A phase II study of a personalized peptide vaccination for chemotherapy-resistant advanced pancreatic cancer patients

  • Authors: Shigeru Yutani, Nobukazu Komatsu, Munehiro Yoshitomi, Satoko Matsueda, Koji Yonemoto, Takashi Mine, Masanori Noguchi, Yuki Ishihara, Akira Yamada, Kyogo Itoh, Tetsuro Sasada
  • View Affiliations

  • Published online on: Thursday, June 20, 2013
  • Pages: 1094-1100
  • DOI: 10.3892/or.2013.2556

Abstract

Pancreatic cancer is one of the most aggressive cancers with a median survival time (MST) of <6 months in chemotherapy-resistant patients. Therefore, the development of novel treatment modalities is needed. In the present study, a phase II study of personalized peptide vaccination (PPV) was conducted, in which vaccine antigens were selected and administered based on the pre-existing IgG responses to 31 different pooled peptides, for 41 chemotherapy-resistant advanced pancreatic cancer patients. No vaccine-related severe adverse events were observed. IgG responses specific to at least one of the vaccine peptides were augmented in 14 of 36 patients (39%) and in 18 of 19 patients (95%) tested after the 5th and 11th vaccination, respectively. MST from the first vaccination was 7.9 months with a 1-year survival rate of 26.8%. Higher serum amyloid A (SAA) and C-reactive protein (CRP) levels in pre-vaccination plasma were unfavorable factors for overall survival (OS). Due to the safety profile and the potential clinical efficacy, the conduction of additional clinical trials of PPV for chemotherapy-resistant advanced pancreatic cancer patients is warranted.

Introduction

Pancreatic cancer, the fourth leading cause of cancer-related mortality worldwide, constitutes one of the most aggressive types of cancer (1). There have been substantial advances in the therapeutic modalities for advanced pancreatic cancer, including carbon beam ion radiotherapy (2), systemic chemotherapies using gemcitabine (GEM), tegaful-gimeracil-oteracil potassium (S-1) (3) and oxaliplatin, irinotecan, fluorouracil, leucovorin (Folfirinox) (4), as well as an EGFR-inhibitor erlotinib (5). However, despite these advances, the median survival time (MST) of advanced pancreatic cancer patients from the first or second line of chemotherapy still remains approximately 7–11 (15) or 4–6 months (2,6), respectively. Therefore, the development of novel therapeutic approaches including cancer vaccines is needed.

We previously devised a new regimen of peptide-based vaccination, named personalized peptide vaccination (PPV), in which vaccine antigens were selected from 31 different pooled peptides, and administered based on both HLA-class IA types and levels of peptide-specific IgG responses before vaccination (710). In our previous clinical trials, immune responses triggered by PPV were well-associated with overall survival (OS) in advanced pancreatic cancer patients under PPV in combination with GEM as the first-line therapy (7,8). GEM did not inhibit immune responses induced by PPV. Furthermore, the MST of advanced pancreatic cancer patients with positive (n=10) or negative (n=8) immune responses was 15.5 and 6 months, respectively, when non-resectable pancreatic cancer patients were treated with PPV and GEM as the first-line therapy. However, there is no trial of PPV for chemotherapy-resistant advanced pancreatic cancer currently available. Consequently, in the present study, a phase II study of PPV in chemotherapy-resistant advanced pancreatic cancer patients was performed.

Materials and methods

Patients

Patients pathologically and/or clinically diagnosed with pancreatic cancer were eligible for inclusion in the present study, when they had failed at least first-line chemotherapy and showed positive IgG responses to at least 2 of the 31 different vaccine candidate peptides as previously reported (10). Additional inclusion criteria were the following: age between 20 and 80 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, positive status for the HLA-A2, -A24, -A3 supertype (A3, A11, A31 or A33) or -A26, life expectancy of at least 12 weeks, and adequate hematologic, hepatic and renal function. Exclusion criteria included pulmonary, cardiac or other systemic diseases, acute infection, a history of severe allergic reactions, pregnancy or nursing, and other inappropriate conditions for enrollment as judged by clinicians. The protocol was approved by the Kurume University Ethics Committee, and was registered in the UMIN Clinical Trials Registry (UMIN #08167). After a full explanation of the protocol, a written informed consent was obtained from all the patients prior to enrollment.

