A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival—with substantially limited side effects compared with chemotherapy—in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well. Clin Cancer Res; 17(12); 3884–91. ©2011 AACR.

Until recently, chemotherapy was the only treatment that had been shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). However, in the last decade, a better understanding of the immune system, combined with innovative treatment approaches, has led to promising improvements in OS, as well as approval by the Food and Drug Administration (FDA) of the first therapeutic anticancer vaccine, sipuleucel-T (Provenge; Dendreon Corp.). Sipuleucel-T is an autologous cellular product in which antigen-presenting cells, obtained by leukapheresis, are enriched and pulsed with a granulocyte macrophage colony-stimulating factor (GM-CSF)/prostatic acid phosphatase (PAP) fusion protein (Fig. 1) (1–3). This product is then administered 3 times over a period of 1 month. Early studies with sipuleucel-T showed no statistically significant improvements in time to progression (primary endpoint); however, improvements were seen in OS (1, 2). On the basis of improvements in OS seen in a 512-patient randomized, double-blinded, controlled, phase III IMPACT trial (25.8 versus 21.7 months, hazard ratio [HR] = 0.775, P = 0.032), the FDA approved sipuleucel-T for use in men with asymptomatic or minimally symptomatic mCRPC (4). It remains unclear why this approach succeeded where other cancer vaccines, in several disease settings, had previously failed. One factor that may have contributed to the success of the IMPACT trial is that trials of sipuleucel-T have generally enrolled asymptomatic or minimally symptomatic patients, an earlier-stage patient population that may be more amenable to immunotherapy, as discussed below. Another important factor may be that the control arm was treated with a placebo vaccine, in contrast to the VITAL-1 trial of the GVAX vaccine, in which the comparator arm was treated with standard chemotherapy. A placebo-controlled trial design for this patient population is reasonable, because there are no data suggesting that earlier use of chemotherapy is more effective. It is also possible that the difference in median predicted survival (by a validated nomogram [5]) of 16 months for VITAL-1 versus 21 months for the IMPACT study, possibly due to the relative reluctance of patients to be randomized to chemotherapy (6), affected trial outcomes, with a survival signal seen only in the earlier-stage patient population. Finally, as discussed below, OS may be a more appropriate endpoint in clinical trials designed for immunotherapy.

Figure 1.

Current immunotherapy approaches for prostate cancer. A, sipuleucel-T. This immunotherapy is made individually for each patient. Cells obtained by leukapheresis are sent to a central facility for processing and manufacture. Monocytes are prepared from the apheresis product and subsequently cultured with a proprietary protein cassette that couples the vaccine target (PAP) to GM-CSF. This process produces an active cellular immunotherapy product that is then shipped to the administering physician's office for i.v. infusion. This process is repeated 3 times over a 4- to 6-week period. B, PROSTVAC-VF. This agent includes plasmid DNA encoding 3 costimulatory molecules, as well as PSA as a vaccine target. Plasmid DNA is incorporated into either vaccinia or fowlpox viruses by means of a packing cell line. Patients are treated with a vaccinia prime followed by a series of fowlpox-based boosts, all given s.c. C, Anti-CTLA-4. This approach is based on the finding that interactions between B7 molecules on antigen-presenting cells and CTLA-4 on tumor-specific T cells are inhibitory. Thus, CTLA-4 engagement negatively regulates the proliferation and function of such T cells. Under certain conditions, blocking CTLA-4 with a monoclonal antibody (ipilimumab or tremilimumab) restores T-cell function. Figure adapted from Drake (55).

Figure 1.

Current immunotherapy approaches for prostate cancer. A, sipuleucel-T. This immunotherapy is made individually for each patient. Cells obtained by leukapheresis are sent to a central facility for processing and manufacture. Monocytes are prepared from the apheresis product and subsequently cultured with a proprietary protein cassette that couples the vaccine target (PAP) to GM-CSF. This process produces an active cellular immunotherapy product that is then shipped to the administering physician's office for i.v. infusion. This process is repeated 3 times over a 4- to 6-week period. B, PROSTVAC-VF. This agent includes plasmid DNA encoding 3 costimulatory molecules, as well as PSA as a vaccine target. Plasmid DNA is incorporated into either vaccinia or fowlpox viruses by means of a packing cell line. Patients are treated with a vaccinia prime followed by a series of fowlpox-based boosts, all given s.c. C, Anti-CTLA-4. This approach is based on the finding that interactions between B7 molecules on antigen-presenting cells and CTLA-4 on tumor-specific T cells are inhibitory. Thus, CTLA-4 engagement negatively regulates the proliferation and function of such T cells. Under certain conditions, blocking CTLA-4 with a monoclonal antibody (ipilimumab or tremilimumab) restores T-cell function. Figure adapted from Drake (55).

