suppression, 45 Gy of EBRT,
tests were used to assess
(up to 19% in 11 tumor cores)
intraprostatic DC injection, and
immune reaction
and limited lymphocytic inltrates,
brachytherapy seed placement.
including CD8 cells. Tests on
circulating lymphocytes showed
Autologous DCs were obtained using
some instances of increased titers
single-treatment apheresis and frozen.
to the test peptides
Before reinfusion after radiation
fractions 5, 15, and 25, cells were
thawed and cultured in vitro for 4 days
with GM-CSF and IL-4
Nonrandomized, open-label Comparison of ipilimumab monotherapy
PSA decline and tumor
Among patients who received
phase I/II trial in 71 men
(n 29; 3, 5, or 10 mg/kg given
response
ipilimumab 10 mg/kg with or
with mCRPC with disease
every 3 weeks in a cycle of up to
without EBRT (n 34), 28 had
progression after
4 doses) or ipilimumab (3 or 10 mg/kg)
evaluable tumors. Of these, 8 had
discontinuation of
in combination with EBRT (n 41).
PSA reductions of at least 50%
antiandrogen therapy
EBRT was given as a single dose of
(duration: 3 to 13 months).
and who had received
8 Gy per target bone lesion for up to
There was 1 complete response
no more than 1 previous
3 lesions per patient, 24 to 48 hours
(observed in the EBRT group;
course of chemotherapy
before the rst ipilimumab dose.
duration 11.3 months) and
Patients with disease progression after
6 patients had stable disease.
an initial response (or stable disease)
PSA changes were seen
could have up to 3 further ipilimumab
irrespective of previous
cycles, but no further EBRT
chemotherapy
Multicenter, randomized,
Patients were randomized to receive
Overall survival
Median overall survival was 11.2
double-blind, phase III
bone-directed radiotherapy (8 Gy in
months with ipilimumab and 10.0
trial in men with mCRPC 1 fraction) followed by either ipilimumab
months with placebo (HR, 0.85;
who had progressed after 10 mg/kg or placebo every 3 weeks for
95% CI, 0.72-1.00; P .053).
docetaxel treatment
up to 4 doses
Prespecied analyses suggested
that ipilimumab might benet
some subgroups, particularly those
with favorable prognostic features

Abbreviations: DC dendritic cell; EBRT external beam radiation therapy; GM-CSF granulocyte-macrophage colony-stimulating factor; Gy Gray; HR hazard ratio; IL interleukin;
mCRPC metastatic castration-resistant prostate cancer; PSA prostate-specic antigen.

3 to  13 months, there was 1 complete response (duration

 11.3 months), and 6 had stable disease.59 PSA changes were
seen irrespective of previous chemotherapy.59
However, a randomized phase III study (NCT00861614) in
patients with mCRPC whose disease had progressed after docetaxel
chemotherapy failed to show improved overall survival when ipilimumab was administered after radiotherapy compared with placebo
(Table 2).60 Future studies might also consider the combination of
radiotherapy and interferon, which has showed some promise in the
treatment of melanoma.66

Conclusion
The aim of cancer immunotherapy is to overcome the problem
of weak immunogenicity of tumor-associated antigenic material
and to provoke a robust immune response to cancer cells.
Conventionally, radiation has been perceived as immunosuppressive, but recent experimental work shows that this is not necessarily
the case and radiotherapy can in fact have a variety of immunostimulatory effects. Emerging data thus show the potential for
radiotherapy to work synergistically with immunotherapy to
enhance antitumor immune responses, inhibit immunosuppression, and/or alter tumor cell phenotype to increase their susceptibility to immune-mediated killing.45
The coordination of focal tumor irradiation and immunotherapy has the potential to maximize the benet of both treatments in patients with prostate and other tumors. Augmentation

of antitumor immune responses appears to be a logical and

promising approach, and the small-scale studies of radiotherapy
in combination with immunotherapy that have been carried
out to date support this view. mCRPC is one of few tumor
types in which immunotherapy is the current standard of care,57
and developments in combination therapy appear to be a logical
route toward future improvements in outlook for affected
patients.
Questions remain as to how best to exploit the full potential of
combination therapy. There might be variations in tumor microenvironment, phenotype, and response brought about by differing
types of radiotherapy, and certain dosages and courses of radiotherapy might be more benecial than others.45 There is also a
possibility that combination therapy might result in an increase in
the local control rate of prostate cancer; however, further studies are
required to clarify this. Optimization of the sequence and timing of
treatments should also assist with maximizing the efcacy of radiation combined with immunotherapy.57 The results of ongoing
studies investigating combinations of immunotherapies, such as
sipuleucel-T or nivolumab, after radiotherapy for the treatment of
prostate cancer are eagerly awaited.

Acknowledgments
Medical writing assistance was provided by Zaavan Baildon and
Chris Dunn (Gardiner-Caldwell Communications, Maccleseld,

Clinical Genitourinary Cancer February 2015

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Immunotherapy and Radiotherapy for Prostate Cancer

United Kingdom) and was funded by Dendreon Corporation. The
authors remain accountable for all aspects of the work and
contributed to the conception/design of the report or the analysis/
interpretation of data, critically revised the manuscript for important
intellectual content, and approved the nal version for submission.

Disclosure
Steven E. Finkelstein reports speaker bureau for Dendreon,
Bayer, Algeta, Medivation, and Spectrum, and advisory boards for
Bayer, Algeta, Dendreon, and Spectrum. Neal D. Shore reports
consultancy for Bayer, Janssen, Medivation, Astellas, Dendreon,
Millenium, and Sano. Todd DeVries is an employee and shareholder at Dendreon. Robert Sims was an employee (during the
drafting of this report) and is a shareholder at Dendreon. The
remaining authors have stated that they have no conicts of interest.

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