Clinical protocol

This was an open-label phase II study, in which the main objectives were to evaluate safety and to address whether PPV in combination with additional chemotherapeutic regimens for chemotherapy-resistant pancreatic cancer patients prolongs MST. Thirty-one peptides, the safety and immunological effects of which were reported in previous clinical studies (811), were employed for vaccination [12 peptides for HLA-A2, 14 for HLA-A24, 9 for HLA-A3 supertype (A3, A11, A31 or A33) and 4 for HLA-A26]. The peptides were prepared under the conditions of Good Manufacturing Practice (GMP) by PolyPeptide Laboratories (San Diego, CA, USA) and the American Peptide Company (Vista, CA, USA).

The peptides for vaccination to individual patients were selected in consideration of the pre-existing host immunity before vaccination, by assessing the titers of IgG specific to each of the 31 different vaccine candidates (10). A maximum of 4 peptides (3 mg/each peptide), which were selected based on the results of HLA typing and peptide-specific IgG titers, in complex with incomplete Freund's adjuvant (Montanide ISA 51; Seppic, Paris, France) were subcutaneously administered once a week for 6 consecutive weeks.

After the first cycle of 6 vaccinations, up to 4 vaccine peptides were re-selected according to the titers of peptide-specific IgG and administered every 2 weeks. Vaccine peptides were re-selected at every cycle of 6 vaccinations until the discontinuation of PPV. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Complete blood counts and serum biochemical tests were performed at every cycle of 6 vaccinations. The clinical responses were evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) with radiological findings of computed tomography (CT) scanning or magnetic resonance imaging (MRI) before and after vaccinations.

Measurement of laboratory markers

Levels of C-reactive protein (CRP), serum amyloid A (SAA) and IL-6 in plasma were examined by ELISA using kits from R&D Systems (Minneapolis, MN, USA), Invitrogen (Carlsbad, CA, USA) and eBioscience (San Diego, CA, USA), respectively. Bead-based multiplex assays were used to measure cytokines, including IL-4, IL-13, IL-21, IP-10, BAFF and TGF-β with the Luminex 200 system (Luminex, Austin, TX, USA).

Measurement of immunoglobulins (Igs) reactive to each of the 31 different peptides

The levels of Igs reactive to each of the 31 different peptides were measured using the Luminex 200 system as previously reported (911). In brief, plasma was incubated with 100 μl of peptide-coupled color-coded beads for 1.5 h at 30°C, followed by washing and incubation with 100 μl of biotinylated goat anti-human IgG (Vector Laboratories, Burligame, CA, USA). After washing, 100 μl of streptavidin-PE (Invitrogen) was added and incubated for 30 min at 30°C. After washing, the fluorescence on the beads was detected using the Luminex 200 system. The Igs levels were expressed in fluorescence intensity units (FIU) as previously reported (911). Peptide-specificity of IgG against each of the 31 peptides was confirmed (unpublished data).

Statistical methods

The Wilcoxon signed-rank test and paired t-test were used to compare differences between pre- and post-vaccination measurements. OS was calculated from the first day of peptide vaccination until the day of death or the last day when the patient was known to be alive. Prognostic factors for OS were evaluated by univariate and multivariate analyses with the Cox proportional hazards regression model. Curves for OS were estimated using the Kaplan-Meier method, and the log-rank test was conducted for the comparison of survival curves. Two-sided P-values of <0.05 were considered to indicate statistically significant differences. All statistical analyses were conducted using the JMP version 10.0.1 software (SAS Institute Inc., Cary, NC, USA).

Results

Patient characteristics

Between November 2008 and March 2011, 41 advanced pancreatic cancer patients who had failed at least first-line chemotherapy were included in the present study. Patient characteristics are listed in Table I. There were 27 male and 14 female subjects with a median age of 61 years (range, 44–78). All patients had advanced stages of cancer (stage IVa, n=7; IVb, n=24; recurrent, n=10). Prior to enrollment, the patients had failed 1 (n=11), 2 (n=24), 3 (n=5) or 4 (n=1) regimen(s) of chemotherapy. The median duration of chemotherapy prior to PPV was 8 months with a range from 1 to 36 months. The performance status at the time of enrollment was grade 0 (n=37) or 1 (n=4). The numbers of vaccine peptides employed at the first cycle of vaccinations were 4 peptides in 33 patients, 3 in 5 patients and 2 in 3 patients. The median number of vaccinations was 10 with a range of 3 to 36. PPV was combined with GEM (n=11), S-1 (n=6), GEM and S-1 (n=8) or other combinations of chemotherapeutic agents including CDDP-based regimens (n=8). PPV alone was administered to 8 patients, since chemotherapy could not be tolerated (n=4) or due to patient refusal (n=4).