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Another recent and important study (7, 8) tested an off-the-shelf vaccine that was developed at the National Cancer Institute and is composed of poxviral vectors (vaccinia prime with fowlpox boost) containing prostate-specific antigen (PSA) and 3 human T-cell costimulatory molecules known as PSA-TRICOM (PROSTVAC; Bavarian Nordic Immunotherapeutics). In this multicenter randomized, double-blinded, controlled, phase II study, men with minimally symptomatic or asymptomatic mCRPC (n = 125) who were treated with PSA-TRICOM had a 44% reduction in death rate (P = 0.006) and an 8.5-month improvement in median OS compared with patients treated with wild-type poxviral vectors (9). This hypothesis-generating study paved the way for a global randomized, controlled, phase III OS endpoint trial that is scheduled to start in 2011. It should be noted that the improved OS associated with therapeutic prostate cancer vaccines was not associated with the substantial treatment-related toxicity that is commonly observed with conventional cytotoxic chemotherapy (Table 1).

Table 1.

Comparison of outcomes after therapeutic vaccination compared with standard chemotherapy

Number enrolledStop treatment due to adverse eventProportion of patients with PSA ↓ ≥50%Improvement in median OSaHazard ratioaReduction in death rateaYear FDA- approvedReferences
Phase III data
Docetaxel 1,006 11% 45% 2.4 mo (18.9 vs. 16.5 mo) 0.76 24% 2004 (32)
Sipuleucel-T 516 1.5% 2.6% 4.1 mo (25.8 vs. 21.7 mo) 0.78 22% 2010 (4)
Phase II data (preliminary)
PSA-TRICOM 125 ∼2% 1% 8.5 mo (25.1 vs. 16.6 mo) 0.56 44% NA (9)
Number enrolledStop treatment due to adverse eventProportion of patients with PSA ↓ ≥50%Improvement in median OSaHazard ratioaReduction in death rateaYear FDA- approvedReferences
Phase III data
Docetaxel 1,006 11% 45% 2.4 mo (18.9 vs. 16.5 mo) 0.76 24% 2004 (32)
Sipuleucel-T 516 1.5% 2.6% 4.1 mo (25.8 vs. 21.7 mo) 0.78 22% 2010 (4)
Phase II data (preliminary)
PSA-TRICOM 125 ∼2% 1% 8.5 mo (25.1 vs. 16.6 mo) 0.56 44% NA (9)

aCompared with comparator arm.

NA, not approved.

A third immunotherapeutic modality, ipilimumab, is currently in phase III trials in prostate cancer. This agent differs from the approaches described above in that ipilimumab does not function as a traditional vaccine. Instead, this fully human monoclonal antibody attenuates negative signals provided to T cells through the cell surface molecule CTLA-4, blocking a negative checkpoint (10, 11). Recent phase III data show that ipilimumab prolongs survival in patients with melanoma (12), and 2 phase III OS trials are investigating the activity of ipilimumab in patients with mCRPC. The first trial is combining radiation with either ipilimumab or placebo in the post-docetaxel setting (13), and the second is evaluating the activity of ipilimumab versus placebo in chemotherapy-naïve patients (14). Given the emerging enthusiasm for immunotherapy in prostate cancer, this article provides a timely review of recent advances in the field of immunotherapy for prostate cancer, lessons learned from early successes and failures, and areas requiring further study.

