University of Groningen
Improving influenza prevention
van Doorn, Eva
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Publication date: 2018
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van Doorn, E. (2018). Improving influenza prevention: Why universal influenza vaccines are needed. Rijksuniversiteit Groningen.
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CHAPTER 4
Safety and tolerability evaluation
of the use of Montanide ISA TM 51 as
vaccine adjuvant: A systematic review
E. van Doorn, H. Liu, A. Huckriede, E. Hak
54
ABSTRACT
Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a comprehensive examination of the safety and tolerability of ISA 51 containing vaccines. A systematic literature search was conducted in PubMed, EMBASE and clinicaltrials.gov. Eligible studies were categorized into: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects, and (C) controlled studies with healthy subjects. Reported adverse events (AEs) were assessed. 91 studies were included in our review. Generally observed AEs included injection site reaction; injection site pain; myalgia; headache; gastro-intestinal disorders; fatigue and fever - regardless of the administration route and subject characteristic. Specific AEs, e.g. injection site reactions and rash, were more frequently reported from subjects receiving ISA 51-adjuvanted vaccines than from subjects receiving antigen or ISA 51 only. The reported AEs were mainly mild to moderate in intensity. Serious AEs (SAEs) were reported in 27% of the uncontrolled trials and 2 trials conducted with healthy subjects. Notably, 2 other trials conducted with healthy subjects were stopped due to unacceptable AEs. Some studies indicate that the mixing procedure of antigen and adjuvant might influence the occurrence of AEs. Reports on SAEs and premature termination of 2 trials advise caution when using ISA 51. Yet, AEs might be preventable by proper mixing of vaccine and adjuvant to a stable emulsion. Trials including an active control group are needed for a fair evaluation of adjuvant safety.
4
55
INTRODUCTION
Adjuvants are substances which are not antigenic themselves but help to induce strong and efficacious immune responses toward specific antigens [1,2]. Adjuvants enhance immune responses by at least one of the following mechanisms: (1) accelerate the onset of an immune response by activating innate immune responses or targeting antigens to professional antigen-presenting cells (APCs); (2) enhance the overall magnitude of an immune response, including the frequency of memory B and T cells; (3) elicit an immune response for a longer duration; (4) skew an immune response toward the desired directions (Th1, Th2, Th17, or balanced Th1/ Th2) and (5) modulate the specificity, affinity and isotype of the elicited antibodies. Based on their modes of action, adjuvants can be classified into immune modulators, delivery vehicles or carriers with immune stimulatory effect [1-4].
Montanide ISATM 51 (Seppic, France), a water-in-oil (W/O) emulsion composed of a mineral oil and a surfactant from the mannide monooleate family, is an adjuvant carrier with immune stimulatory effect [2-6]. When mixed with antigens in a ratio of 50/50 v/v (1:1), ISA 51 enhances antigen specific antibody titers and cytotoxic T-lymphocyte (CTL) responses [7]. The immune enhancing effect of ISA 51 is suggested to be associated with depot formation (and thus slow the release of antigens at the immunization site), inflammation (which stimulates the recruitment of APCs) and lymphocyte-trapping (which stimulates the accumulation of lymphocytes in draining lymph nodes) [8, 9]. It has been given to thousands of subjects subcutaneously (s.c.) or intramuscularly (i.m.) in vaccine trials requiring cellular immune responses, such as vaccine trials for cancer, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and malaria [5, 6]. A therapeutic lung cancer vaccine containing ISA 51 as emulsion adjuvant has been recently licensed in Cuba [10]. Recently, ISA 51 was also tested in influenza vaccine trials [11,12].
The inclusion of a vaccine adjuvant should be justified by a favorable risk/benefit ratio; the risk including local and systemic Adverse Events (AEs) [3]. To our knowledge, this is the first systematic review on the assessment of the safety and tolerability of ISA 51 and ISA 51-adjuvanted vaccines.
56
MATERIALS AND METHODS
Search strategy
Vaccine trials using ISA 51 adjuvant were systematically searched. Published medical studies were obtained from searches of PubMed and EMBASE with the free-text term “ISA 51”OR“ISA51” and ‘ISA 51’OR‘ISA51’, respectively. References from the databases were extracted and imported to RefWorks where duplicate entries were removed. The clinical trial register (clinicaltrials.gov) was hand searched for unpublished trials for which study results were available. References given by the trials identified from clinicaltrials.gov were examined for relevancy. No protocol is registered for the systematic review.
Study selection
Title and abstract of the extracted references were screened for relevant studies. Studies were included if: (1) they were clinical trials; (2) they used ISA 51 as vaccine adjuvant; and (3) they were reported in English. Comment letters, reviews and conference abstracts and/ or presentations were excluded. Full-text articles from the resulting pre-screened studies were obtained for the second stage evaluation. Studies were excluded if (1) they did not report safety, tolerability and/or toxicity data, (2) they were case reports or (3) letters to an editor, and (4) full-text was not available from the University Medical Center Groningen library. The screening and full-text evaluation procedures were performed independently by 2 members of the study team. Consensus on study selection was achieved. In case of disagreement, a third member of the study team made the final decision.
Data extraction
Data on study design, study population, study treatments (including trial vaccine and administration route), study endpoints and safety, tolerability and/or toxicity outcomes were extracted from the selected studies by one study team member. The extracted information was independently validated by a second team member. Trials included in the systematic review were categorized by the following subject characteristics and study design: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects and (C) controlled studies with healthy subjects. A control group could be an active control (immunization with the tested antigens without adjuvants or with adjuvants used in licensed vaccines, e.g., alum, MF-59, AS03 and AS04); a placebo-control (immunization with saline buffer); or an adjuvant control (immunization with ISA 51 in saline buffer).
Quality assessment
The methodological quality of the controlled studies selected for the review was evaluated by the Jadad score. The scoring system judged the procedure and description of randomization (0, 1 or 2 point), double-blinding (0, 1 or 2 point) and the description of withdrawals and drop outs (0 or 1 point). Using this scoring system a maximum score of 5 could be obtained; a score of ≤ 2 was considered as indicating poor methodological quality [48].
57
RESULTS
Search results and study selection
A systematic literature search performed on 9th February 2014 identified 580 studies from PubMed and EMBASE (Fig. 1). Additional, 12 trials on ISA 51-adjuvanted vaccine were identified from clinicaltrials.gov and one study obtained from a previous literature search on universal influenza vaccines. After removing duplicate entries, 462 studies were evaluated for inclusion based on the title and/or abstract, after which 114 potentially relevant studies were included for full-text examination; the majority of excluded studies were reviews or animal studies and 6 studies were not reported in English. From the 114 studies, full-text was unavailable for one study [13], 2 studies were duplicates published under different titles [14,15], one study only described the study design [16] and 6 studies did not report safety, tolerability and/or toxicity results [7,17-21]. These together with 11 case reports [22-32] and 2 letters to the editor were excluded [33,34]. Ultimately, a total of 91 studies were included in the systemic safety review. The full list of the 91 eligible studies including citations is provided in Supplemental Table 1.
