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A Phase 2 Randomized Controlled Trial of Personalized Peptide Vaccine Immunotherapy with Low-dose Dexamethasone Versus Dexamethasone Alone in Chemotherapy-naive Castration-resistant Prostate Cancer
European Urology, In Press, Corrected Proof, Available online 15 January 2016, Available online 15 January 2016
It is well known that the prognosis of castration-resistant prostate cancer (CRPC) is poor, and several immunotherapeutic strategies have been applied to the clinical trials. Research on immunotherapy has been of special interest for the treatment of CRPC for years.
To evaluate the safety of personalized peptide vaccine (PPV) immunotherapy and its clinical outcomes.
Design, setting, and participants
A phase 2 randomized controlled trial of PPV immunotherapy with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive CRPC began in 2008. Eligible patients (prostate-specific antigen [PSA] <10 ng/ml) were human leukocyte antigen (HLA) A02, A24, or A03 superfamily positive and had asymptomatic or minimally symptomatic CRPC. Patients were allocated (1:1) to PPV plus dexamethasone (1 mg/d) or to dexamethasone (1 mg/d) alone. A maximum of four HLA-matched peptides (each 3 mg) was selected based on the preexisting immunoglobulin G responses against the 24 warehouse peptides and administered every 2 wk.
Outcome measurements and statistical analysis
PSA, progression-free survival (PFS), time to initiation of chemotherapy, and overall survival (OS) were analyzed using the Kaplan-Meier method, a log-rank test, and proportional hazard analysis.
Results and limitations
Overall, 37 patients received peptide vaccinations and 35 received dexamethasone alone. The primary end point was PSA PFS, which was significantly longer in the vaccination group than in the dexamethasone group (22.0 vs 7.0 mo; p = 0.0076). Median OS was also significantly longer in the vaccination group (73.9 vs 34.9 mo; p = 0.00084). The relatively small number of patients enrolled is the major limitation of the study.
PPV immunotherapy was well tolerated and associated with longer PSA PFS and OS in men with chemotherapy-naive CRPC. A larger phase 3 study is needed to confirm our findings.
We compared clinical outcomes of the treatment with personalized peptide vaccine plus dexamethasone versus dexamethasone alone. Our data provide promising evidence of clinical benefit for peptide vaccines.
Keywords: Castration-resistant prostate cancer, Low-dose dexamethasone, Peptide vaccine immunotherapy.
Since Charles Huggins reported that prostate cancer (PCa) would regress in response to androgen ablation in 1941, primary androgen deprivation still remains the initial therapy for metastatic PCa. However, the disease becomes lethal when progression occurs despite the low levels of testosterone, which is then referred to as castration-resistant prostate cancer (CRPC). During the past few years, the treatment options for metastatic CRPC (mCRPC) have changed remarkably. During that time, several new agents have become available to treat men with mCRPC including abiraterone , enzalutamide , cabazitaxel , and sipuleucel-T . Despite these advances, median survival for patients with postchemotherapy mCRPC is about 2 yr . In phase 3 trials of abiraterone and enzalutamide in the chemotherapy-naive mCRPC setting, the median overall survival (OS) in the treatment arm was 34 and 32 mo, respectively  and . Immunotherapy with sipuleucel-T is the first therapeutic cancer vaccine demonstrated to improve outcomes in an advanced malignancy and provides possibilities for further investigation of immunotherapy for mCRPC.
Under these circumstances, multiple immune approaches beyond sipuleucel-T are currently under development that include antigen-directed immunotherapies as well as monoclonal antibodies against immune checkpoints. Combination therapies of immunotherapy and conventional therapies are also being evaluated.
Personalized peptide vaccination (PPV) is an immunotherapy that uses multiple cancer peptides based on the preexisting host immunity. Tumor-associated antigen peptides derived from the tumor cells are recognized by antigen presenting cells that in turn present these to CD4+ and CD8+ T cells by way of major histocompatibility complexes class I and II molecules, respectively. This interaction leads to the induction and proliferation of cytotoxic T lymphocyte (CTL) precursors, which will then establish an antigen-specific population aimed at destroying cancer cells. We previously reported that PPV was safe and improved clinical outcomes with immune responses in phase 1 and 2 clinical trials in patients with CRPC , , and . In addition, low-dose dexamethasone is known as one of the treatment options by itself or with PPV for CRPC patients , , and . The longer acting dexamethasone could elicit more effective suppression of adrenocorticotropic hormone, and as a result, it shows higher antitumor activity. Dexamethasone is reported to have an antiangiogenic effect in vivo and also has the effect of reducing expression of androgen receptors  and .