The clinical trials of sipuleucel-T and PSA-TRICOM described above demonstrated a statistically significant and clinically meaningful improvement in OS in patients with mCRPC. However, none of these studies showed an associated improvement in progression-free survival. In the context of traditional cytotoxic therapies, this apparent disconnect at first seems difficult to explain. However, it must be understood that a therapeutic cancer vaccine differs from conventional therapy in several distinct ways. First, its primary target is not the tumor itself but the immune system, which subsequently targets the tumor. It may take weeks to months to mount a clinically significant immune response following vaccination (15). However, a vaccine can lead to the development of long-lived memory cells with the potential to supply continuing immunologic pressure, resulting in a slowing of the tumor's net growth rate. In a tumor, new cells are constantly being produced while other cells are dying. The rate of tumor growth is thus influenced by tumor biology (e.g., formation of new daughter cells) offset by host biology (e.g., loss of tumor cells resulting from antitumor immune response), combined with factors introduced into the tumor environment (e.g., conventional therapies). An effective anticancer immune response may reset the tumor growth equilibrium so that more tumor cells are killed by the immune system. This effect may not translate into objective responses or short-term (within 3–4 months) improvements in progression-free survival, but because this effect may be long-lasting and may be augmented by subsequent therapies (16, 17), improved OS may ultimately ensue. Indeed, recently published data from prostate cancer vaccine trials at the National Cancer Institute support the concept of decreased growth rate following a therapeutic vaccination (18). It is interesting to note that a recently published phase III trial of ipilimumab in metastatic melanoma (12) showed a similar lack of improvement in median progression-free survival but a statistically significant, clinically meaningful improvement in OS, suggesting that this effect may be typical of immunotherapies as a class.

This new understanding of the kinetics of a clinical response after a therapeutic vaccination, coupled with clinical experience showing that OS may be the only endpoint that can be a discriminator of activity in single-agent vaccine studies, poses a dilemma for investigators seeking to accelerate proof-of-concept studies. Because trials with a survival endpoint typically take years to accrue and mature, the ability to identify and validate intermediate endpoints is crucial to facilitate an efficient life cycle of phase II studies in prostate cancer, perhaps especially for immunotherapy studies. Circulating tumor cells (CTC) may be a reasonable biomarker for nonimmunotherapy studies (19); however, the altered kinetics of a clinical response following vaccination may have only a minimal impact on CTCs, at least in the short term. Although research into correlating cellular and humoral immune responses after vaccination with OS is ongoing, data from prospectively designed, controlled studies are currently insufficient to demonstrate the utility of such approaches.

If it is true that resetting the equilibrium of tumor growth rate leads to improved outcome, it follows that the earlier this equilibrium is reset, the greater will be the potential long-term survival benefit (Fig. 2). This concept is supported by data from a recently published phase II clinical trial of PSA-TRICOM (20), in which OS was compared with predicted survival based on a validated nomogram (5). For patients with a predicted survival of <18 months (about 50% of patients), the median OS of vaccine-treated patients exceeded the median predicted survival by about 2 months. However, for patients with a predicted survival of ≥18 months, the median OS of vaccinated patients had not yet been reached and will be ≥16 months longer than predicted. These data strongly support the concept that patients with earlier-stage disease benefit the most from treatment with PSA-TRICOM, and perhaps other immunotherapies as well.

Figure 2.

If therapeutic vaccines can eventually lead to prolonged slowing of tumor growth rate due to continuous immune pressure from an ongoing, dynamic antitumor immune response, then even if tumor growth slows at an identical rate in 2 different patients, the patient who is given the vaccine earlier in the disease course (A) might have a much improved outcome compared with the patient who receives the vaccine later in the disease course (B). Dashed line, disease trajectory if no therapy is given;†, death from cancer.

Figure 2.

If therapeutic vaccines can eventually lead to prolonged slowing of tumor growth rate due to continuous immune pressure from an ongoing, dynamic antitumor immune response, then even if tumor growth slows at an identical rate in 2 different patients, the patient who is given the vaccine earlier in the disease course (A) might have a much improved outcome compared with the patient who receives the vaccine later in the disease course (B). Dashed line, disease trajectory if no therapy is given;†, death from cancer.

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Of interest, the median predicted survival in the IMPACT study and the multicenter PSA-TRICOM study was about 21 months, whereas the VITAL-1 trial comparing an allogeneic whole tumor cell vaccine (genetically engineered to express GM-CSF) and docetaxel had a median predicted survival of 16 months (6). In the latter study, there was a crossover in the curves, with an apparent survival advantage of receiving chemotherapy for patients destined to die earlier but an apparent advantage to receiving vaccine for patients who lived longer. In a retrospective analysis, patients with a predicted survival of ≥18 months showed a trend to improved OS when treated with a cell-based vaccine, compared with treatment with docetaxel. Also of note are the similar Kaplan–Meier curves of OS in these immunotherapy trials (Fig. 3). Multiple controlled studies have shown a delayed separation in the curves, with no evidence of benefit for immunotherapy in the first 6 to 12 months, indicating that the up to 15% to 25% of patients destined to succumb within that period of time gained no benefit from the vaccine (21). These data affected the decision to include only patients with a life expectancy of ≥12 months in the planned phase III trial of PSA-TRICOM.