Table I

Patient characteristics.

Table I

Patient characteristics.

CharacteristicValue
Age (years), median (range)61 (44–78)
Gender, n
 Male27
 Female14
Disease location, n
 Head14
 Body15
 Limbs6
 Body and limbs6
Performance status, n
 037
 14
Stage, n
 IVa7
 IVb24
 Recurrent10
No. of previous regimens, n
 111
 224
 35
 41
Duration of previous treatment (months), median (range)8 (1–36)
No. of vaccinations, median (range)10 (3–36)
Combined treatment, n
 (−)8
 GEM11
 S-16
 GEM and S-18
 Other regimens8
Treatment response, n
 SD28
 PD13
Overall survival time (days), median (95% CI)238 (151–313)

[i] GEM, gemcitabine; S-1, tegaful-gimeracil-oteracil potassium; SD, stable disease; PD, progressive disease; CI, confidence interval.

Toxicities

A grade 1 or 2 dermatological reaction at the injection site was observed in 39 cases. Anemia (n=15), lymphocytopenia (n=20), thrombocytopenia (n=11), leukocytopenia (n=7), hypoalbuminemia (n=15) and hyperglycemia (n=8) were also frequently observed. Grade 3 adverse events included anemia (n=1), lymphocytopenia (n=1), hypertension (n=1), GGT increase (n=1) and creatinine increase (n=1). According to assessment by the Independent Safety Evaluation Committee in this trial, all the grade 3 adverse events were concluded to be not directly associated with PPV.

Humoral responses to peptides

IgG responses specific to the vaccine peptides in pre- and post-vaccination plasma samples were analyzed. Post-vaccination plasma samples were available from 36 and 17 patients after the 5th and 11th vaccination, respectively. When peptide-specific IgG titers to at least one of the vaccine peptides in the post-vaccination plasma were >2-fold higher compared to those in the pre-vaccination plasma, antigen-specific humoral responses were considered to be increased. The IgG responses specific to at least one of the vaccine peptides were augmented in 14 of 36 patients (39%) and in 18 of 19 patients (95%) after the 5th and 11th vaccination, respectively (Table II).

Table II

IgG responses to the vaccinated peptides.

Table II

IgG responses to the vaccinated peptides.