At the time the study was conducted, low-dose dexamethasone was considered the standard of care and hence had the rationale to be provided as monotherapy in the comparator arm. In this article, clinical outcomes of PPV immunotherapy in combination with low-dose dexamethasone are compared with dexamethasone alone in a randomized controlled study.
2. Patients and methods
2.1. Patient eligibility
The eligible criteria included that patients had positive regional lymph nodes and/or distant metastases at the diagnosis of PCa. Patients <80 yr of age with progressive CRPC regardless of androgen deprivation, life expectancy >3 mo, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, prostate-specific antigen (PSA) <10 ng/ml, and a castrate testosterone level (<50 ng/dl), and human leukocyte antigen (HLA) A2, A24, or A03 positive and pathologically confirmed adenocarcinoma of the prostate were eligible. PSA progression was defined as two consecutive 25% increases from baseline PSA levels at least 2 wk apart as described by Bubley et al . Antiandrogen agent was discontinued for 4 wk before enrollment for patients receiving flutamide and 6 wk for those receiving bicalutamide. Patients without orchiectomy continued on androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist throughout the study. Patients needed to have positive immunoglobulin G (IgG) responses to at least one of the candidate cancer peptides. Other eligibility criteria included adequate hematologic, hepatic, and renal function, and negative serologic tests for hepatitis B, hepatitis C, and human immunodeficiency virus. Patients with evidence of serious illness, active secondary malignancy within the last 5 yr prior to enrollment, immunosuppression, or autoimmune disease were excluded from the study. This study was approved by both the Kinki University and Jikei University institutional review boards (IRBs), and all patients signed IRB-approved informed consent forms before beginning screening procedures. This study was registered at the UMIN clinical trial registry (UMIN-CTR, #000000959), on January 1, 2008.
2.2. Peptide preparation
A total of 24 peptides restricted with HLA-A02, A24, or A03 were prepared under conditions of Good Manufacturing Practice by the PolyPeptide Laboratories (San Diego, CA, USA) or the American Peptide Company (Vista, CA, USA) (Table 1). Previous studies have indicated that all peptides can induce HLA-A02, A24, or A03-restricted and tumor-specific CTL activity in peripheral blood mononuclear cells (PBMCs) of cancer patients , , and . For each patient, HLA-type specific peptides were chosen based on the evaluation of both antipeptide IgG levels in plasma and CTL precursors in PBMCs as described previously , , and . Only the reactive peptides (a maximum of four) were used for vaccinations.
|Origin protein||Amino acid sequence||Origin protein||Amino acid sequence||Origin protein||Amino acid sequence|
|p56 lck||KLVERLGAA||p56 lck||HYTNASDGL||p56 lck||ILEQSGWWK|
|p56 lck||DVWSFGILL||p56 lck||DYLRSVLEDF||p56 lck||VIQNLERGYR|
HLA = human leukocyte antigen.
2.3. Study design and treatment protocol
This randomized controlled study involved two institutions in Japan. Patients were randomly assigned to one of the two arms designated as the vaccination arm and the dexamethasone arm. A centrally administered randomization method was used to assign patients to the arms in a 1:1 ratio. The primary end point was PSA progression-free survival (PFS). The secondary end points were time to initiation of chemotherapy and OS.
In the vaccination arm, 3 mg peptides was injected subcutaneously into the thigh area with Montanide ISA51VG (Seppic, Paris, France) every 2 wk (a maximum of four peptides per vaccination). The peptide vaccination was continued at 2-wk intervals in six vaccination cycles, until death, intolerance, marked disease progression, major violations, or patients’ withdrawal of consent. Also, 1 mg dexamethasone per day was administered throughout the treatment. In the dexamethasone arm, only 1 mg dexamethasone per day was initially administered, and when the patient was evaluated with progressive disease (PD) by PSA testing, those in this arm were allowed to cross over to the vaccination arm, and peptide vaccination was added in the same manner as in the vaccination arm (Supplementary Fig. 1). When PSA progression was found even after vaccination, patients in both arms were offered poststudy treatments including chemotherapy. Physical examinations, baseline blood tests, and toxicity evaluations were conducted every 2 wk.