Figure 3.

OS curves for (A) sipuleucel-T (n = 127; reproduced from Small et al. [1]), (B) sipuleucel-T (n = 516; reproduced from Kantoff et al. [4]), and (C) PSA-TRICOM (n = 125; reproduced from Kantoff et al. [9]). Note that there is no separation in OS curves (vaccine versus control) until 6–12 months after initiation of the trial, suggesting that patients who died within the first 6–12 months had no benefit from the vaccine.

Figure 3.

OS curves for (A) sipuleucel-T (n = 127; reproduced from Small et al. [1]), (B) sipuleucel-T (n = 516; reproduced from Kantoff et al. [4]), and (C) PSA-TRICOM (n = 125; reproduced from Kantoff et al. [9]). Note that there is no separation in OS curves (vaccine versus control) until 6–12 months after initiation of the trial, suggesting that patients who died within the first 6–12 months had no benefit from the vaccine.

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There is also a biological rationale for using therapeutic vaccines earlier in the disease process. Although more than a decade of research has shown that therapeutic vaccines can overcome immunologic tolerance and generate tumor-associated, antigen-specific T cells, in order to be active, these T cells must traffic to, recognize, and remain functional at the tumor site. However, as a tumor mass grows, its microenvironment becomes increasingly hostile to an effective immune response (22). Negative regulatory cytokines such as TGF-β and interleukin (IL)-10, are expressed, making the tumor a haven for regulatory T cells (Tregs) and myeloid-derived suppressor cells. Another immunologically relevant molecule found in tumors is indoleamine 2,3-dioxygenase (IDO), an inducible enzyme involved in tryptophan catabolism. The depletion of tryptophan in tumors by IDO decreases the functionality of effector T cells and causes dendritic cells to become immunosuppressive (23). Tumors also may downregulate MHC molecules, depriving antitumor T cells of a means of recognizing these cells (24). Thus, tumor size may reach a tipping point beyond which therapeutic vaccines may be ineffective as a single modality. It is possible that for larger or more aggressive tumors, combination immunotherapy might be required to achieve an optimal antitumor response.

In clinical oncology, very few metastatic cancers are currently treated with single-agent chemotherapy. Indeed, combination chemotherapy can be curative for patients with testicular cancer and a number of hematologic malignancies. Thus, it seems natural to assume that combination immunotherapy might also hold clinical promise. In this regard, prostate cancer is unique among solid tumors in that initial treatment with androgen ablation is nearly universally successful (25). Surprisingly, androgen ablation is not an immunologically neutral manipulation. Several studies have shown that chemical castration results in a profound influx of activated immune cells into the prostate gland (26, 27), a mitigation of prostate-specific T-cell tolerance (28), and thymic regeneration accompanied by the output of new T-cell specificities (29). Preclinical (30) and clinical (31) studies support this concept, but large-scale clinical testing of combined hormonal/immunotherapeutic approaches in androgen deprivation-naïve patients is complicated by the relatively long time horizon required for a definitive (survival or time to metastasis) endpoint. One solution to this difficulty might be to restrict enrollment to patients with more aggressive disease (e.g., higher Gleason score, more rapid PSA doubling). However, these aggressive tumors may be precisely the subset in which immunotherapy is less likely to be effective.

Because docetaxel chemotherapy every 3 weeks with daily prednisone is currently the standard of care for men with mCRPC (32–34), combinations of chemotherapy and immunotherapy might be considered as well. Patients given lower, more frequent doses of docetaxel (without daily steroids) combined with vaccine have demonstrated an ability to mount an immune response to the vaccine (35). However, studies that combine vaccine ith higher doses of docetaxel are challenged by the lymphodepleting properties of chemotherapy, as well as by standard clinical practice, in which docetaxel is administered with continuous corticosteroids. These immunosuppressive effects may be at least partially offset by the homeostatic proliferation of T cells that occurs after chemotherapy (36), as well as by additional proinflammatory phenomena such as Treg depletion (37, 38), augmentation of vaccine-specific immune responses (39), and antigen release (40). One way to sidestep these issues might be to sequentially combine immunotherapy and chemotherapy by administering immunotherapy before chemotherapy, in part to avoid the immunosuppressive effects of chemotherapy, but also to engender a proinflammatory microenvironment in which tumor-cell destruction by chemotherapy can be augmented by immune-mediated lysis. This approach will be formally evaluated in a recently opened Eastern Cooperative Oncology Group trial (E1809) comparing chemotherapy alone with PSA-TRICOM followed by chemotherapy.