Figure 1 Flowchart outlining study selection process for the ISA 51-adjuvanted vaccines studies included in the review
Studies excluded after full-text evaluation N = 23 Reasons for exclusion:
•No full text available (N = 1)
•Duplicate (N = 2)
•Only study design (N = 1)
•No safety data (N = 6)
•Case report (N = 11)
•Letter to the editor (N = 2) Studies screened after removal of
duplicates N = 462 Id en tif ic at ion
Studies excluded based on title and abstract
N = 348 Studies identified from
PubMed and EMBASE N = 580 In clu de d Eli gib ili ty Sc re enin g
Studies identified from clinicaltrials.gov
N = 12
Studies identified from a previous literature
search N = 1
Studies selected for full-text examination N = 114
Studies selected for systematic review N = 91
A) Uncontrolled studies with non-healthy subjects (N=81) B) Controlled studies with non-healthy
subjects (N=4)
C) Controlled studies with healthy subjects (N=6)
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Characteristics of included studies
Uncontrolled studies with non-healthy subjects
Of the 91 studies, 81 studies were conducted in non-healthy subjects without a control group. Except for the study by Pinto et al. which was conducted in HIV-infected subjects 35, all studies were conducted in cancer patients. Among these studies, 14% were pilot studies (11/81), 38% were phase I trials (31/81), 12% were phase I/II trials (10/81), 30% were phase II trials (24/81) and 2% were phase III trials (2/81) - 3 studies (4%) did not specify the trial phase. Among the trials, different administration routes were used, including s.c. (56/81, 69%), i.m. (5/81, 6%), intradermal (i.d.) (10/81, 12%), intracutaneous (2/81, 2%) and a combination of i.d. and s.c. (8/81, 10%).
Controlled studies with non-healthy subjects
Four studies were conducted in non-healthy adults (aged ≥ 18 years) and included control group(s). In the phase Ib trial of Boffito et al., HIV-positive males were randomized to receive a single s.c. administration of HIV vaccines at different doses, alone or adjuvanted with ISA 51 [36]. The study also included placebo (saline only) and adjuvant (ISA 51) controls. In the phase I trial of Sabbatini et al. and phase II trials of Goldinger et al. and NCT00273910, cancer patients were administered with multiple dosages of cancer vaccines with or without ISA 51 [37-39]. Sabbatini et al. included ovarian cancer patients, while both Goldinger et al. and NCT00273910 included melanoma patients. All subjects in Sabbatini et al. received s.c. administrations. The same route was used for the administration of ISA 51-adjuvatend cancer vaccines in the other 2 trials. In Goldinger et al. and NCT00273910, the active control group (containing the same vaccine antigen but without ISA 51 or with a licensed adjuvant) received plain vaccine antigens given by the intranodal or the i.d. route respectively. The main characteristics of the 4 studies are summarized in Table 1. In total the studies included 212 non-healthy subjects of whom 50 were treated with vaccine antigens only (arm 1) and 77 were treated with ISA 51-adjuvanted cancer vaccines (arm 2 and also arm 3 for NCT00273910). In addition, 11 subjects received saline buffer alone or emulsified with ISA 51 in the trial of Boffito et al., and 74 subjects received the non- or ISA 51-adjuvanted antigen with imiquimod or poly ICLC in the other studies. The methodological quality of 3 of the 4 trials was judged to be poor with Jadad scores of 1, 1 and 2 for the trial performed by Goldinger et al., Sabbatini et al. and NCT00273910, respectively (Table 1; Table S2). Only the study performed by Boffito et al. was of good quality and reached a Jadad score of 4.
59 Table 1 Main char act eristics o f the contr
olled studies with non-health
y subject s St ud y Tr ia l ph as e St ud y p op ul at ion Va cc in e ant ig en s Tr eat m en t g rou ps V ac ci ne v ol um e A dmi ni st ra ti on rout e Ja da d sc or e B offi to e t a l. [3 6] Ib 59 H IV p at ie nt s. A ge d 1 8-48 ye ar s. O nl y m al e. H IV-v A rm 1 : H IV -v ( n = 2 3; 1 1 fo r 2 50 µ g a nd 1 2 fo r 50 0 µ g) A rm 2 : H IV -v /I SA 5 1 ( n = 2 5; 1 3 fo r 2 50 µ g a nd 12 fo r 5 00 µ g) A rm 3 : I SA 5 1 A rm 4 : S al in e bu ffe r 0. 5 m L fo r a ll ar m s ( 0, 25 m L IS A 5 1) s.c . fo r a ll a rm s 4 G ol di ng er e t al . [3 8] II a 21 p at ie nt s w ith s ta ge I II o r I V m al ig na nt m el an om a. A ge d 29 -8 2 y ea rs . B ot h g en de rs . M el Qb G 10 A rm 1 : M el Q bG 10 ( n = 5 ) A rm 2 : M el Q bG 10 /I SA 5 1 ( n = 5 ) A rm 3 : M el Q bG 10 /I SA 5 1 w ith I m iq ui m od cr ea m ( n = 6 ) A rm 4 : M el Q bG 10 I m iq ui m od c re am ( n = 5 ) N ot s pe ci fie d i n th e s tu dy In tr an od al fo r ar m 1 a nd s .c . fo r a rm 2 -4 1 Sa bb at in i e t al . [ 37 ] I 28 p at ie nt s w ith s ta ge I I o r I V epit he lia l c ar ci nom a a ri si ng in t he o va ry , f al lo pi an t ub e o r pe ri ton eu m . A ge d 4 4-73 y ea rs . O nl y fe m al e. N Y-ES O -1 OL P A rm 1 : N Y-ES O -1 O LP ( n = 4 ) A rm 2 : N Y-ES O -1 O LP /I SA 5 1 ( n = 1 3) A rm 3 : N Y-ES O -1 O LP /I SA 5 1/ Po ly I C LC ( n = 1 1) A rm 1 : 0 ,5 m L A rm 2 : 1 ,0 m L (0 ,5 m L I SA 5 1) A rm 3 : 2 ,0 m L (1 ,0 m l I SA 5 1) s.c . fo r a ll a rm s 1 NC T0 02 73 91 0 [3 9] II 10 4 p at ie nt s w ith c lin ic al ly di se as e f re e f ro m m el an om a. M ea n a ge ± S D 4 7, 6 ± 1 0, 65 . Bo th g en der s. gp 10 0: 209 -21 7 ( 210 M ) pep tid e A rm 1 : g p1 00 p ep tid e ( n = 1 8) A rm 2 : g p1 00 p ep tid e/ IS A 5 1 ( vo rt ex ) ( n = 1 9) A rm 3 : g p1 00 p ep tid e/ IS A 5 1 ( 2 s yr in ge ) ( n = 15) Arm 4 : g p1 00 p ep tid e w ith I m iq ui m od c re am (n = 1 9) A rm 5 : g p1 00 p ep tid e/ IS A 5 1 ( vo rt ex ) w ith Im iq ui m od c re am ( n = 1 9) A rm 6 : g p1 00 p ep tid e/ IS A 5 1 ( 2 s yr in ge ) w ith Im iq ui m od c re am ( n = 1 4) N ot s pe ci fie d i n th e s tu dy i.d . fo r a rm 1 and 4 s.c . fo r a rm 2 , 3, 5 a nd 6 2 O LP : o ve rla pp in g l on g p ep tid es ; s .c .: s ub cu ta ne ou s; i .d .: i nt ra de rm al ; i .m .: i nt ra m us cu la r; n : n um be r o f p ar tic ip an ts ; m L: m ill ili te r; v or te x: a nt ig en a nd I SA 5 1 e m ul sion w er e m ix ed w ith v or te x; 2 s yr in ge : a nt ig en a nd I SA 5 1 e m ul sion w er e m ix ed by 2 s yr in ge s; I m iq ui m od : a t ol l-l ik e 7 l ig an d [ 2] . Th e c re am w as a pp lie d t op ic al ly .