2.4. Statistical analyses
All patients who received more than six vaccinations were considered evaluable for response. To detect the difference of PSA PFS, use of the log-rank test of equal proportions required 36 patients per arm with a two-sided α of 0.05 and 80% power. Therefore, we planned to recruit 40 patients per arm to ensure 36 evaluable patients. Data were analyzed at the end of March 2015 using commercially available computer software. Survival was calculated from the date of first administration to the date of any cause of death. Patients lost to follow-up were censored at the last known date of survival. The Kaplan-Meier method was used to estimate actuarial survival curves, and the groups were compared using a log-rank test and proportional hazard analysis (for estimation of hazard ratio [HR]). Differences were considered statistically significant when p < 0.05.
3.1. Patient characteristics
Between April 2008 and October 2013, 83 patients were assessed for eligibility at the two study centers. Ten patients did not meet the inclusion criteria. A total of 37 patients were randomly assigned to the peptide vaccination arm, and 36 patients were randomly assigned to the dexamethasone arm (Fig. 1). The 73 patients (37 in the vaccination arm and 36 in the dexamethasone arm) comprised the primary analysis set. Table 2 shows the main baseline patient characteristics and reveals that the arms were favorably balanced allowing for 1:1 randomization. Most patients had a Gleason score of 7–10 (89.2% in the vaccination arm and 88.6% in the dexamethasone arm). The median PSA levels at baseline were 4.39 ng/ml (vaccination arm) and 5.32 ng/ml (dexamethasone arm), respectively. No patients in both arms discontinued the treatment protocol for reasons other than disease progression such as intolerance or protocol violation.
|Treatment arm||Vaccine and Dex|
n = 37
n = 36
|Median (IQR)||68 (64–73)||67 (63–67)|
|Median (IQR)||4.39 (2.16–6.85)||5.32 (3.45–7.38)|
|Years from initial diagnosis|
|Median (IQR)||2.9 (1.5–4.4)||2.7 (1.2–4.1)|
|Site of metastasis||25||26|
Dex = dexamethasone; EBRT = external-beam radiation therapy; IQR = interquartile range; LHRH = luteinizing hormone-releasing hormone; LN = lymph node; PSA = prostate-specific antigen.
3.2. Short-term cancer control and overall survival
A decline from baseline >50% of PSA levels at 12 wk was found in 59.6% patients in the vaccination arm and in 54.3% in the dexamethasone arm, respectively, which revealed no statistical difference (Fig. 2). Five patients in the vaccination arm (13.5%) and seven patients in the dexamethasone arm (20.0%) showed >90% decline of PSA.
Median PSA PFS was 665 d (22.0 mo) in the vaccination arm and 210 d (7.0 mo) in the dexamethasone arm, respectively (Fig. 3a). The HR estimated from stratified proportional hazard analysis is 0.389 (95% confidence interval [CI], 0.222–0.684), and the stratified log-rank p value for PSA PFS is 0.0076. Median time to initiation of chemotherapy was 1576 d (52.4 mo) in the vaccination arm and 719 d (23.8 mo) in the dexamethasone arm, respectively (Fig. 3b; p = 0.047). In the vaccination arm, median number of vaccinations was 32 times (range: 4–107 times). In the dexamethasone arm, all patients received peptide vaccinations after disease progression. Median PSA level at crossover was 5.49 ng/ml (range: 0.35–20.41), and median number of vaccinations was 6 times (range: 3–10 times). Median PSA PFS after crossover was 84 d (range: 28–161 d) (Supplementary Table 1).