A more innovative approach to combination immunotherapy would be to pair 2 or more immunotherapeutic agents, such as a vaccine to stimulate T-cell proliferation and a checkpoint blocking agent to attenuate negative regulation. In prostate cancer, the immune checkpoint blocking agent anti-CTLA-4 (ipilimumab) has been combined with both PSA-TRICOM (41) and a GM-CSF-secreting whole tumor cell vaccine (GVAX; BioSante Pharmaceuticals). Neither study has been fully reported yet; however, preliminary results are encouraging. Such studies have traditionally used the 2 agents simultaneously, but it is not clear that this approach gives optimal clinical results. In terms of immune checkpoints, recent data suggest that the checkpoint mediated by programmed death (PD)-1 (42) may prove to be an even more suitable target than CTLA-4 for prostate cancer immunotherapy, as the majority of CD8 cells that infiltrate the gland appear to express this target (43). Furthermore, recent clinical studies suggested that PD-1 blockade has a more benign toxicity profile than CTLA-4 blockade (44).

Although OS has been the only endpoint to demonstrate clinical benefit in clinical trials of therapeutic vaccine alone in prostate cancer, it is possible that combination studies of therapeutic vaccines with other modalities may lead to earlier discriminatory endpoints, such as time to progression or PSA response, which could accelerate proof-of-concept (phase II) studies.

With approval of a new class of agents, areas of controversy often emerge. In addition to the notion that immunotherapy approaches can lead to improved OS without quantifiable differences in time to progression, several additional issues regarding sipuleucel-T should be discussed. Perhaps first among these is cost. Sipuleucel-T costs $93,000 per patient for a complete course of treatment (over about 1 month). Compared with the cost of docetaxel infusion, this cost may seem exorbitant. However, if one considers the total costs of docetaxel chemotherapy, including infusion, potential hospitalizations, and the use of growth factors, the overall cost for 6 to 8 months of chemotherapy (a typical treatment course) may approach that of sipuleucel-T ($45,000 to \$60,000; ref. 53.). Of course, this analysis does not take into account the substantially reduced side effects of immunotherapy relative to chemotherapy or the cost of lost work due to multiple scheduled visits and potential hospitalizations. A second issue, as previously discussed, is the impact of age on immune response. To date, the IMPACT study has provided the only appropriate data for evaluating the effect of age on a patient's ability to mount an immune response. In this study, the relative benefit of sipuleucel-T in terms of OS was the same in patients below and above the median age (4). Some investigators have argued that reinfusion of the control arm with only a third of the cells obtained by apheresis (to allow for eventual manufacture of active vaccine for crossover) led to relative immunosuppression in that cohort, which may explain the differences in outcome. However, several facts argue against this notion. First, although up to 50% of circulating lymphocytes may be removed during apheresis, this represents <1% of the total body lymphocyte pool—a clinically and immunologically insignificant percentage (54). In addition, there were no differences in infection rate between the 2 arms, confirming a lack of meaningful immunosuppression in the control arm.

Prostate cancer may seem a surprising choice as the target for the first FDA-approved therapeutic immunotherapy, given the relatively greater amount of investment in immunotherapy for melanoma and renal cell cancer. The approved agent, sipuleucel-T, is generally well tolerated and provides a clinically meaningful survival benefit. However, studies have not reported other short-term indicators of clinical benefit, such as time to progression and PSA responses, and trials of several other agents seem to support the notion that the only reliable endpoint for clinical trials of immunotherapy for prostate cancer is OS. This creates a less than optimal clinical scenario in which a long period of time is required for trials to mature.

Complicating the issue is the generally accepted notion that immunotherapy should be administered early in the disease course, when it is most likely to benefit patients with minimal tumor burden. Current clinical practice reflects these considerations, and immunotherapy is commonly administered prior to cytotoxic chemotherapy. The pending incorporation of novel hormonal therapies into the clinical compendium raises interesting questions regarding the optimal sequencing of immunotherapy and hormonal therapy—questions that are best addressed by appropriate clinical trials. Perhaps the most exciting concept to arise from recent trials is the use of combination immunotherapy, involving either multiple immunologic agents or immunotherapy combined with conventional treatments. Although such trials raise additional questions about sequential versus simultaneous administration, preclinical data overwhelmingly suggest that combination approaches could lead to major advances in clinical benefit.

