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Keywords:

  • prostate;
  • immunotherapy;
  • vaccines;
  • metastatic prostate cancer;
  • sipuleucel;
  • ipilimumab

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vaccines
  5. Antibodies
  6. Discussion
  7. Conflict of Interest
  8. References
  • Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12–24 months. Historically, castration-resistant prostate cancer (CRPC) had been considered a chemoresistant tumour.
  • In 2004, docetaxel received USA Food and Drug Administration approval as a first-line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel-T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium-223 (not suitable for docetaxel or after docetaxel).
  • The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy.
  • Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti-androgen therapy, chemotherapy, or radiotherapy.
  • Here we provide a review of the main important immune treatments in CRPC.

Abbreviations
AE

adverse event

APC

antigen-presenting cell

CD

cluster of differentiation

CTLA-4

cytotoxic T-lymphocyte antigen 4

CRPC

castration-resistant prostate cancer

D+P

docetaxel plus prednisone

ECOG

Eastern Cooperative Oncology Group

FDA

USA Food and Drug Administration

GM-CSF

granulocyte-macrophage colony stimulating factor

HR

hazard ratio

MUC1

mucin 1

OS

overall survival

PAP

prostatic acid phosphatase

PD-1

programmed death 1

PSMA

prostate-specific membrane antigen

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vaccines
  5. Antibodies
  6. Discussion
  7. Conflict of Interest
  8. References

Prostate cancer is the most common cancer diagnosed in men, and it is the second leading cause of cancer death after lung cancer [1]. About 5−10% of patients present with metastatic disease at diagnosis, and another 25% with localised or locally advanced disease will develop metastases during the course of their disease.

Initial therapy for metastatic disease consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that lasts between 12 and 24 months [2, 3]. After this period, the tumour becomes castration resistant and will progress even at undetectable levels of testosterone. Hence, this stage of the disease is now known as castration-resistant prostate cancer (CRPC) instead of hormone-resistant prostate cancer. Historically, CRPC had been considered chemoresistant. This paradigm changed when several studies showed that mitoxantrone-prednisone combined therapy provided a symptomatic benefit in one-third of patients with minimal toxicity [4, 5]. However, none of these studies reported a survival benefit.

In 2004, docetaxel received USA Food and Drug Administration (FDA) approval as a first-line treatment for metastatic prostate cancer. Approval was granted after two independent phase III trials showed an increased survival benefit for patients treated with docetaxel compared with mitoxantrone [6, 7]. Since then, docetaxel has become the standard treatment for patients with metastatic CRPC. Three new drugs, abiraterone [8], cabazitaxel [9] and enzalutamide [10], have been approved by the FDA and European Medical Agency (enzalutamide was under evaluation at the time that this manuscript was prepared) for patients with CRPC, who have been previously treated with docetaxel. In addition, abiraterone has recently shown benefit in the pre-docetaxel setting [11]. These drugs have been approved based on respective phase III trials that showed an increased survival in CRPC after progressing to docetaxel chemotherapy. Moreover, another drug, alpharadin (radium-223 dichloride), has recently shown a survival benefit, and will probably soon be approved by the FDA. This α emitter [12] has been shown to improve survival in patients after docetaxel, but also in those patients not suitable to receive docetaxel as first-line treatment. The assessment of new drugs targeting prostate cancer is hampered by several limitations, including the absence of measurable disease as the main limitation. For this reason, the main endpoint for most studies is overall survival (OS). Although several studies have shown a correlation between PSA response in the first 3 months or symptomatic improvement and survival, at present none of these variables has been accepted as a surrogate endpoint of OS [13-17].

Because the main goal in cancer immunotherapy is to induce an immune response mediated by T lymphocytes specifically against cancer cells, the identification of antigens in normal prostate tissue or prostate cancer, which are recognised by immune effectors cells, has resulted in several new studies based on immunotherapy (Table 1).