4
60
Controlled studies with healthy subjects
Six trials were conducted in healthy adults (aged ≥ 18 years) and included control group(s) [11,12,40-43]. I.m. administration was used in 5 studies, Pleguezuelos et al. used s.c. administration. The phase I trials from Graham et al., Herrera et al. and Wu et al. included an adjuvant (ISA51) control group. Subjects in the Graham et al. study were randomized to receive a cocktail of HIV peptides (1 mg or 4 mg) adjuvanted with ISA 51 or ISA 51 emulsion alone. Herrera et al. and Wu et al. both tested a malaria antigen. Subjects were randomized to receive ISA 51 emulsion only or a mixture of synthetic peptides (50 mg or 100 mg per peptide) or one of 2 recombinant surface proteins (Pvs25 or Pfs25) adjuvanted with ISA 51, respectively [41,43]. Subjects in the Herrera et al. study were also randomized to receive the tested antigen adjuvanted with Montanide ISA 720 [41]. The phase I/II trial by Atsmon et al. and the phase I trial from Pleguezuelos et al. randomized subjects to receive a placebo, ISA51 emulsion only, or different doses of influenza antigens (250 mg or 500 mg of recombinant protein or polypeptides harboring diverse influenza B and T cell epitopes) with or without ISA 51 [11,12]. In the study of Atsmon et al. 2 immunizations were given and in the study of Pleguezuelos et al. one immunization was given. Subjects in the phase I study of Pialoux et al. all received 2 dosages of vCP125 antigens before they were randomized to receive 2 dosages of rgp160 antigens adjuvanted with alum or ISA 51 [42]. The main study characteristics of the 6 studies are summarized in Table 2. In total there were 231 healthy adults of which 53 were treated with vaccine antigens alone or with a licensed vaccine adjuvant (arm 1 for Atsmon et al., Pialoux et al. and Pleguezelos et al.), 31 with only ISA 51 emulsion (arm 2 or 3) and 117 were treated with ISA 51-adjuvanted vaccines.
In addition, 14 subjects received saline buffer only and 16 subjects received ISA 720-adjuvanted vaccines. Except for the trial performed by Pialoux et al. which has a Jadad score of 2, all the other trials had a score ≥ 3 (Table 2; Table S3).
61 Table 2 Main char act eristics o f the contr
olled studies with health
y subject s St ud y Tr ia l ph as e St ud y p op ul at ion V ac ci ne a nt ige ns Tr eat m en t g rou ps Va cc in e vo lu m e A dmi ni st ra ti on rout e Ja da d sc or e A ts m on et al . [1 1] I/ II 63 v ol un te er s. A ge d 1 8, 1-48 ,5 ye ar s. B ot h gen der s. M ul tim er ic -0 01 A rm 1 : M ul tim er ic-00 1 ( n = 2 3; 3 fo r 1 25 µ g, 1 0 fo r 2 50 µ g a nd 10 fo r 5 00 µ g) A rm 2 : M ul tim er ic-00 1/ IS A 5 1 ( n = 2 0; 1 0 fo r 2 50 µ g a nd 1 0 fo r 50 0 µ g) A rm 3 : I SA 5 1 ( n = 1 0) A rm 4 : S al in e bu ffe r ( n = 1 0) 0, 2 m L fo r a ll ar m s ( 0, 1 m L IS A 5 1) i.m . fo r a ll a rm s 3 G ra ha m et a l. [4 0] I 24 v ol un te er s. A ge d 1 8-58 . B ot h gen der s. H IV -1 C 4-V 3 A rm 1 : H IV -1 C 4-V 3/ IS A 5 1 ( n = 2 1; 1 2 fo r 1 m g p ep tid e a nd 9 fo r 4 m g) A rm 2 : I SA 5 1 ( n = 3 ) 0. 5 m L fo r a ll ar m s ( 0, 25 m L I SA 5 1) i.m . fo r a ll a rm s 5 H er re ra e t a l. [4 1] I 40 v ol un te er s. A ge d 1 9-41 .B ot h gen der s. M ix tu re s o f N , R a nd C L SP de ri ve d f ro m P . vi va x A rm 1 : P ep tid e m ix tu re /I SA 5 1 ( n = 1 6; 8 fo r 5 0 µ g/ pe pt id e a nd 8 fo r 1 00 µ g/ pe pt id e) A rm 2 : P ep tid e m ix tu re /I SA 7 20 ( n = 1 6; 8 fo r 5 0 µ g/ pe pt id e an d 8 fo r 1 00 µ g/ pe pt id e) A rm 3 : I SA 5 1 o r I SA 7 20 ( n = 8 ) (A ll s ub je ct s r ec ei ve d on e d os e w ith N a nd C p ep tid es , a nd t w o do se s w ith a ll t hr ee p ep tid es ) 0. 5 m L fo r a ll ar m s i.m . fo r a ll a rm s 3 Pi al ou x et a l. [4 2] I 20 v ol un te er s. A ge d 3 0-54 y ea rs . Bo th g en der s. vC P1 25 a nd rg p1 60 A rm 1 : r gp 16 0/ al um ( n= 1 0) A rm 2 : r gp 16 0/ IS A 5 1 ( n= 10 ) (A ll s ub je ct s r ec ei ve d t w o v C P1 25 v ac ci na tion s pr io r t o a rm ra nd om iz at io n) 1, 0 m L fo r a ll ar m s ( 0, 5 m L ad juv an t) i.m . fo r a ll a rm s 2 Ple gu ez ue lo s et a l. [1 2] I 48 v ol un te er s. A ge d 1 8-40 . O nl y m ale . FL U -v A rm 1 : F LU -v ( n= 20 ; 1 0 fo r 2 50 µ g a nd 1 0 fo r 5 00 µ g) A rm 2 : F LU -v /I SA 5 1 ( n = 2 0; 1 0 fo r 2 50 µ g a nd 1 0 fo r 5 00 µ g) A rm 3 : I SA 5 1 ( n= 4 ) A rm 4 : S al in e bu ffe r ( n= 4 ) 1, 0 m L fo r a ll ar m s ( 0, 5 m L IS A 5 1) s.c . fo r a ll a rm s 4 Wu e t a l. [ 43] I 36 v ol un te er s. A ge d 1 9-48 . B ot h gen der s. Pf s25 a nd P vs25 A rm 1 : P fs 25 /I SA 5 1 ( n = 1 0) A rm 2 : P vs 25 /I SA 5 1 ( n = 2 0; 1 0 fo r 5 µ g a nd 1 0 fo r 2 0 µ g) A rm 3 : I SA 5 1 ( n = 6 ) 0. 5 m L fo r a ll ar m s ( 0, 25 m L I SA 5 1) i.m . fo r a ll a rm s 3 LS P: l on g s yn th et ic p ep tid es ; P . v iv ax : P la smo di um v iv ax ; m L: m ill ili te r; i .m .: i nt ra m us cu la r:; s .c .: s ub cu ta ne ou s
4
62
Adverse events
Uncontrolled studies with non-healthy subjects