IgG response

Patient no.PeptidePre5th11th
1ppMAPkkk-4324340na
WHSC2-1036869na
HNRPL-501191638na
HNRPL-140209189na
2SART3-1092261,896na
Lck-4224466na
CypB-1292345na
WHSC2-103322401na
3PSA-248284,99928,025
MRP3-129375703,259
SART2-16137387,860
Lck-486383123,697
4MRP3-5035756na
MRP3-12937969na
SART2-1615153na
Lck-48653NDna
5CypB-12916112012,717
ppMAPkkk-432368NDND
UBE2V-4339639960,508
SART3-30227223511,267
HNRPL-501150343ND
6HNRPL-14013NDna
SART3-30240NDna
7SART3-1094252na
SART3-51127NDna
Lck-9013NDna
Lck-44945NDna
8SART2-933218na
PAP-2131,2491,573na
EGF-R-80040NDna
MRP3-5039838na
SART3-1092311na
9Lck-2463766233,264
UBE2V-43188ND16,549
UBE2V-852943142,053
SART3-3022073301,929
HNRPL-140ND4942,780
10HNRPL-501578NDND
UBE2V-8570ND14
SART3-30236NDND
SART3-30918NDND
11SART3-10921ND653
MRP3-50369ND14,787
PTHrP-10214NDND
12SART2-93164NDna
Lck-20820613na
Lck-486245298na
EZH2-735388503na
Lck-422783532na
HNRPL-140456380na
13SART3-1091,4751,279na
Lck-4861,6441,833na
14SART3-1092,3092,1366,782
MRP3-1293434023,180
SART2-1613227ND
Lck-4861,5151,234267,768
15SART3-1091,5005,872180,917
SART2-16131223,278
Lck-48665022458,780
Lck-488543721,889
SART3-5119957ND
16SART3-5111,6991,5031,522
PAP-2487069ND
Lck-422180ND16
WHSC2-103188ND2,629
Lck-90354563
CypB-129162320
17ppMAPkkk-4328388ND
SART3-1096249ND
Lck-4862,1762,191 3,523,034
PTHrP-102129162135
SART2-934710059
18MRP3-1293103NDna
Lck-4865,73110,510na
PSMA-62499NDna
ppMAPkkk-432126115na
SART3-1095550na
Lck-4883835na
19CypB-1295753na
ppMAPkkk-43210690na
HNRPL-501974934na
SART3-3024732,233na
Lck-2461761na
20Lck-2464094412,349
EGF-R-80083134183
Lck-486957237,353
EZH2-735117ND10,454
CypB-129183192190
ppMAPkkk-432120185233
21PAP-2134898na
Lck-4862022na
22CypB-129109112393
Lck-246221356
WHSC2-14122ND15
SART3-3026311,4595,168
Lck-422141278
23PAP-213131234,179
Lck-486255802,552
Lck-449373743
WHSC2-1034014165
SART3-511ND289173
PAP-248ND1,20063
24PAP-213122122na
Lck-449129102na
CypB-129186183na
WHSC2-10369NDna
25PAP-213162,772na
PSA-248641,372na
Lck-48617105na
26CypB-1299081105
Lck-246201239
SART3-309123744,738
PAP-24821NDND
27SART2-9311ND55
SART3-1091562221,871
Lck-48618531312,511
Lck-48815123,980
PAP-213ND14ND
28PAP-2133144657
PSA-2484544615,954
EGF-R-80030332,926
Lck-486222311,356
29SART2-931111na
Lck-48625NDna
Lck-4881416na
30CypB-129246232na
WHSC2-14131721na
SART3-30286865na
Lck-208112,016na
31SART2-934037478
Lck-48623322,567
Lck-488314720,641
PTHrP-1024046523
32WHSC2-14143339820,518
PSA-248292,10913,221
MRP3-1293149
121
4,15511,903
Lck-48612118,577
33SART2-93225160
SART3-10914ND16
Lck-48639ND2,479
SART2-161ND7659
34CypB-129263239na
WHSC2-10343NDna
WHSC2-141231125na
SART3-73432NDna
35MRP3-129362NDna
Lck-48685NDna
SART3-734123NDna
CypB-12914993na
36SART2-93131112
SART3-10911,20010,65710,093
Lck-48816132,017
EGF-R-800ND11ND

[i] Underlined peptides indicate the selection of new peptides for the second cycle of PPV. Bold values represent increased IgG responses. na, not applicable; ND, no data.

Laboratory markers

Two inflammation markers, CRP and SAA, and 7 cytokines including IL-4, IL-6, IL-13, IL-21, IP-10, BAFF and TGF-β, were examined in plasma before and after the 5th vaccination. Since 5 of 41 patients did not complete the first cycle of 6 vaccinations due to rapid disease progression, they were excluded from the marker analysis. However, no significant differences before and after vaccinations were observed in the markers tested (data not shown).

Clinical outcome

No complete response (CR) or partial response (PR) was observed during PPV. Optimum clinical responses after the 6th vaccination or at discontinuation of PPV were observed in 28 cases of stable disease (SD) and 13 cases of progressive disease (PD) (Table I). MST from the first vaccination was 7.9 months (238 days) with a 1-year survival rate of 26.8% (Table I). All the 41 patients, except for 1 patient, had succumbed to the disease at the time of examination. Survival curve is shown in Fig. 1. MST in patients treated with PPV in combination with (n=33) or without (n=8) chemotherapies was 9.6 or 3.1 months, respectively (P=0.0013) (data not shown). When calculated from the initiation of the first-line chemotherapy, MST of all 41 cases was 19.0 months [95% confidence interval (CI), 15.0–25.0 months].