Table 1. Completed clinical trials of immunotherapy for patients with metastatic castration-resistant prostate cancer
AgentPhasenSettingTarget antigenPlatformComparison treatmentTime to progressionOS
  1. PMBCs, peripheral blood mononuclear cells.

Sipuleucel-TIII127Asymptomatic metastatic CRPCPAP/GM-CSF fusionCultured autologous PMBCsPlacebo (autologous cells)11.7 vs 10 weeks (HR 1.45, 95% CI 0.99–2.11; P = 0.052)25.9 vs 21.4 months (HR 1.70, 95% CI 1.13–2.56; P = 0.01)
Sipuleucel-TIII512Asymptomatic metastatic CRPCPAP/GM-CSF fusionCultured autologous PMBCsPlacebo (autologous cells)HR 0.951, 95% CI 0.77–1.17; P = 0.62825.8 vs 21.7 months (HR 0.775, 95% CI 0.614–0.974; P = 0.032)
GVAXIII626Asymptomatic metastatic CRPCAllogenic tumour linesGM-CSF transduced cell linesDocetaxel/prednisone20.7 vs 21.7 mo (HR 1.03, 95% CI 0.83–1.28; P = 0.78)
GVAX plus docetaxelIII408Symptomatic metastatic CRPCAllogenic tumour linesGM-CSF transduced cell linesDocetaxel/prednisone12.2 vs 14.1 month (HR 1.70, 95% CI 1.15–2.53; P = 0.008)
PROSTVAC-VFII125Minimally symptomatic metastatic CRPCPSAVaccinia-fowl poxControl Vector3.8 vs 3.7 months (HR 0.884, 95% CI 0.568–1.375; P = 0.6)25.1 vs 16.6 months (HR 0.56, 95% CI 0.37–0.85; P = 0.006)

Prostate cancer provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only biochemical progression), there is a biological marker that can detect relapse early (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti-androgen therapy, chemotherapy, or radiotherapy.

Vaccines

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vaccines
  5. Antibodies
  6. Discussion
  7. Conflict of Interest
  8. References

Sipuleucel-T (APC8015, Provenge)

It is known that dendritic cells, which are antigen-presenting cells (APCs), are frequently deficient in number and function in patients with cancer. Therefore, antigen presentation is an effective method to improve the immune response mediated by T-cells [18].

Sipuleucel-T (Provenge, APC8015) contains mature, autologous APCs. APCs are obtained from the patient via a standard leukapheresis procedure ≈2 days before each scheduled infusion. The patient's APCs are co-cultured with a recombinant fusion protein (PA2024) containing prostatic acid phosphatase (PAP) and granulocyte-macrophage colony stimulating factor (GM-CSF). The activated, antigen-loaded APCs are then re-infused into the patient, where they stimulate a T-cell response against prostate cancer cells. The process is performed three times over the course of a 4-week period (Fig. 1) [19]. Results from phase I and II trials showed an increase in T-cell mediated immune responses against PAP and a 50% decrease in the serum PSA levels with low toxicity in 10% of patients [20-23]. However, this effect on PSA was not confirmed in phase III trials.

figure

Figure 1. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous APCs, with a recombinant protein comprising a tumour-associated antigen (PAP) and GM-CSF.

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Three phase III trials have been conducted with this vaccine in prostate cancer. In the first study (D9901) [24], 127 men with asymptomatic CRPC were randomised (2:1 patient ratio) to receive either sipuleucel-T (82 patients), given as three i.v. infusions every 2 weeks, or placebo (45). The primary endpoint was the time to progression, which was 11.7 weeks in the vaccine group vs 10 weeks in the placebo group (P = 0.052). However, the vaccine produced an immune response and a median survival of 25.9 months compared with 22 months in the placebo group (P = 0.02).