The AE reporting methods vary among the identified trials. For those where specific AEs were reported, commonly reported AEs include injection site reaction, fatigue, fever, gastro-intestinal (GI) disorders including diarrhea, nausea and vomiting, and injection site or local erythema. Most of the observed AEs were not immunization route specific (Table 3). Nevertheless, chills were more commonly reported in trials using the i.m. route (80%), and headache was more commonly reported in trials using other administration route(s) (40%). The severity of reported AEs were mainly mild (grade I) to moderate (grade II). Severe (grade III) AEs, such as fever, headache, fatigue, nausea, hyperglycemia, neutropenia, were reported in 32% of the trials (26/81); 27% of the trials (22/ 81) reported serious (grade IV) AEs (SAEs), such as neutropenia, hyperglycemia, hepatic toxicity and renal failure. A possible cause due to co-intervention (e.g., GM-CSF, IL-2 or gemcitabine) and/or underlying disease could not be excluded.
Table 3 Frequency of commonly reported adverse events from uncontrolled studies with non-healthy subjects and the frequency of serious adverse events
Adverse event Severity Frequency n/N (%) a
i.m. s.c. other routes Total
Fatigue Grade I-IV 0/5 (0,0 %) 30/56 (53,6%) 8/20 (40,0%) 38/81 (46,9%) Fever Grade I-IV 5/5 (100,0%) 23/56 (41,1%) 10/20 (50,0%) 38/81 (46,9%) GI disorders Grade I-IV 3/5 (60,0%) 18/56 (32,1%) 9/20 (45,0%) 30/81 (37,0%) Injection site or
local erythema Grade I-III 3/5 (60,0%) 15/56 (26,8%) 7/20 (35,0%) 25/81 (30,9%) Injection site
reaction Grade I-III 4/5 (80,0%) 38/56 (67,9%) 15/20 (75,0%) 57/81 (70,4%) Serious adverse
event 0/5 (0,0%) 15/56 (26,8%) 7/20 (35,0%) 22/81 (27,2%)
grade I: mild; grade II: moderate; grade III: severe; grade IV: serious; i.m.: intramuscular; s.c.: subcutaneous; other routes: intradermal, intracutaneous, and a combination of intradermal and subcutaneous
a n = number of trials reporting adverse event, N = total number of trials, % = percentage of trials reporting adverse
event
Controlled studies with non-healthy subjects
In the study of Boffito et al. a total of 476 AEs were reported from different treatment group with equal frequency. Most of the reported AEs were mild. Moderate and severe AEs were more often reported from the study groups receiving a high antigen dose. Boffito et al. identified five SAEs, namely gastroenteritis, Kaposi’s sarcoma, perinanal abscess, Shigellosis and lower abdominal pain, which were all considered not to be caused by the HIV vaccine. The safety reporting system used by Boffito et al. did not allow us to extract information on the number of subjects experiencing a specific AE and the total number of AEs experienced in the study. As stated by Boffito et al. the most frequent AEs experienced in this study were injection site pain (12,8%), headache (9,2%) and fatigue (9%) [36].
63
The cancer vaccine trials performed by Goldinger et al., Sabbatini et al. and NCT00273910 included an active control group and reported the number of subjects experiencing a specific AE after the study treatment. The study from Goldinger et al. only reported the occurrence of AEs with an incidence >3 while studies from Sabbatini et al. and NCT00273910 both reported the occurrence of all AEs. Table 4 summarizes the AEs reported in at least 2 of these trials. In general, treatment related AEs were more often observed in the ISA 51-adjuvanted vaccine group than in the active control group. Specific AEs including injection site reaction, pruritus, myalgia and skin and subcutaneous tissue disorders were more commonly reported from the ISA 51-adjuvanted vaccine group. Other AEs reported only by a single study include injection site rash, pain and erythema, skin neoplasm excision, skin nodule, oral herpes, sweating, decreased serum phosphate, hypersensitivity, vomiting, nausea and diarrhea. Notably, most of the AEs reported by subjects in the NCT00273910 trial were reported from subjects receiving the ISA 51-adjuvanted study vaccine prepared by vortex. In this trial, 19 and 14 cancer patients received ISA 51-ajduvanted study antigens prepared by vortex and 2-syringe mixing respectively. All patients receiving the adjuvanted study antigens developed injection site reaction regardless of the preparation process. However, AEs such as leukocyte count decrease, GI disorders, chills, fatigue, sweating and myalgia were only reported from the group receiving the vaccine prepared by vortex mixing. In addition, pruritus was reported in 5 and one patient(s) in the group of vortex and 2-syringe mixing, respectively. Rash was reported in 2 and one patient(s) in the 2 treatment groups, respectively.
While the severity of the AEs reported from NCT00273910 was not available, most of the reported AEs reported from Goldinger et al. and Sabbatini et al. were mild or moderate. SAEs were only reported by Goldinger et al., which were 6 hospitalizations due to tumor progression. None of them was considered related to the study treatment.