Dr. Drake has served as a paid consultant for Dendreon and Bristol-Myers Squibb (BMS) and is a co-inventor for a patent licensed to BMS. No potential conflicts of interest were disclosed by Dr. Gulley.

The authors thank Jeffrey Schlom for his insightful comments, and Bonnie L. Casey for her editorial assistance in the preparation of this manuscript.

Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (J.L. Gulley); and National Institutes of Health (R01 CA127153 and 1P50CA58236–15), Patrick C. Walsh Fund, OneInSix Foundation, and Prostate Cancer Foundation (C.G. Drake). C.G. Drake is a Damon Runyon-Lilly Clinical Investigator.

1.
Small
EJ
,
Schellhammer
PF
,
Higano
CS
,
Redfern
CH
,
Nemunaitis
JJ
,
Valone
FH
, et al
Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer
.
J Clin Oncol
2006
;
24
:
3089
94
.
2.
Higano
CS
,
Schellhammer
PF
,
Small
EJ
,
Burch
PA
,
Nemunaitis
J
,
Yuh
L
, et al
Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer
.
Cancer
2009
;
115
:
3670
9
.
3.
R
,
Gulley
J
.
Sipuleucel-T: harbinger of a new age of therapeutics for prostate cancer
.
Expert Rev Vaccines
2010
;
10
:
141
50
.
4.
Kantoff
PW
,
Higano
CS
,
Shore
ND
,
Berger
ER
,
Small
EJ
,
Penson
DF
, et al
Sipuleucel-T immunotherapy for castration-resistant prostate cancer
.
N Engl J Med
2010
;
363
:
411
22
.
5.
Halabi
S
,
Small
EJ
,
Kantoff
PW
,
Kattan
MW
,
Kaplan
EB
,
Dawson
NA
, et al
Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer
.
J Clin Oncol
2003
;
21
:
1232
7
.
6.
RA
,
Mohebtash
M
,
Schlom
J
,
Gulley
JL
.
Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design
.
Expert Opin Biol Ther
2010
;
10
:
19
28
.
7.
RA
,
Arlen
PM
,
Mohebtash
M
,
Hodge
JW
,
Gulley
JL
.
Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer
.
Expert Opin Investig Drugs
2009
;
18
:
1001
11
.
8.
Arlen
PM
,
Skarupa
L
,
Pazdur
M
,
Seetharam
M
,
Tsang
KY
,
Grosenbach
DW
, et al
Clinical safety of a viral vector based prostate cancer vaccine strategy
.
J Urol
2007
;
178
:
1515
20
.
9.
Kantoff
PW
,
Schuetz
TJ
,
Blumenstein
BA
,
Glode
LM
,
Bilhartz
DL
,
Wyand
M
, et al
Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer
.
J Clin Oncol
2010
;
28
:
1099
105
.
10.
D
,
Fong
L
.
.
J Clin Oncol
2005
;
23
:
8926
8
.
11.
Gulley
JL
,
Dahut
WL
.
Future directions in tumor immunotherapy: CTLA4 blockade
.
Nat Clin Pract Oncol
2007
;
4
:
136
7
.
12.
Hodi
FS
,
O'Day
SJ
,
McDermott
DF
,
Weber
RW
,
Sosman
JA
,
Haanen
JB
, et al
Improved survival with ipilimumab in patients with metastatic melanoma
.
N Engl J Med
2010
;
363
:
711
23
.
13.
National Cancer Institute
[homepage on the Internet]
.
Study of immunotherapy to treat advanced prostate cancer
.
Clinical trials
(PDQ) [cited 2010 Dec 31]. Available from:
http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=638738&version=HealthProfessional&protocolsearchid=8522842
14.
National Cancer Institute
[homepage on the Internet]
.
Phase 3 study of immunotherapy to treat advanced prostate cancer
.
Clinical trials
(PDQ) [cited 2010 Dec 31]. Available from:
http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=665475&version=HealthProfessional&protocolsearchid=8522842
15.
Harty
JT
,
VP
.
Shaping and reshaping CD8+ T-cell memory
.
Nat Rev Immunol
2008
;
8
:
107
19
.
16.
Schlom
J
,
Arlen
PM
,
Gulley
JL
.
Cancer vaccines: moving beyond current paradigms
.
Clin Cancer Res
2007
;
13
:
3776
82
.
17.
Gulley
JL
,
RA
,
Arlen
PM
.
Enhancing efficacy of therapeutic vaccinations by combination with other modalities
.
Vaccine
2007
;
25
[Suppl 2]
:
B89
96
.
18.
Stein
WD
,
Gulley
J
,
Schlom
J
,
RA
,
Dahut
W
,
Figg
WD
, et al
Tumor regression and growth rates determined in five intramural NCI prostate cancer trials. The growth rate as an indicator of therapeutic efficacy
.
Clin Cancer Res
2011
;
17
:
907
.
19.
Danila
DC
,
Fleisher
M
,
Scher
HI
.
Circulating tumor cells as biomarkers in prostate cancer
.
Clin Cancer Res
2011
;
17
:
3903
12
.
20.
Gulley
JL
,
Arlen
PM
,
RA
,
Tsang
KY
,
Pazdur
MP
,
Skarupa
L
, et al
Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer
.
Cancer Immunol Immunother
2010
;
59
:
663
74
.
21.
Hoos
A
,
Eggermont
AM
,
Janetzki
S
,
Hodi
FS
,
Ibrahim
R
,
Anderson
A
, et al
Improved endpoints for cancer immunotherapy trials
.
J Natl Cancer Inst
2010
;
102
:
1388
97
.
22.
Drake
CG
,
Jaffee
E
,
Pardoll
DM
.
Mechanisms of immune evasion by tumors
.
2006
;
90
:
51
81
.
23.
Soliman
H
,
Mediavilla-Varela
M
,
Antonia
S
.
Indoleamine 2,3-dioxygenase: is it an immune suppressor?
Cancer J
2010
;
16
:
354
9
.
24.
Chang
CC
,
Ferrone
S
.
Immune selective pressure and HLA class I antigen defects in malignant lesions
.
Cancer Immunol Immunother
2007
;
56
:
227
36
.
25.
SR
,
Isaacs
JT
.
A history of prostate cancer treatment
.
Nat Rev Cancer
2002
;
2
:
389
96
.
26.
M
,
Bodner
BK
,
Moser
MT
,
Kwon
PS
,
Park
ES
,
Manecke
RG
, et al
T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer
.
Proc Natl Acad Sci U S A
2001
;
98
:
14565
70
.
27.
Gannon
PO
,
Poisson
AO
,
Delvoye
N
,
Lapointe
R
,
Mes-Masson
AM
,
F
.
Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients
.
J Immunol Methods
2009
;
348
:
9
17
.
28.
Drake
CG
,
Doody
,
Mihalyo
MA
,
Huang
CT
,
Kelleher
E
,
Ravi
S
, et al
Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen
.
Cancer Cell
2005
;
7
:
239
49
.
29.
Sutherland
JS
,
Goldberg
GL
,
Hammett
MV
,
Uldrich
AP
,
Berzins
SP
,
Heng
TS
, et al
Activation of thymic regeneration in mice and humans following androgen blockade
.
J Immunol
2005
;
175
:
2741
53
.
30.
Koh
YT
,
Gray
A
,
Higgins
SA
,
Hubby
B
,
Kast
WM
.
Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization
.
Prostate
2009
;
69
:
571
84
.
31.
Arlen
PM
,
Gulley
JL
,
Todd
N
,
Lieberman
R
,
Steinberg
SM
,
Morin
S
, et al
Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer
.
J Urol
2005
;
174
:
539
46
.
32.
Tannock
IF
,
de Wit
R
,
Berry
WR
,
Horti
J
,
Pluzanska
A
,
Chi
KN
, et al
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer
.
N Engl J Med
2004
;
351
:
1502
12
.
33.
Petrylak
DP
,
Tangen
CM
,
Hussain
MH
,
Lara
PN
Jr
,
Jones
JA
,
Taplin
ME
, et al
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer
.
N Engl J Med
2004
;
351
:
1513
20
.
34.
RA
,
Pal
SK
,
Sartor
O
,
Dahut
WL
.
Overcoming chemotherapy resistance in prostate cancer
.
Clin Cancer Res
2011
;
17
:
3892
902
.
35.
Arlen
PM
,
Gulley
JL
,
Parker
C
,
Skarupa
L
,
Pazdur
M
,
Panicali
D
, et al
A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer
.
Clin Cancer Res
2006
;
12
:
1260
9
.