The estimated median OS for the vaccination arm and dexamethasone arm was 2219 d (73.9 mo) and 1054 d (34.9 mo), respectively. Figure 3c shows graphs of the Kaplan-Meier estimator of the survival distributions. The HR estimated from stratified proportional hazard analysis is 0.412 (95% CI, 0.205–0.828), and the stratified log-rank p value for OS is 0.00084. Table 3 summarizes these results. After progression, patients in both arms were offered poststudy treatments including cabazitaxel (none in the vaccination arm and 3 in the dexamethasone arm), docetaxel (14 patients in the vaccination arm and 19 in the dexamethasone arm), abiraterone acetate (each 1 in both arms), enzalutamide (1 in the vaccination arm and 2 in the dexamethasone arm), and estramustine phosphate (4 patients in the vaccination arm and eight in the dexamethasone arm) (Supplementary Table 2).
|Vaccination and Dex|
n = 37
n = 36
|PSA response rates (%)|
|>50% decline||22 (59.6)||19 (54.3)|
|>90% decline||5 (13.5)||7 (20.0)|
|PSA progression-free survival, median, d||665||210|
|Median 95% Cl||277–1054||156–264|
|Hazard ratio (95% CI)||0.39 (0.22–0.68)|
|Time to chemotherapy initiation, median, d||1576||719|
|Median 95% Cl||1203–1949||634–804|
|Hazard ratio (95% CI)||0.50 (0.25–1.003)|
|Overall survival, median, d||2219||1054|
|Median 95% Cl||1546–2892||769–1340|
|Hazard ratio (95% CI)||0.41 (0.21–0.83)|
CI = confidence interval; Dex = dexamethasone; PSA = prostate-specific antigen.
3.3. Adverse events
No patient showed any toxicities of grade ≥3. Moon face of grade 1 or 2 was noted in 13 vaccination patients and 8 dexamethasone patients, respectively. Of the 37 patients in the vaccination arm, 30 patients developed a grade 1 or 2 local skin reaction at the injection sites with induration, redness, and itching. Two patients with a grade 1 and one patient with a grade 2 fever were noted, but no medication was required. Grade 1 fatigue was observed in two patients. Grade 1 headache was noted in one patient, and two patients complained of rash that resolved without any medications. In this study, no case revealed any vascular adverse events of grade ≥3, such as hypertension, bleeding, and thromboembolism, and no hepatic or renal toxicities (higher than grade 3) were found during vaccination (Supplementary Table 3).
This randomized controlled phase 2 study was designed and powered for the primary end point of PSA PFS, and it succeeded in finding a statistical significance between the two treatment arms. A strong association between treatment arm and OS was revealed. PPV immunotherapy in combination with low-dose dexamethasone for patients with chemotherapy-naive CRPC significantly prolonged OS. This study strongly suggests that PPV immunotherapy may have an OS benefit. Thus it may offer a new complementary approach to treating CRPC. One of the reasons for these clinical outcomes may be due to the study setting. In this study, patients with an ECOG performance status of 0 or 1 and PSA <10 ng/ml were enrolled. This suggests that patients with early-stage CRPC may receive more preferable clinical benefits regarding PSA PFS, OS, and also time to initiation of chemotherapy.
The results of this study have demonstrated parallels regarding clinical approaches of other immunotherapies for mCRPC. Treatment of metastatic PCa patients with a good prognosis with dendritic cell vaccine therapy (sipuleucel-T) provided an improved median OS of 4.5 mo (25.9 mo for sipuleucel-T vs 21.4 mo for controls) and OS benefit (3-yr OS of 33% vs 11%), yet it revealed only a trend toward delayed short-term disease progression .
A larger phase 3 study with >500 patients confirmed these results . In addition to sipuleucel-T immunotherapy, viral-based immunotherapy has also been reported. PSA-TRICOM (PROSTVAC; Bavarian Nordic, Copenhagen, Denmark) showed promising efficacy and tolerability in a clinical trial  and . PROSTVAC is a vector-based therapeutic cancer vaccine composed of a series of poxviral vectors (vaccinia during the initial priming vaccine and fowlpox for all boosts) engineered to express PSA and a triad of human T-cell costimulatory molecules (B7.1, ICAM-1, and LFA-3). Although there was no improvement in PFS, the primary end point of the study, and PSA responses were infrequent, the vaccine improved OS when compared with placebo (25.1 vs 16.6 mo; p = 0.006). Other immunotherapies for mCRPC are found in the literature , , and .
These immunotherapy trials in PCa may represent an emerging theme of prolonged OS, without a remarkable signal of tumor shrinkage or short-term cancer control. In the present study, the initial decline of PSA was almost identical in both the vaccination and nonvaccination group. This response may be due to the effect of low-dose dexamethasone. Venkitaraman et al recently reported a phase 2 trial of dexamethasone, in which they concluded that dexamethasone might be more active than prednisolone in CRPC .