Controlled studies with healthy subjects
In the trial of Graham et al., the frequency of the subjects experiencing a specific AE was not given. AEs were classified as local (including pain, tenderness, erythema and induration) or systemic (including malaise, myalgia, headache, fever and nausea) and were graded by severity [40]. Most of the reported AEs were mild. Moderate AEs were more commonly reported from the high antigen dose group (where the amount of ISA 51 was the same as in the low antigen dose group). Severe (systemic) AEs were only reported from the high dose antigen group after the second immunization. Subject dropouts were reported from those receiving the ISA 51-adjuvanted HIV vaccines, at both low and high antigen doses. The dropouts were caused by the painful swelling which occurred after the first immunization. The trial was prematurely terminated (after the second immunization) due to the development of sterile abscesses at the injection site in 4 out of the 21 subjects (19,0%) who received the ISA 51-adjuvanted vaccine. None of subjects in the adjuvant control (ISA 51 in saline buffer) developed sterile abscess and AEs above an intensity of mild.
64
Sterile abscess was also observed in the trial performed by Wu et al. of which the number of volunteers in each vaccination group experiencing a solicited AE was reported. One out of the first 30 (3,3%) enrollees from the ISA 51-adjuvanted vaccine group reported sterile abscess. Aside from frequent occurrence of injection site pain, subjects in both the ISA 51-adjuvanted vaccine groups and adjuvant control group experienced local pain, tenderness and erythema, headache, malaise, nausea and leukopenia. AEs only reported by subjects in the ISA 51-adjuvanted vaccine group included local induration and swelling, arthralgia and myalgia. Although most of the reported AEs were mild, Wu et al. observed severe (grade III) systemic AEs in the group of high Pvs25 antigen dose adjuvanted with ISA 51. In addition, erythema nodosum (an inflammatory panniculitis) were reported from 2 out of the 10 subjects (20,0%) receiving the high dose Pvs25 malaria antigen adjuvanted with ISA 51. The erythema nodosum reactions were judged to be probably related to vaccination and were the cause for the premature termination of the study. Wu et al. observed no significant differences in the incidence of AEs observed after the first and the second immunization. None of the participants in the adjuvant control groups developed AEs above moderate [43].
The prophylactic vaccine trials performed by Atsmon et al., Herrera et al. and Pialoux et al. reported the number of AEs after each immunization [11,41,42]. For the trial of Pleguezuelos et al., only the number of systemic AEs that occurred after a single injection could be extracted. Table 5 summarizes the reported AEs from the ISA 51-adjuvanted vaccine group and the different control groups which were reported in at least 2 of the 4 trials. The reported treatment related AEs were in general evenly distributed between the ISA 51-adjuvanted vaccine groups, the active control groups and the adjuvant control groups. Only injection site pain or tenderness were more commonly reported in the ISA 51-adjuvanted vaccine group compared to the control groups. Other AEs reported only by a single study include local swelling and erythema, redness, warmth, fatigue, rhinorrhea/nasal congestion, diarrhea, dizziness, abdominal pain, adenopathy, asthenia and malaise. The AEs reported by the 4 studies were classified as mild and moderate. Only Pleguezuelos et al. and Herrera et al. reported AEs with an intensity above moderate; 2 severe AEs (appendicitis and pre-syncope) and 2 cases of SAEs (chronic cholecysitis and acute urolithiasis), respectively. In both studies these events were considered not directly caused by the vaccine [12,41].
65
Table 4 Frequency of adverse events reported in at least two controlled studies with non-healthy subjects
Study ISA 51-adjuvanted study
vaccine n/N (%) a Active control n/N (%) a
1. Any treatment related adverse event
Goldinger et al. b
NCT00273910 34/34 (100,0%) 18/18 (100,0%)
Sabbatini et al. 12/13 (92,3%) 2/4 (50,0%)
Total 46/47 (97,9%) 20/22 (90,9%) 2. General disorders and administration site conditions c
2.1 Any adverse event from the category general disorders and administration site conditions Goldinger et al. b
NCT00273910 34/34 (100,0%) 18/18 (100,0%)
Sabbatini et al. 12/13 (92,3%) 2/4 (50,0%)
Total 46/47 (97,9%) 20/22 (90,9%)
2.2 Injection site inflammation (edema (or swelling) and redness), damage or induration
Goldinger et al. b 2/5 (40,0%) 1/5 (20,0%) NCT00273910 34/34 (100,0%) 18/18 (100,0%) Sabbatini et al. 7/13 (53,8%) 1/4 (25,0%) Total 43/52 (82,7%) 20/27 (74,1%) 2.3 Pruritus (itching) Goldinger et al. b 0/5 (0,0%) 0/5 (0,0%) NCT00273910 6/34 (17,6%) 0/18 (0,0%) Sabbatini et al. 1/13 (7,7%) 0/4 (0,0%) Total 7/52 (13,5%) 0/27 (0,0%) 2.4 Fatigue Goldinger et al. b 3/5 (60,0%) 4/5 (80,0%) NCT00273910 4/34 (11,8%) 0/18 (0,0%) Sabbatini et al. 6/13 (46,2%) 2/4 (50,0%) Total 13/52 (25,0%) 6/27 (22,2%)
2.5 Influenza like illness
Goldinger et al. b 2/5 (40,0%) 2/5 (40,0%)
NCT00273910 0/34 (0,0%) 0/18 (0,0%)
Sabbatini et al. 2/13 (15,4%) 0/4 (0,0%)
Total 4/52 (7,7%) 2/27 (7,4%) 3. Blood and lymphatic system disorders c
Lymphadenopathy Goldinger et al. b 1/5 (20,0%) 3/5 (60,0%) NCT00273910 0/34 (0,0%) 0/18 (0,0%) Sabbatini et al. 1/13 (7,7%) 0/4 (0,0%) Total 2/52 (3,8%) 3/27 (11,1%) 4. Investigations c
Total (leukocyte count decreased and abnormal neutrophil count)
Goldinger et al. b 0/5 (0,0%) 0/5 (0,0%)
NCT00273910 1/34 (2,9%) 1/18 (5,6%)
Sabbatini et al. 1/13 (7,7%) 0/4 (0,0%)
Total 2/52 (3,8%) 1/27 (3,7%) 5. Musculoskeletal and connective tissue disorders c
Myalgia
Goldinger et al. b 0/5 (0,0%) 0/5 (0,0%)
NCT00273910 2/34 (5,9%) 0/18 (0,0%)
Sabbatini et al. 2/13 (15,4%) 0/4 (0,0%)
Total 4/52 (7,7%) 0/27 (0,0%) 6. Skin and subcutaneous tissue
disorders c Rash Goldinger et al. b 0/5 (0,0%) 0/5 (0,0%) NCT00273910 3/34 (8,8%) 0/18 (0,0%) Sabbatini et al. 1/13 (7,7%) 0/4 (0,0%) Total 4/52 (7,7%) 0/27 (0,0%)
a n = number of participants in the study experiencing adverse events, N = total number of participants in the
study, % = percentage of participants in the study experiencing adverse event. b The original article only reported
the adverse events with an incidence > 3 among the study participants.
c Classification adverse events are based on the Medical Dictionary for Regulatory Activities (MedRA) Version 17.0
(March 2014).