A similar phase III study (D9902A) was initiated, but enrollment was stopped after 98 patients, based on initial results in D9901, and an integrated analysis of D9901 and D9902A was reported [25]. In all, 225 patients were randomised to sipuleucel-T (147 patients) or placebo (78). The results showed a median benefit in OS of 4.3 months for sipuleucel-T (23.2 vs 18.9 months), translating to a 33% reduction in the risk of death [hazard ratio (HR) 1.50, P = 0.011]. In both studies, the vaccine was well tolerated and the most common side-effects were flu-like symptoms. Treatment effect with sipuleucel-T remained a strong predictor of OS after adjustment for prognostic factors.

Finally, the third phase III trial (IMPACT or D9902B) [26] randomly assigned 512 patients to receive either sipuleucel-T (341 patients) or placebo (171) in a 2:1 patient ratio. Unlike previous studies, OS was the primary endpoint. There was a relative reduction of 22% in the risk of death as compared with the placebo group (HR 0.78; P = 0.03), which represents an increase of 4.1 month in the OS for the sipuleucel-T group (25.8 vs 21.7 months). The 36-month survival probability was 31.7% and 23.0% in the sipuleucel-T and placebo groups, respectively. Paradoxically, there was no benefit in the time to disease progression. Common adverse events (AEs) reported in the sipuleucel-T group included chills, fever, and headache. On 29 April 2010, sipuleucel-T was approved by the FDA for the treatment of patients with asymptomatic or minimally symptomatic CRPC.

A recent publication showed a correlation between immune responses assessed by APC numbers, APC activation, total nucleated cell numbers, and antigen-specific T-cell activation and OS in the three randomised, controlled phase III studies [27]. APC activation, determined by cluster of differentiation 54 (CD54) upregulation, was seen after the first sipuleucel-T dose and was further increased in subsequent doses. In addition, immunological response assessed by antigen-specific T-cell proliferation and interferon γ ELISPOT assay against PA2024 was seen in patients receiving sipuleucel-T. Antigen-specific responses were present in most of the treated patients at week 26, indicating persistent specific memory T-cells. These results indicate that sipuleucel induces a robust and lasting immune response, both at the cellular and humoral levels, that positively correlates with survival benefit.

There are several ongoing studies with this vaccine alone, and one combined with bevacizumab.

GVAX

GVAX (Cell Genesys, Inc., SanFrancisco, CA, USA) is a vaccine obtained from prostate cancer cells genetically modified to secrete GM-CSF. Unlike sipuleucel-T, where PAP is the antigen source, GVAX uses whole tumour cells as antigens. Two different cell lines have been used to generate GVAX, PC-3 cells derived from bone metastatic CRPC, and LNCaP cells derived from metastatic nodular CRPC with mutated androgenic receptors. The use of whole cells has been reported to induce antigen presentation in dendritic cells, as well as immune response activation mediated by T-cells and macrophages [28].

GVAX was shown in phase II studies to be immunogenic, clinically active, and generally well tolerated. Studies in patients with CRPC found that GVAX increased the time to progression, and reduced the values of the markers associated with osteoclastic activity.

In an initial trial [29], 55 chemotherapy-naïve patients with CRPC with radiological metastases (34 patients) or elevated PSA levels only (21), received an initial dose of 5 × 108 cells followed by 12 booster doses of either 1 × 108 cells (low-dose) or 3 × 108 cells (high-dose) biweekly for 6 months. Actual median survival was compared with estimated median survival obtained using the Halabi nomogram [30], a pretreatment prognostic model. The metastatic group showed an increased median survival, when compared with predicted values of 26.2 vs 19.5 months, respectively. The median survival for high- and low-dose treatment was 34.9 (10 patients) and 24 months (24), respectively. The median time to bone scan progression was 5.0 months in the high-dose group and 2.8 months in the low-dose group. The rising PSA group received low-dose only, and they reached a median OS of 37.5 months and a median time to bone scan progression of 5.9 months. There were no dose-limiting toxicities. The most common AEs were injection site reactions and fatigue.