Prognostic factors for OS

Pre-vaccination prognostic biomarkers for OS were investigated in 36 patients who completed at least the first cycle of 6 vaccinations. SAA levels in pre-vaccination samples were found to be inversely associated with OS using the univariate Cox proportional hazards model [hazard ratio (HR) per 1 mg/dl increment = 1.10, 95% CI=1.03–1.15, P=0.004] (Table III). CRP levels also showed a significant association (HR per 1 mg/dl increment = 1.68, 95% CI=1.03–2.58, P=0.039). Similar results were obtained using the multivariate Cox proportional hazards model. The patients were allocated into two subgroups according to the median value of SAA or CRP. The survival curves were estimated by the Kaplan-Meier method and differences in survival rates were compared using the log-rank test. The patients with higher SAA (P=0.0043) or CRP levels (P=0.0019) in the pre-vaccination samples exhibited worse prognosis (Fig. 2). In addition, concerning post-vaccination samples, the patients with boosted IgG responses (n=19) [in response to the vaccinated (n=14) or unvaccinated peptides selected for the 2nd cycle of PPV (n=5)] exhibited better prognosis compared to those with no IgG boosting (n=17) (P=0.0485) (data not shown).

Table III

Univariate and multivariate analyses with pre-vaccination clinical findings and laboratory data.

Table III

Univariate and multivariate analyses with pre-vaccination clinical findings and laboratory data.

Univariate analysisMultivariate analysis


FactorHazard ratio (95% Cl)P-valueaHazad ratio (95% Cl)P-valuea
Age (years)1.58 (0.40–6.44)0.52
Gender (female<male)0.98 (0.52–1.95)0.96
Clinical stage (IVa<recurrent<IVb)1.18 (0.78–1.80)0.43
Duration of previous chemotherapy (months)0.98 (0.94–1.02)0.27
Regimen no. of previous chemotherapy0.93 (0.59–1.44)0.75
Lymphocyte count (x102/mm3)1.00 (1.00–1.00)0.39
Hemoglobin (g/dl)0.93 (0.75–1.16)0.53
Albumin (g/dl)0.58 (0.32–1.10)0.09
Creatinine (mg/dl)1.88 (0.51–5.23)0.31
SAA (mg/dl)1.09 (1.03–1.15)0.004b1.08 (0.99–1.18)0.09
CRP (mg/dl)1.68 (1.03–2.58)0.039b0.95 (0.41–2.06)0.91

a P-values determined by Cox proportional hazard regression model;

b significant difference.

{ label (or @symbol) needed for fn[@id='tfn5-or-30-03-1094'] } Cl, confidence interval; SAA, serum amyloid A; CRP, C-reactive protein.

Discussion

The MST of 41 chemotherapy-resistant advanced pancreatic cancer patients under PPV was 7.9 months with a 1-year survival rate of 26.8%. Among them, the MST in patients treated with PPV combined with (n=33) or without (n=8) chemotherapies was 9.6 or 3.1 months, respectively (P=0.0013). OS of the patients treated with PPV not combined with chemotherapies was significantly short, suggesting that PPV alone did not provide survival benefits to advanced pancreatic cancer patients. This failure was expected based on the results from our previous study (13). These results suggest that PPV has the potential to improve OS in chemotherapy-resistant advanced pancreatic cancer patients when administered in combination with chemotherapeutic agents.

With regard to post-vaccination biomarkers, several factors, including CTL responses, Th1 responses, delayed-type hypersensitivity (DTH) and autoimmunity, have been reported to be associated with clinical responses in some clinical trials (14,15). We have also shown that an increase in peptide-specific IgG and/or CTL responses after PPV is significantly associated with longer OS (11,12). In contrast to such post-vaccination biomarkers, there are currently no validated pre-vaccination prognostic biomarkers widely used. Therefore, this issue was addressed in the present study. As a result, plasma SAA and CRP levels were inversely correlated with OS. These results were expected based on our previous study on PPV (10). These biomarkers are suggested to be important not only in cancer vaccines, but also in other treatment modalities for advanced pancreatic cancers.

Collectively, due to the safety profile and the potential clinical efficacy of PPV, further clinical trials to determine a protocol suitable for PPV-based therapy in chemotherapy-resistant advanced pancreatic cancer patients are warranted.

Acknowledgements

This study was supported in part by grants from the Regional Innovation Cluster Program, a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Sendai Kousei Hospital, Japan.

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Journal Cover

September 2013
Volume 30 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

2013 Impact Factor: 2.191
Ranked #33/202 Oncology
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