66
DISCUSSION
We have assessed the safety and tolerability of ISA 51 as a vaccine adjuvant. A total of 91 clinical trials on ISA 51-adjuvanted vaccines which provided information on safety, tolerability and/ or toxicity were reviewed. Of these 91 trials, 81 were uncontrolled studies with non-healthy subjects, 4 were controlled studies with non-healthy subjects and 6 were controlled studies with healthy subjects.
Commonly reported AEs from uncontrolled trials included fever, fatigue, GI disorders, injection site erythema and injection site reaction. These AEs were also reported from controlled trials. For controlled trials with non-healthy subjects the frequency of AEs was generally higher in the ISA 51-adjuvanted vaccine group compared with the active control group. However, for controlled studies with healthy subjects the reported AEs were in general evenly distributed between the treatment groups except for injection site pain or tenderness. These AEs were more commonly reported in the ISA 51-adjuvanted vaccine group compared to the active and adjuvant control groups. Since the immune response and the sensitivity to pain and discomfort can be expected to be different between non-healthy and healthy subjects, we classified the reviewed studies into 2 subject backgrounds. However, the reported AEs were found to be neither subject specific nor immunization route specific.
In general, the observed AEs from controlled trials with nonhealthy as well as healthy individuals were mild to moderate in intensity. However, it should be noted that 2 controlled studies on ISA 51-adjuvanted vaccines in healthy subjects were terminated prematurely due to unacceptable AEs [40,43]. The study of Wu et al. was stopped after the 2 reported cases of erythema nodosum, which was not observed from other ISA 51-adjuvanted vaccine studies. The trial by Graham et al. was stopped after 4 cases of sterile abscess, which was also reported by one subject who had erythema nodosum in the trial of Wu et al. and by subjects in 2 other uncontrolled therapeutic vaccine studies in breast cancer patients. In the study of Carr et al., one of the 21 patients (4,8%) was reported to develop a small abscess after receiving the ISA 51-adjuvanted cancer vaccine [44]. The same vaccine was later used in the trial by Mulens et al. where two of the 38 patients (5,3%) who received the ISA 51-adjuvanted vaccine developed
severe abscess after the vaccination [45]. Since none of the subjects in the adjuvant control group of Graham et al. and Wu et al. was reported to have erythema nodosum, sterile abscess, and/or AEs with an intensity above mild, it is unlikely that the unwanted side effects were caused by ISA 51 alone. Wu et al. noted that the same production lot of malaria Pvs25 antigen was used to produce alum-adjuvanted Pvs25 vaccine, and was shown to be well tolerated in humans [46]. This ruled out the possibility that the unacceptable AEs were caused by the antigen alone. It is therefore most likely that the AEs were caused by the combination of ISA 51 and vaccine antigens. Thus, the mixing procedure for ISA 51 emulsified adjuvant and antigens and other factors involved in the final presentation of the combined product (e.g., antigen dose, dose volume, etc.) should be investigated as possible cause(s) for the observed serious AEs.
4
67
Table 5 Frequency of adverse events reported in at least two controlled studies with healthy subjects
Study ISA 51-adjuvanted study vaccine n/N
(%) a
Active control n/N
(%) a Adjuvant control n/N (%) a Placebo control n/N (%) a
1. General disorders and administration site conditions b
1.1 Injection site pain or tenderness
Atsmon et al. 1/38 (2.6%) 0/40 (0,0%) 0/20 (0,0%) 0/20 (0,0%) Herrera et al. 35/46 (76,1%) NA 15/24 (62,5) NA Pialoux et al. 8/20 (40,0%) 11/20 (55,0%) NA NA Pleguezuelos et al. c Total 44/104 (42,3%) 11/60 (18,3%) 15/44 (34,1%) 0/20 (0,0%) 1.2 Fever Atsmon et al. 4/38 (10,5%) 2/40 (5,0%) 2/20 (10,0%) 1/20 (5,0%) Herrera et al. 1/46 (2,2%) NA 4/24 (16,7%) NA Pialoux et al. 1/20 (5,0%) 1/20 (5,0%) NA NA Pleguezuelos et al. 0/20 (0,0%) 0/20 (0,0%) 0/4 (0,0%) 0/4 (0,0%) Total 6/124 (4,8%) 3/80 (3,8%) 6/48 (12,5%) 1/24 (4,2%) 1.3 Fatigue Atsmon et al. 7/38 (18,4%) 13/40 (32,5%) 6/20 (30,0%) 0/20 (0,0%) Herrera et al. 0/46 (0,0%) NA 0/24 (0,0%) NA Pialoux et al. 0/20 (0,0%) 0/20 (0,0%) NA NA Pleguezuelos et al. 4/20 (20,0%) 5/20 (25,0%) 0/4 (0,0%) 0/4 (0,0%) Total 11/124 (8,9%) 18/80 (22,5%) 6/48 (12,5%) 0/24 (0,0%) 2. Gastrointestinal disorders b Nausea Atsmon et al. 2/38 (5,3%) 3/40 (7,5%) 3/20 (15,0%) 1/20 (5,0%) Herrera et al. 3/46 (6,5%) NA 3/24 (12,5%) NA Pialoux et al. 0/20 (0,0%) 0/20 (0,0%) NA NA Pleguezuelos et al. 3/20 (15,0%) 1/20 (5,0%) 0/4 (0,0%) 0/4 (0,0%) Total 8/124 (6,5%) 3/80 (3,8%) 6/48 (12,5%) 1/24 (4,2%) 3. Musculoskeletal and connective tissue disorders
Myalgia Atsmon et al. 3/38 (7,9%) 5/40 (12,5%) 1/20 (5,0%) 0/20 (0,0%) Herrera et al. 0/46 (0,0%) NA 0/24 (0,0%) NA Pialoux et al. 1/20 (5,0%) 1/20 (5,0%) NA NA Pleguezuelos et al. 6/20 (30,0%) 1/20 (5,0%) 1/4 (25,0%) 0/4 (0,0%) Total 10/124 (8,1%) 7/80 (8,8%) 2/48 (4,2%) 0/24 (0,0%) 4. Nervous system disorders
Headache Atsmon et al. 5/38 (13,2%) 14/40 (35,0%) 3/20 (15,0%) 2/20 (10,0%) Herrera et al. 6/46 (13,0%) NA 4/24 (16,7%) NA Pialoux et al. 5/20 (25,0%) 1/20 (5,0%) NA NA Pleguezuelos et al. 4/20 (20,0%) 7/20 (35,0%) 1/4 (25,0%) 1/4 (25,0%) Total 20/124 (16,1%) 22/80 (27,5%) 8/48 (16,7%) 3/24 (12,5%) a n = number of adverse events experienced by the study participants, N = number of vaccines given, % = percentage
of adverse events per immunization .
b Classification of adverse events is based on the Medical Dictionary for Regulatory Activities (MedRA) Version 17.0
(March 2014).
c The number of local adverse events experienced by the study participants per treatment group could not be
extracted from the study of Pleguezuelos et al.