Immunogenicity and clinical activity were dose-dependent as reported in another multicenter phase I/II trial [31]. In all, 80 patients with metastatic CRPC were enrolled in a dose-escalation study. Dose levels ranged from 1 × 108 cells for 28 days × 6, to 5 × 108 cells prime, and 3 × 108 cells boost for 14 days × 11. The median OS was 35.0, 20.0, and 23.1 month for the high-, medium-, and low-dose groups, respectively. The median survival time exceeded the Halabi predicted survival time by 13 months in patients receiving high-dose regimens (22 vs 35 months). In patients in the medium- and low-dose level groups, there was a lower benefit (medium-dose, 20 vs 20 months; low-dose, 18 vs 23.1 month). There were similar safety profiles as in the previously discussed study.

These results led to two phase III studies. The first (VITAL-1) [32] compared high-dose GVAX (5 × 108 cells prime/3 × 108 cells boost doses, for 2 weeks × 13 doses) to docetaxel plus prednisone (D+P) in asymptomatic chemotherapy-naïve patients with CRPC. The study was prematurely terminated based on the results of a previously unplanned futility analysis, which determined that the study had a <30% chance of meeting its predefined primary endpoint of improvement in OS. The median survival was 20.7 months in the GVAX group and 21.7 months in the D+P group, but these differences were not statistically significant. However, the group of patients who received GVAX had a tendency to improved survival after 22 months, suggesting that immunotherapy may especially benefit patients with an expected survival of >18 months.

The second phase III trial (VITAL-2) [33] compared D+P to docetaxel-GVAX in symptomatic taxane-naïve patients with CRPC. The study was designed to enroll 600 patients, but was prematurely terminated after performing a futility analysis after accrual of 408 patients. Results from a non-preplanned interim analysis done after the futility analysis, showed a higher survival in the standard treatment group due to an excess of deaths in the GVAX group, 76 deaths in the D+P group vs 85 in the docetaxel-GVAX group (HR 1.4; P = 0.02).

Several ongoing trials with different schedules of GVAX alone are in progress in order to optimise the efficacy. In addition, GVAX is being evaluated combined with other drugs to potentiate synergistic immunomodulatory effects.

PROSTVAC-VF Vaccine (PSA-TRICOM)

Immunotherapy using viral vectors is intended to mediate a controlled natural infection to promote a targeted (controlled) anti-tumour immune response.

Vaccination using whole viruses presents several advantages, such as the inherent immunogenicity of the virus and high levels of gene expression. Poxviruses are a family of double-stranded DNA viruses that have been extensively explored for tumour and cancer vaccinations in preclinical models.

PROSTVAC-VF [34] is a recombinant vaccine based on the vaccinia virus and a fowlpox virus encoding human PSA and three co-stimulatory agents, lymphocyte function-associated antigen 3 (LFA-3), intercellular adhesion molecule 1 (ICAM-1), and B7-1. Both vaccines infect APCs, resulting in expression of proteins on the surface of APCs. The interaction of transduced APCs with T-cells promotes a targeted immune response and T-cell-mediated tumour cell destruction. This vaccine successfully showed immunological activity with a low toxicity profile in several phase I trials [35-37]. These positive results encouraged further assessment of this product in several phase II studies.

The Eastern Cooperative Oncology Group (ECOG) published a phase II study evaluating the response to vaccinations in 64 patients with biochemical progression after local therapy and different schedules [38]. The primary endpoint was PSA response at 6 months. At 19 months, 45.3% of the patients were free of PSA progression and overall time to PSA progression was 13.6 months. The most common AEs were injection site reaction and hyperglycaemia, and the treatment was associated with minimal toxicity.

A phase II study [39], based on the same population, included 50 patients. At the time the results were presented only 29 patients were evaluated. In all, 66% of patients were free of PSA progression at 6 months (primary endpoint).

