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Review

Combining Immunotherapy and Radiationfor Prostate Cancer*

Steven E. Finkelstein,

1

Sharon Salenius,

2

Constantine A. Mantz,

2

Neal D. Shore,

3

Eduardo B. Fernandez,2 Jesse Shulman,1 FranciscoA. Myslicki,1 Andre M. Agassi,1

Yosef Rotterman,1 Todd DeVries,4 Robert Sims4

AbstractRadiotherapy 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 reviewthis 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 immunostimu-

latoryeffects,and that tumor cell death,coupled with relatedchanges in antigen availabilityand in

ammatory signals, canaffect 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

IntroductionRadiotherapy has historically been thought of as immunosup-

pressive and therefore not appropriate for combination with treat-ments 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 immunostimula-

tory. 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

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 theImmune System

The accepted rationale for using radiotherapy in cancer is under-

pinned 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

minimizingtoxic effects on normal tissue around thetreatmenteld.1,2

Inevitably, irradiation of living tissue involves damage to that

tissue, whether it is tumor tissue, normal host stroma, normalhost parenchyma, or leukocytes.1 The attenuation of lymphocyte

numbers by radiotherapy, as previously reported in patients un-

dergoing 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 hemato-

logic malignancies), who experience prolonged pancytopenia.5

Studies have described reductions in numbers of T, B, and

*This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

121st Century Oncology Translational Research Consortium, Scottsdale, AZ221st Century Oncology Translational Research Consortium, Fort Myers, FL3Carolina Urologic Research Center, 21st Century Oncology, Myrtle Beach, SC4Dendreon Corporation, Seattle, WA

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 OncologyTranslational Research Consortium (TRC), 7340 E Thomas Rd, Scottsdale,

AZ 85251Fax: 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 Clinical Genitourinary Cancer February 2015 - 1

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natural killer (NK) cells, apoptosis or alteration of antigen-

presenting cells (APCs), including dendritic cells (DCs) and mac-

rophages, 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 neo-

plasms.3,4 Similarly, studies on radiotherapy in patients with stage I

to III breast cancer have shown lymphopenia, low functional ac-tivity of NK cells, decreased monocyte phagocytosis, and decreased

tumor necrosis factor (TNF)-a production.7

Observations such as these have contributed to the conven-

tional 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 contribu-

tions and reactions of systemic and locoregional cell populations

and the differing effects of dose and delivery methods might in-

uence 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) sig-

naling pathway. The resultant damage-associated molecular

patterns (apoptotic and necrotic cellular debris) can generate

antigen-specic immunity through DC maturation and presen-

tation of DC-processed antigen to T cells.9

Activation of the SAPK/JNK signaling pathway and the pres-

ence of damage-associated molecular patterns might also be partly

responsible for other immunological effects seen after radio-

therapy.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 in-

terferons.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, co-

stimulatory molecules, adhesion molecules (such as intercellular

Figure 1 Radiation Effects on Immune Cells and Consequent Modulation by Radiotherapy.9 Apoptosis Can Be Initiated by Radiation-Induced 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 PKRExpression, Which in Turn Induces MHC and Cytokines via NF-kB. Radiation Treatment Induces Cellular Expression of MHCClass I, Adhesion Molecules, Co-Stimulatory Molecules, Heat Shock Proteins, Inammatory Mediators, ImmunomodulatoryCytokines, and Death Receptors

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

Immunotherapy and Radiotherapy for Prostate Cancer

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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 ef-

fect of radiation on tumors has been reported, in which radio-

therapy modies the phenotype of tumor cells to render them

more susceptible to vaccine-mediated T-cell killing.12 As a com-

bined 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 someof the components of the immune system is described in the

following sections.

Effects of Radiation Therapy on White Blood Cell Countsin 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 differ-

ential data on prospectively collected blood samples. CBC data

were collected before radiotherapy and at up to 4 time pointsthereafter (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,

median WBC and then ALC increased gradually to 5800 and 1250

cells/mL, respectively, approximately 6 to 12 months after radio-

therapy (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, immu-

notherapy requires an active immune system, and the stability of cell

Table 1 White Blood Cell Count (WBC) andAbsolute Lymphocyte Counts (ALC) at Baseline and After Radiotherapy in 26 Patients WithAdenocarcinoma of the Prostate13

Parameter Statistic Baseline

Days After Radiotherapy

1-90 91-180 181-360 >360

WBC, Cells/mL n 26 18 13 21 20

Mean 6527 5806 6362 6038 6085

Median 6050 5350 6000 5800 5200

Minimum 4000 3500 3500 3400 4400

Maximum 10,100 13,100 11,000 13,100 10,000

ALC, Cells/mL n 21 11 9 10 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.

Figure 2 Median Baseline andSubsequent Cell Counts AfterRadiation Therapy.13 (A) White Blood Cell (WBC)Counts; (B) Absolute Lymphocyte Counts (ALC)

A

B

Abbreviation: AUC Area Under the Curve.

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and destroy tumor cells.34 In addition, tumor cells can be pheno-

typically 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 mightsupport 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 stim-

ulant 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 possi-

bilities for rening radiotherapy techniques so that they favor

stimulant effects.