NA = not applicable; control group not included in the study
68
The effect of the method used for mixing ISA 51 and vaccine antigen was particularly addressed in the trial NCT00273910. In this trial, subjects receiving the ISA 51-adjuvanted study vaccine prepared by vortex experienced more AEs, e.g., pruritus, rash, GI disorders, chills, fatigue and myalgia, compared to subjects receiving the study vaccine by 2-syringe mixing. The increased frequency of AEs observed from the vortex mixing group is likely resulted from the poor quality of the mixed ISA 51/antigen emulsions. Vortex mixing probably did not generate enough shear strength to produce stable emulsions [5]. With unstable emulsions, coalescence and change in the droplet size will occur. The antigen is thus no longer entrapped but readily released into the injected environment. Moreover, the escaped mineral oils might cause unwanted local or systemic side effects. Therefore, mixing by syringe is recommended for small volume preparations to obtain homogenous and stable emulsions [5].
To properly address the effect of ISA 51 on vaccine safety and tolerability, the AEs reported from ISA 51-adjuvanted vaccine need to be compared to those from an active control group. The inclusion of an active control group, however, was found to be rare among the reviewed studies. This might be due to ethical consideration (e.g. it may be considered unethical to give patients suboptimal treatments) or due to lack of a scientific interest. Only seven out of the 91 reviewed studies has an active control group. This limited the power to detect statistically significant differences between the ISA 51-adjuvanted vaccine group and the active control group. Therefore, the incidence of AEs could only be compared in a descriptive way.
This review has several limitations. AEs reported by Goldinger et al. were pre-selected and only those with an AE incidence of more than 3 in the study population were presented. Therefore, the AEs with an incidence of zero in Table 4 for the study of Goldinger et al. may not reflect the real situation. Besides, 5 of the 11 controlled studies (45,5%) included for the review had a low methodological quality based on the Jadad scores. Except the trials performed by Boffito et al., Graham et al., Herrera et al. and Pleguezelos et al. the other included controlled studies might have detection and performance biases since there were no blinding procedures for the study participants, personnel and the investigators [47]. Such potential biases might result in giving more attention to those study participants that receive the ISA 51-adjuvanted vaccines. This may have resulted in an overestimation of (S)AEs in the participants receiving an ISA 51-adjuvanted vaccine. Furthermore, 3 of the 6 controlled trials with non-healthy subjects may be subject to selection bias since no randomization procedure was mentioned. However, it is not clear to us what the likely direction the potential selection bias may cause [47]. Last but not least, different AE classifications and reporting systems used by the reviewed studies limited the possibility to present a complete overview of the occurrence and the frequency of AEs experienced by subjects who received ISA 51-adjuvanted vaccines. This could have led to an underestimation of the AEs, especially for the uncontrolled trials.
69
CONCLUSION
AEs are frequently reported among trials testing ISA 51-adjuvanted antigens including non-healthy subjects as well as non-healthy subjects. In addition, SAEs are frequently reported among studies with non-healthy subjects and 2 trials testing ISA 51-adjuvanted prophylactic vaccines with healthy subjects are stopped due to unacceptable AEs which were most likely caused by the combination of ISA 51 adjuvant and the vaccine antigens. Studies indicate that the mixing procedure of the study antigen with ISA 51 might influence the occurrence of AEs. Therefore, for future trials caution should be taken when mixing ISA 51 and the vaccine antigen, especially with regards to small volumes, in order to produce stable emulsions and to prevent unwanted side effects. In addition, trials including an active control group are urgently needed for a fair evaluation of adjuvant safety and tolerability and adjuvant effect on immune boosting, preferably using a standardized reporting system for vaccine related AEs such as the MedRA reporting system.
70
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SUPPLEMENTARY MATERIALS
Table 1. List of the 91 eligible studiesA) Uncontrolled studies with non-healthy subjects (N = 81)
Aruga et al (2014) Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer. J Transl Med 12
Barve M et al (2008) Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer. J Clin Oncol 26:4418-25.
Block MS et al (2011) Pilot study of granulocyte-macrophage colony-stimulating factor and interleukin-2 as immune adjuvants for a melanoma peptide vaccine. Melanoma Res 21:438-45. Carr A et al (2003) Immunotherapy of advanced breast cancer with a heterophilic ganglioside
(NeuGcGM3) cancer vaccine. J Clin Oncol 21: 1015-21.
Celis E et al (2007) Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma: evidence of systemic immune dysfunction. Cancer 110:203-14.
Chianese-Bullock et al
(2008) A multipeptide vaccine is safe and elicits T-cell responses in participants with advanced stage ovarian cancer. J Immunother 31:420-30. Chianese-Bullock et al
(2005) Autoimmune toxicities associated with the administration of antitumor vaccines and low-dose interleukin-2. J Immunother 28:412-9. Diefenbach et al
(2008) Safety and immunogenicity study of NY-ESO-1b peptide and montanide ISA-51 vaccination of patients with epithelial ovarian cancer in high-risk first remission. Clin Cancer Res 14:2740-8.
Fenoglio et al (2013) A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer. Cancer Immunol Immunother 62:1041-52.
Feyerabend et al
(2009) Novel multi-peptide vaccination in Hla-A2+ hormone sensitive patients with biochemical relapse of prostate cancer. Prostate 69:917-27. Filipazzi P et al (2012) Limited induction of tumor cross-reactive T cells without a measurable clinical
benefit in early melanoma patients vaccinated with human leukocyte antigen class I-modified peptides. Clin Cancer Res 18:6485-96.
Giannopoulos et al
(2010) Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8 T-cell responses in patients with chronic lymphocytic leukemia. Leukemia 24:798-805.
Gonzalez et al (2003) Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy. Ann Oncol 14:461-6.