A phase II trial analysed the effect of PSA-TRICOM with or without GM-CSF in 32 chemotherapy-naïve patients with metastatic CRPC [40]. In all, 12 of 32 patients had a PSA decline (37.5%) and 22 of 32 patients had a longer survival compared with those predicted based on the Halabi score.

Finally, a randomised double-blind phase II trial was conducted in 125 men with asymptomatic CRPC [41]. Similar to the sipuleucel-T phase III study, the primary endpoint, progression-free survival, was not met (3.8 months in the PROSTVAC group and 3.7 months in the control group), but the treatment was associated with a 44% reduction in the risk of death and a 8.5 months improvement in median OS (25.1 vs 16.6 months).

A randomised phase III trial of PROSTVAC-V/F +/– GM-CSF in asymptomatic or minimally symptomatic CRPC is currently ongoing (NCT01322490).

TG4010

Mucinous glycoprotein mucin 1 (MUC1) is overexpressed in most epithelial cancers. In prostate tumours, overexpression of MUC1 can be as high as 60–90%, which makes it an interesting target for vaccine immunotherapy.

Modified vaccinia Ankara (MVA)-MUC1-interleukin 2 (TG4010) is a recombinant MVA viral vector encoding MUC1 and interleukin 2, which has been shown in phase I trials to be safe [42, 43]. It has not been investigated in CRPC, but was assessed in a randomised phase II study in patients with PSA progression after local treatment and a PSA doubling time of <10 months [44]. The primary endpoint was the rate of objective response, defined as a decrease of 50% in the 40 patients that were included. The primary endpoint was not achieved because none of the patients showed a 50% decline in PSA. However, 10 patients had stabilised PSA for >8 months.

Antibodies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vaccines
  5. Antibodies
  6. Discussion
  7. Conflict of Interest
  8. References

Ipilimumab (Anti-cytotoxic T-lymphocyte Antigen 4 [CTLA-4], MDX-010)

T-cell activation depends on the ability of T-cell receptors to recognise antigenic peptides expressed by APCs, such as dendritic cells. Two receptors, CD28 and CTLA-4, expressed on the surface of T-cells are responsible for ligand recognition and regulation of activation. While ligand binding to CD28 may stimulate T-cells, the interaction between CTLA-4 and the ligand may inhibit stimulation of T-cells [45]. CTLA-4 binds B7.1 and B7.2 (expressed on APC) and mediates negative signalling, which triggers inhibition of T-cell activity

The hypothesis relies on the use of an antibody to prevent interaction between CTLA-4 and its ligands, to enhance the immune response against these antigens. Therefore, blocking CTLA-4 represents a possible mechanism to enhance stimulation of T-cells and consequently boost the response against the tumour cells (Fig. 2).

figure

Figure 2. Ipilimumab mechanism of action. TCR, T-cell receptor; MHC, major histocompatibility complex.

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Ipilimumab is a human anti-CTLA-4 monoclonal antibody. In a phase I trial [46] of ipilimumab, 14 patients with CRPC (50% had previously received chemotherapy) were treated with a single infusion of 3 mg/kg ipilimumab. Two patients had a PSA decline of ≥50% that lasted 135 and 60 days. Ipilimumab was generally well tolerated, except from one patient who developed grade 3 rash/pruritis requiring systemic corticosteroids. Most common AEs were arthralgia, malaise, bone pain, pallor, back pain, constipation, fatigue, and decreased appetite.

In a phase II study [47], the combination of ipilimumab with docetaxel was tested. In all, 43 patients were treated with ipilimumab at 3 mg/kg for 4 weeks × 4 doses (23 patients or ipilimumab at the same dose and a single dose of docetaxel 75 mg/m2 on day 1, 20 patients). PSA responses were observed in six patients (three in each group). The most common AEs were fatigue, pruritus, nausea, rash, constipation, and weight loss. In all, there were 52 serious AEs in 18 patients; five of these 52 seroius AEs, reported in three patients, were considered to be related to ipilimumab treatment. These included adrenal insufficiency (one), diarrhoea, colitis and melena (all in one patient), and colitis (one).