We estimated 6 mo of median PSA PFS with dexamethasone monotherapy in chemotherapy-naive CRPC patients. It is suggested that a specific antitumor immunity induced by peptide vaccinations resulted in the significant delay of PSA progression compared with dexamethasone alone (7.0 vs 22.0 mo). Despite the fact that the patients in the dexamethasone arm were allowed to cross over the treatment, considerable longer survival was observed in the vaccination arm (73.9 vs 34.9 mo; p = 0.00084). Estimated median OS at the time of study commencement was calculated at about 27 mo in both arms when using the Halabi nomogram . Although all the patients with PSA progression in the dexamethasone arm received vaccination therapy with the same protocol after disease progression, clinical benefits were not often seen as described in the results. However, it would seem unlikely that this treatment protocol delayed receiving effective subsequent therapy with other agents and had an impact on survival. In this study, the treatment rates of abiraterone and enzalutamide were low. Thus this study was done mostly before these agents were approved in Japan.
In the treatment of cancer, immunotherapies can produce different response patterns and have a safety profile distinct from conventional antitumor therapies. This is because immunotherapies elicit antitumor effects by inducing or enhancing patients’ immune responses. These effects can be delayed and may manifest as a gradual reduction in tumor growth, resulting in prolonged OS, which is not often accompanied with objective short-term tumor responses. Cytotoxic therapies such as chemotherapy and radiotherapy elicit their effects directly on cancer cells and reveal rapid tumor shrinkage in responding patients. However, studies of immunotherapy against cancer have demonstrated that several tumor responses characterized as PD by the standard response criteria such as Response Evaluation Criteria in Solid Tumors may actually be responses to treatment . Before a clinical response, growth of existing target lesions occurs resulting in an apparent initial tumor increase and the development of new lesions while others show shrinkage. These mixed response patterns are characteristic of immunotherapies compared with conventional cytotoxic chemotherapy or radiotherapy. Therefore, it is necessary to evaluate the efficacy of immunotherapies in individual patients by using modified response criteria to obtain clinical benefit, especially on OS.
In this study, detectable antibody titers to peptides were found (data not shown). This is consistent with our previous observations , , , and . In addition to antibody response, CTL activity was also evaluated in every patient that demonstrated PPV immunotherapy induced adequate CTL responses enough to attack cancer cells (data not shown). PPV immunotherapy was well tolerated. Most adverse events were injection site reactions, and no patient showed any toxicities of grade ≥3.
PPV immunotherapy in this randomized controlled study was associated not only with an improved PSA PFS but also with a remarkable prolonged OS. The observed differences in median PSA PFS, time to initiation of chemotherapy, and survival compared with the dexamethasone arm suggest significant impact. It is plausible to speculate that patients with early-stage mCRPC could achieve maximum clinical benefits from this PPV immunotherapy. Further randomized trials are needed to confirm these results.
Author contributions: Hirotsugu Uemura had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Uemura.
Acquisition of data: Yoshimura, Minami, Nozawa, Kimura, Egawa, Fujimoto, Yamada, Itoh, Uemura.
Analysis and interpretation of data: Uemura.
Drafting of the manuscript: Yoshimura, Minami, Nozawa, Kimura, Egawa, Fujimoto, Yamada, Itoh, Uemura.
Critical revision of the manuscript for important intellectual content: Uemura.
Statistical analysis: Yoshimura.
Obtaining funding: Uemura.
Administrative, technical, or material support: Yamada, Itoh.
Other (specify): None.
Financial disclosures: Hirotsugu Uemura certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hirotsugu Uemura receives honoraria from Pfizer, Novartis, Astellas, Bayer, and Takeda.
Funding/Support and role of the sponsor: This work was in partly supported by the Health Labour Science Research Grant from the Ministry of Health, Labour and Welfare Japan.
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a Department of Urology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
b Department of Urology, Jikei University School of Medicine, Minato-ku, Tokyo, Japan
c Department of Urology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
d Kurume University Research Center for Innovative Cancer Therapy, Kurume, Fukuoka, Japan
e Kurume University Cancer Vaccine Center, Kurume, Fukuoka, Japan
Corresponding author. Department of Urology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, 589-8511, Osaka, Japan. Tel. +81 72 366 0221; Fax: +81 72 365 6273.
© 2016 European Association of Urology, Published by Elsevier B.V.