36.
Brown
IE
,
Blank
C
,
Kline
J
,
Kacha
AK
,
Gajewski
TF
.
Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection
.
J Immunol
2006
;
177
:
4521
9
.
37.
Machiels
JP
,
Reilly
RT
,
Emens
LA
,
Ercolini
AM
,
Lei
RY
,
Weintraub
D
, et al
Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice
.
Cancer Res
2001
;
61
:
3689
97
.
38.
S
,
Yoshimura
K
,
Hipkiss
EL
,
Harris
TJ
,
Yen
HR
,
Goldberg
MV
, et al
Cyclophosphamide augments antitumor immunity: studies in an autochthonous prostate cancer model
.
Cancer Res
2009
;
69
:
4309
18
.
39.
Garnett
CT
,
Schlom
J
,
Hodge
JW
.
Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement
.
Clin Cancer Res
2008
;
14
:
3536
44
.
40.
Zitvogel
L
,
Apetoh
L
,
Ghiringhelli
F
,
André
F
,
Tesniere
A
,
Kroemer
G
.
The anticancer immune response: indispensable for therapeutic success?
J Clin Invest
2008
;
118
:
1991
2001
.
41.
R
,
Mohebtash
M
,
Arlen
P
,
Vergati
M
,
Steinberg
SM
,
Tsang
KY
, et al
Overall survival (OS) analysis of a phase l trial of a vector-based vaccine (PSA-TRICOM) and ipilimumab (Ipi) in the treatment of metastatic castration-resistant prostate cancer (mCRPC)
.
J Clin Oncol
2010
;
28
:
7s
.
Abstract 2550
.
42.
Chen
L
.
Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity
.
Nat Rev Immunol
2004
;
4
:
336
47
.
43.
Sfanos
KS
,
Bruno
TC
,
Meeker
AK
,
De Marzo
AM
,
Isaacs
WB
,
Drake
CG
.
Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+
.
Prostate
2009
;
69
:
1694
703
.
44.
Brahmer
JR
,
Drake
CG
,
Wollner
I
,
Powderly
JD
,
Picus
J
,
Sharfman
WH
, et al
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates
.
J Clin Oncol
2010
;
28
:
3167
75
.
45.
[homepage on the Internet]
.
Vaccines, blood & biologics: PROVENGE
(sipuleucel-T) [cited 2010 Dec 31]. Available from:
http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm210012.htm
46.
Reid
AH
,
Attard
G
,
Barrie
E
,
de Bono
JS
.
CYP17 inhibition as a hormonal strategy for prostate cancer
.
Nat Clin Pract Urol
2008
;
5
:
610
20
.
47.
Massard
C
,
Fizazi
K
.
Targeting continued androgen receptor signaling in prostate cancer
.
Clin Cancer Res
2011
;
17
:
3876
83
.
48.
Ryan
CJ
,
Smith
MR
,
Fong
L
,
Rosenberg
JE
,
Kantoff
P
,
Raynaud
F
, et al
Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy
.
J Clin Oncol
2010
;
28
:
1481
8
.
49.
Reid
AH
,
Attard
G
,
Danila
DC
,
Oommen
NB
,
Olmos
D
,
Fong
PC
, et al
Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate
.
J Clin Oncol
2010
;
28
:
1489
95
.
50.
Attard
G
,
Reid
AH
,
de Bono
JS
.
Abiraterone acetate is well tolerated without concomitant use of corticosteroids
.
J Clin Oncol
2010
;
28
:
e560
1
;
.
51.
Ryan
CJ
.
Reply to G. Attard et al
.
J Clin Oncol
2010
;
28
:
e562
.
52.
Fairchok
MP
,
Trementozzi
DP
,
Carter
PS
,
Regnery
HL
,
Carter
ER
.
Effect of prednisone on response to influenza virus vaccine in asthmatic children
.
1998
;
152
:
1191
5
.
53.
Fitch
K
,
Pyenson
B
.
Cancer patients receiving chemotherapy: opportunities for better management
.
Milliman Client Report
2010
;
March 30
:
1
27
.
54.
Blum
KS
,
Pabst
R
.
Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs?
Immunol Lett
2007
;
108
:
45
51
.
55.
Drake
CG
.
Prostate cancer as a model for tumour immunotherapy
.
Nat Rev Immunol
2010
;
10
:
580
93
.