A phase I dose-escalation trial [48] evaluated ipilimumab-GVAX in patients with metastatic CRPC. PSA responses of >50% were seen in seven of 28(25%) patients. The most common AEs were injection-site reactions, fatigue, and pyrexia. Two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis.

Another phase I trial [49] tested the PROSTVAC-ipilimumab combination and this combination did not seem to exacerbate the immune-related AEs associated with ipilimumab. Grade 3 toxicities included hepatitis, adrenal insufficiency, alveolitis, and hypophysitis. However, the maximum tolerated dose was not determined.

The addition of radiotherapy as a potential immune enhancer to improve clinical responses to ipilimumab has also been reported, in phase I and II trials, to be well tolerated [50, 51]. A randomised double-blind phase III trial comparing ipilimumab vs placebo after radiotherapy in patients with CRPC, who received prior treatment with docetaxel, has just finished the recruitment phase [52]. In most of these studies, immune-related AEs seemed to correlate with anti-tumour activity.

Prostate-specific Membrane Antigen (PSMA) and Antibodies (J5091)

PSMA is a glycoprotein that is expressed on the membrane cell surface of both normal and prostate tumour tissue [53, 54]. It has been reported that PSMA is upregulated after androgen-deprivation therapy [55].

J591 is a monoclonal antibody that binds to the external domain of PSMA, and has been used combined with radionuclei for therapeutic purposes. After a phase I trial [56] of lutetium-177-labelled J591 (177Lu-J591) that reported biological activity in four patients with a duration ranging from 3 to 8 months, the same group presented a phase II study [57] with 30 patients, where 18 (60%) patients had progressed to docetaxel chemotherapy. There was a decline of >50% and 30% in PSA in 10% and 30% of patients, respectively. The most common AE was thrombocytopenia.

A randomised 2:1 double-blind phase II trial [58] in patients with high-risk CRPC (PSA doubling time of <8 months, and/or PSA level of >20 ng/mL) and rising PSA, is currently ongoing. The primary endpoint is 18-month metastasis-free survival.

In a phase I trial of yttrium-90-labelled J591 (90Y-J591) [59], there was anti-tumour activity in two patients, who had 85% and 70% PSA declines with a duration of 8 and 8.6 months, respectively. These PSA declines were associated with objective responses. Thrombocytopenia was the dose-limiting toxicity.

Anti-programmed Death 1 (PD-1; MDX-1106/BMS-936558/ONO-4538)

PD-1 is an inhibitory co-receptor expressed on antigen-activated T- and B-cells [60]. MDX-1106, a human monoclonal antibody that blocks PD-1, has been tested in phase I trials. A maximum tolerated dose was not defined. The most common treatment-related AEs were fatigue, rash, diarrhoea, pruritus, and nausea. Drug-related AEs with potential immune-related causes included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis and thyroiditis. There were no responses in the 17 patients with prostate cancer [61].

Several studies are currently ongoing with all of these drugs in different settings (Table 2).

Table 2. On-going clinical trials of immunotherapy for patients with metastatic castration-resistant prostate cancer
AgentPhasenTarget antigenComparison treatmentPrimary endpointClinicalTrials.gov Identifier (accessed 19 November 2012)Status
Ipilimumab       
Ipilimumab plus GM-SCFII54CTLA-4IpilimumabPSA responseNCT01530984Not yet recruiting
Ipilimumab plus GVAXI28CTLA-4SafetyNCT01510288Terminated
Ipilimumab plus abiraterone/prednisoneI/II25CTLA-4Safety/efficacyNCT01688492Recruiting
IplimumabI/II66CTLA-4Safety/efficacyNCT00323882Active, not recruiting
Ipilimumab plus sargamostimI36CTLA-4SafetyNCT00064129Active, not recruiting
IpilimumabIII600CTLA-4PlaceboOSNCT01057810Active, not recruiting
IpilimumabII CTLA-4Ipilimumab plus docetaxelSafety/efficacyNCT00050596Completed
Radiotherapy plus placeboIII800CTLA-4Radiotherapy plus placeboOSNCT00861614Active, not recruiting
Ipilimumab plus PROSTVACI30