Guthmann et al (2004) Active specific immunotherapy of melanoma with a GM3 ganglioside-based vaccine: A report on safety and immunogenicity. J Immunother 27:442-51. Hamid et al (2007) Alum with interleukin-12 augments immunity to a melanoma peptide vaccine:
Correlation with time to relapse in patients with resected high-risk disease. Clin Cancer Res 13:215-22.
Ishikawa et al (2014) Phase I clinical trial of vaccination with LY6K-derived peptide in patients with advanced gastric cancer. Gastric Cancer 17:173-80.
Ishikawa et al (2012) Phase I clinical trial of vaccination with URLC10-derived peptide for patients with advanced esophageal cancer. Esophagus 9:105-12.
Iwahashi et al (2010) Vaccination with peptides derived from cancer-testis antigens in combination with CpG-7909 elicits strong specific CD8+ T cell response in patients with metastatic esophageal squamous cell carcinoma. Cancer Sci 101:2510-17.
Izumoto et al (2008) Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg 108:963-71.
Kaida et al (2011) Phase 1 trial of Wilms tumor 1 (WT1) peptide vaccine and gemcitabine
combination therapy in patients with advanced pancreatic or biliary tract cancer. J Immunother 34:92-9.
74
A) Uncontrolled studies with non-healthy subjects (N = 81)
Kakimi et al (2011) A phase I study of vaccination with NY-ESO-1f peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen. Int J Cancer 129:2836-46.
Karbach et al (2010) Tumor-reactive CD8+ T-cell responses after vaccination with NY-ESO-1 peptide, CpG 7909 and Montanide(registered trademark) ISA-51: Association with survival. Int J Cancer 126:909-18.
Kenter et al (2008) Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity. Clin Cancer Res 14:169-77. Kouiavskaia et al
(2009) Vaccination with agonist peptide PSA: 154-163 (155L) derived from prostate specific antigen induced CD8 T-cell response to the native peptide PSA: 154-163 but failed to induce the reactivity against tumor targets expressing PSA: A phase 2 study in patients with recurrent prostate cancer. J Immunother 32:655-66.
Krug et al (2010) WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer. Cancer Immunol Immunother 59:1467-79.
Kuball et al (2011) Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909. Cancer Immunol Immunother 60:161-71.
Lee et al (2001) Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol 19:3836-47.
Lennerz et al (2014) Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors. Cancer Immunol Immunother 63:381-94. Leffers et al (2009) Immunization with a P53 synthetic long peptide vaccine induces P53-specific
immune responses in ovarian cancer patients, a phase II trial. Int J Cancer 125:2104-13.
Markovic et al (2006) Peptide vaccination of patients with metastatic melanoma: Improved clinical outcome in patients demonstrating effective immunization. Am J Clin Oncol 29:352-60.
Maslak et al (2010) Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia. Blood 116:171-9.
Matsushita et al (2013) Phase I clinical trial of a peptide vaccine combined with tegafur-uracil plus leucovorin for treatment of advanced or recurrent colorectal cancer. Oncol Rep 29:951-9.
Mavroudis et al (2006) A phase I study of the optimized cryptic peptide TERT572Y in patients with advanced malignancies. Oncology (Switzerland) 70:306-14.
M.D. Anderson
Cancer Center (2012) PR1 vaccination in myelodysplastic syndrome (MDS) (NCT00893997).
Miyazawa et al (2010) Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer. Cancer 101:433-9.
Morita et al (2006) A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: Safety assessment based on the phase I data. Jpn J Clin Oncol 36:231-6.
Morse et al (2011) MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer. Clin Cancer Res 17:3408-19.
Mulens et al (2010) Immunogenicity and safety of a NeuGcGM3 based cancer vaccine: Results from a controlled study in metastatic breast cancer patients. Hum Vaccin 6:736-44. National Cancer
Institute (2013) Anti-MART-1 F5 lymphocytes to treat high-risk melanoma patients (NCT00706992). National Cancer
Institute (2012) Lymphocyte re-infusion during immune suppression to treat metastatic melanoma (NCT00001832).
75
A) Uncontrolled studies with non-healthy subjects (N = 81)
National Cancer
Institute (2012) Peptide vaccination for patients at high risk for recurrent melanoma (NCT0059475). National Cancer
Institute (2012) Radiation, chemotherapy, vaccine and anti-MART-1 and anti-gp100 cells for patients with metastatic melanoma (NCT00923195). National Cancer
Institute (2014)
Vaccine therapy with tumor specific mutated VHL peptides in adult cancer patients with renal cell carcinoma (NCT00001703).
National Cancer
Institute (2012) Vaccine treatment of kidney cancer (NCT00089778).
Nishida et al (2014) Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J Immunother 37: 105-14.
Nistico et al (2009) Chemotherapy enhances vaccine-induced antitumor immunity in melanoma patients. Int J Cancer 124:130-9.
Noguchi et al (2004) Phase I trial of patient-oriented vaccination in HLA-A2-positive patients with metastatic hormone-refractory prostate cancer. Cancer Sci 95:77-84.
Noguchi et al (2012) Phase II study of personalized peptide vaccination for castration-resistant prostate cancer patients who failed in docetaxel-based chemotherapy. Prostate 72:834-45. Odunsi et al (2007) Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces
integrated humoral and T cell responses in ovarian cancer. Proc Natl Acad Sci U S A 104:12837-42.
Ohno et al (2009) Wilms’ tumor 1 (WTl) peptide immunotherapy for gynecological malignancy. Anticancer Res 29:4779-84.
Ohno et al (2012) Phase I trial of Wilms’ tumor 1 (WT1) peptide vaccine with GM-CSF or CpG in patients with solid malignancy. Anticancer Res 32:2263-9.
OHSU Knight Cancer
Institute (2011) Vaccine therapy in treating patients with chronic phase chronic myelogenous leukemia (NCT00428077). Oka et al (2003) Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia
from myelodysplastic syndrome (MDS) or MDS with myelofibrosis. Int J Hematol 78:56-61.
Osorio et al (2008) Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: Results of a Phase Ib/IIa study. Cancer Biol Ther 7:488-95.
Pinto et al (1999) HIV-specific immunity following immunization with HIV synthetic envelope peptides in asymptomatic HIV-infected patients. AIDS 13:2003-12.
Pollack et al (2013) Peptide vaccine therapy for childhood gliomas. Neurosurgery 60: 113-9.
Rahma et al (2012) A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: Subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother 61:373-84.
Rahma et al (2010) A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic Renal Cell Carcinoma. J Transl Med 8.
Rezvani et al (2012) Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy. Cancer Immunol Immunother 61:1125-36.
Rezvani et al (2008) Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 111:236-42. Rosenberg et al (2010) Different adjuvanticity of incomplete Freund’s Adjuvant derived from beef or
vegetable components in melanoma patients immunized with a peptide vaccine. J Immunother 33:626-9.
Sanderson et al (2005) Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741-50.