Combination of Radiotherapy andImmunotherapy for ProstateCancer

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 CancerNew ndings are constantly being made in animal models of

oncology immunotherapy, and these often have important impli-

cations 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 tar-

gets 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 mini-mally symptomatic metastatic castration-resistant prostate cancer

(mCRPC)50 and by the European Medicines Agency for asymp-

tomatic or minimally symptomatic metastatic (nonvisceral)

castration-resistant prostate cancer in male adults in whom

chemotherapy was not yet clinically indicated.51 Approval was pri-

marily 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, 0.61-

0.98; 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 ofrst-line immunotherapy with sipuleucel-T in

men with mCRPC and good performance status (category 1;

Figure 3). The guidelines also emphasize the importance of radio-

therapy for patients with high-risk localized tumors, and clinical

practice has shown the value of EBRT and stereotactic body radi-ation 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 TherapyNotably, 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 inl-

tration. 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 dif-

culty in targeting a tumor using biopsies (the organ rather thanthe tumor is targeted), and it therefore appears that the identi-

cation 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 inter-

feron-g-producing cells by enzyme-linked immunosorbent spot.

Tests showed a detectable increase from baseline in prostate-

specic 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 sipuleucel-

T 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 administra-

tion (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

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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 TestPositive 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 HepaticMetastases or Life Expectancy

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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 ipili-

mumab 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

ConclusionThe 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 immunosuppres-

sive, but recent experimental work shows that this is not necessarily

the case and radiotherapy can in fact have a variety of immunos-

timulatory effects. Emerging data thus show the potential for

radiotherapy to work synergistically with immunotherapy to

enhance antitumor immune responses, inhibit immunosuppres-

sion, and/or alter tumor cell phenotype to increase their suscep-

tibility to immune-mediated killing.45

The coordination of focal tumor irradiation and immuno-

therapy has the potential to maximize the benet of both treat-

ments 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 carriedout 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 micro-

environment, phenotype, and response brought about by differing

types of radiotherapy, and certain dosages and courses of radio-

therapy 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 arerequired to clarify this. Optimization of the sequence and timing of

treatments should also assist with maximizing the efcacy of radi-

ation 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.

AcknowledgmentsMedical writing assistance was provided by Zaavan Baildon and

Chris Dunn (Gardiner-Caldwell Communications, Maccleseld,

Table 2 Overview of Clinical Trials Evaluating Immunotherapy Combined With Radiation for Prostate Cancer

Citation Design Treatment Measurements Activity

Finkelstein et al, 201258 Nonrandomized, open-label

pilot study in 5 men withlocalized tumors without

radiologically evidentmetastases but with

high risk of recurrence

Twenty-eight months of androgensuppression, 45 Gy of EBRT,

intraprostatic DC injection, andbrachytherapy seed placement.

Autologous DCs were obtained usingsingle-treatment apheresis and frozen.

Before reinfusion after radiationfractions 5, 15, and 25, cells were

thawed and cultured in vitro for 4 dayswith GM-CSF and IL-4

Interval biopsies and bloodtests were used to assess

immune reaction

Biopsies showed some apoptosis(up to 19% in 11 tumor cores)

and limited lymphocytic inltrates,including CD8 cells. Tests oncirculating lymphocytes showed

some instances of increased titersto the test peptides

Slovin et al, 201359 Nonrandomized, open-label

phase I/II trial in 71 menwith mCRPC with disease

progression afterdiscontinuation of

antiandrogen therapyand who had received

no more than 1 previouscourse of chemotherapy

Comparison of ipilimumab monotherapy(n 29; 3, 5, or 10 mg/kg givenevery 3 weeks in a cycle of up to

4 doses) or ipilimumab (3 or 10 mg/kg)in combination with EBRT (n 41).EBRT was given as a single dose of

8 Gy per target bone lesion for up to3 lesions per patient, 24 to 48 hours

before the rst ipilimumab dose.Patients with disease progression afteran initial response (or stable disease)could have up to 3 further ipilimumab

cycles, but no further EBRT

PSA decline and tumorresponse

Among patients who receivedipilimumab 10 mg/kg with or

without EBRT (n 34), 28 hadevaluable tumors. Of these, 8 had

PSA reductions of at least 50%(duration: 3 to 13 months).

There was 1 complete response(observed in the EBRT group;duration 11.3 months) and

6 patients had stable disease.PSA changes were seenirrespective of previous

chemotherapy

Kwon et al, 201460 Multicenter, randomized,double-blind, phase III

trial in men with mCRPCwho had progressed after

docetaxel treatment

Patients were randomized to receivebone-directed radiotherapy (8 Gy in

1 fraction) followed by either ipilimumab10 mg/kg or placebo every 3 weeks for

up to 4 doses

Overall survival Median overall survival was 11.2months with ipilimumab and 10.0months with placebo (HR, 0.85;95% CI, 0.72-1.00; P .053).Prespecied analyses suggested

that ipilimumab might benetsome subgroups, particularly thosewith 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.

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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.

DisclosureSteven E. Finkelstein reports speaker bureau for Dendreon,

Bayer, Algeta, Medivation, and Spectrum, and advisory boards forBayer, Algeta, Dendreon, and Spectrum. Neal D. Shore reports

consultancy for Bayer, Janssen, Medivation, Astellas, Dendreon,

Millenium, and Sano. Todd DeVries is an employee and share-

holder 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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