CTLA-4

PSA

SafetyNCT00113984Completed
PROSTVAC       
PROSTVACI75PSASafetyNCT00001382Completed
PROSTVAC plus docetaxel/prednisoneII144PSADocetaxel/prednisoneOSNCT01145508Active, not recruiting
PROSTVAC plus GM-CSFIII1200PSAPROSTVAC plus placebo or placebo plus placeboOSNCT01322490Recruiting
Sipuleucel T       
Sipuleucel-T plus abirateroneII60APC8015Safety/efficacyNCT01487863Recruting
Sipuleucel-T plus IndoximodII50APC8015Sipuleucel T plus placeboSafety/efficacyNCT01560923Recruting
Sipuleucel-TII45APC8015Product manufacturedNCT01477749Recruting
Sipuleucel-TII80APC8015Immune responsesNCT00901342Active, not recruiting
Sipuleucel-TII90APC8015Safety/efficacyNCT01338012Recruting
Sipuleucel-T plus DNA vaccineII30APC8015Sipuleucel-TEfficacyNCT01706458Recruting
Sipuleucel-T (differing antigen concentrations)II120APC8015Sipuleucel-TSafety/efficacyNCT00715078Active, not recruiting
Sipuleucel-T plus low-dose cyclophosphamide ± anti PD-1 monoclonal antibodiesII57

APC8015

PD-1

Sipuleucel-TSafetyNCT01420965Recruting
GVAX       
GVAX plus ipilimumabI28CTLA-4EfficacyNCT01510288Terminated

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vaccines
  5. Antibodies
  6. Discussion
  7. Conflict of Interest
  8. References

Although immunotherapy provides possible new treatments for CRPC, many aspects of this approach remain unclear. One of the most important issues is the lack of correlation between response to treatments, as measured by the usual parameters, and the impact of the treatments on OS. Progression-free survival or PSA decline have not been shown to be appropriate predictors of OS, as evidenced in the sipuleucel-T [26] and PROSTVAC-VF [41] studies. This reflects an obvious weak point of the development of clinical studies and the need to adapt such studies to the immunotherapy paradigm. To address the different characteristics of the clinical evaluation of immunotherapy, it is necessary to establish methods to measure the immune response, identify reliable surrogate biomarkers, improve study designs and distinguish new response criteria. In this direction, an important challenge is the radiological evaluation of response. Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, which have been traditionally used to evaluate the reduction of tumour burden for cytotoxic therapies, do not seem to be completely reliable in assessing these therapies. In contrast to cytotoxic agents, which induce early tumour shrinkage, stable disease or even increased tumour size at initial evaluation followed by subsequent tumour regression was reported in certain studies [62, 63].

It is likely that these limitations, which limit the scope of immunotherapeutic treatments, have been involved in some of the negative outcomes of these studies. Justification for this treatment might be the slow effect of immunotherapy, because effects are not detected in the short term, although OS does finally improve [64-66].

We therefore need to better understand the mechanisms of action, and need to better define the endpoints of immunotherapy treatments and studies. In addition, it would be helpful to identify the target population of patients that may benefit from these treatments. The delayed effect of such treatments suggests that the more suitable patients could be those with a greater expected survival.

Immunotherapy is a new method in CRPC treatment. However, because of its uncertainties we are in the developmental stages of this therapy and improved outcomes might be achievable. Further research in this field is expected to promote a better understanding of the immune response and stimulate the use of multiple therapies resulting in exploitation of synergistic therapeutic effects.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vaccines
  5. Antibodies
  6. Discussion
  7. Conflict of Interest
  8. References
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