© 2006 European Society for Medical Oncology
phase I and pharmacokinetics |
The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of the AGO-OVAR
1 Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein
2 Klinik für Gynäkologie und Gynäkologische Onkologie, HSK Dr. Horst Schmidt Klinik, Wiesbaden
3 Klinik für Frauenheilkunde und Geburtshilfe, Charité Campus Virchow-Klinikum, Berlin
4 Klinik für Gynäkologie und Geburtshilfe, Klinikum der J.W. Goethe-Universität, Frankfurt/M
5 Klinik für Gynäkologie, Gyn. Endokrinologie und Onkologie, Universitätsklinikum Giessen und Marburg, Standort Marburg
6 Koordinierungszentrum für Klinische Studien, Philipps-Universität Marburg
7 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Carl Gustav Carus, Dresden
8 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Klinikum der Ernst-Moritz-Arndt Universität Greifswald
9 Frauenklinik, Universitätsklinikum Essen
10 Universitätsfrauenklinik, Otto von Guericke Universität Magdeburg
11 Frauenklinik, Universitätsklinikum Ulm, Germany
* Correspondence to: Prof. Dr. med. J. Pfisterer, Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Michaelisstr. 16, D-24105 Kiel, Germany. Tel: +49-431-597-4089; Fax: +49-431-597-4090; E-mail: jpfisterer{at}email.uni-kiel.de
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc).
Patients and methods: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response.
Results: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFN
-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups.
Conclusions: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.
Key words: abagovomab, anti-idiotypic antibody, ovarian cancer, phase I trial, recurrence
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Despite the progress over recent years in the treatment of ovarian cancer, the majority of patients will recur and finally die [1, 2]. Thus, further improvement of first-line therapy is urgently required. Additionally, although many patients respond to second-line chemotherapy, nearly all of them will ultimately die due to their disease. For both scenarios, in patients with minimal or subclinical residual disease at the end of chemotherapy consolidation strategies are needed. Thus, immunologic approaches are an attractive option in this minimal disease state.
Anti-idiotype (anti-id) vaccine development represents an innovative option to target tumor-associated antigen-expressing cells. The anti-id antibody abagovomab (formerly ACA125) targets the low immunogenic CA125 which is expressed by the broad majority of ovarian cancer cells and is targetable to induce specific humoral and cellular immune response [3–5].
The ‘immune network hypothesis’ attempts to transform epitope structures into idiotypic determinants expressed on the surface of antibodies [6, 7]. This approach assumes that immunization with a given antigen will generate the production of antibodies against this antigen, termed Ab1. Ab1 can generate anti-id antibodies against Ab1, termed Ab2. Some of the anti-id antibodies (Ab2ß) express the internal image of the antigen recognized by the Ab1 and can cause the production of anti-anti-id antibodies, Ab3, that recognize the corresponding original antigen identified by Ab1 [8, 9]. The anti-idiotype approach has been used in a variety of clinical studies including patients with colon cancer, melanoma, small cell lung cancer and neuroblastoma. Immune responses have been demonstrated, and some have suggested a benefit in those patients in whom active immunization was generated [10–15]. Preliminary clinical data in ovarian cancer patients with intramuscular (i.m.) injection of abagovomab showed good tolerability and safety and indicated that immune response is associated with improved survival, prompting the need to evaluate the optimal application route, dose and regimen of abagovomab vaccination [16, 17].
Therefore, we conducted a phase I trial of abagovomab in patients with recurrent ovarian, fallopian tube or peritoneal cancer after completion of chemotherapy for recurrence comparing two subcutaneous (s.c.) vaccination schedules.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The study was designed and performed in accordance with good clinical practice guidelines, German drug law, relevant laws regarding the realization of clinical studies, and the Declaration of Helsinki. Centers of the AGO-OVAR participated after having obtained approval of their respective local ethics committees. All patients provided written informed consent before entry into the study.
Patients with histologically proven epithelial cancer of the ovary or fallopian tube or with extraovarian papillary serous carcinoma FIGO (Fédération Internationale de Gynécologie et d'Obstétrique [18]) stage I–IV at primary diagnosis were eligible for inclusion in this study. Additionally, they had to have received initial surgery and chemotherapy with at least one platinum-based chemotherapy regimen and had to have relapsed. Furthermore, completed chemotherapy for recurrent disease within the previous 6 weeks was required. Eligible patients were those who would have been appropriate to enter a period of observation if standard management had been considered. Patients were required to have adequate hematologic, renal and hepatic function. Exclusion criteria were any other active concomitant malignancy, uncontrolled infection, autoimmune disease, immune deficiency or immunosuppressive therapy or known allergy to murine proteins. Patients could not be included if they had had cytotoxic chemotherapy, radiotherapy or immunotherapy or biological modifiers within 3, 4 and 6 weeks, respectively, before enrolment, or in case of any prior anti-cancer vaccine. All women of child-bearing potential were required to have a negative pregnancy test and to use an adequate contraceptive method throughout the study period.
study design
The study was an open-label phase I trial to compare two different s.c. vaccination schedules of abagovomab: a long arm (L) group received nine injections versus a short arm (S) group receiving six injections. Primary endpoint was drop-out rate due to toxicity. Secondary endpoints were humoral immunological responses in terms of Ab3 and human anti-mouse antibody (HAMA) induction and cellular responses in terms of CA125-specific cytotoxicity of CD8+ and CD4+ T-cells. Clinical efficacy (e.g. response) was not an endpoint and was therefore not assessed.
treatment
Abagovomab was administered subcutaneously (injection in buttocks, thighs, abdomen or arm) at a dosage of 2 mg in 1 ml volume in one syringe. Both groups received four injections every 2 weeks (induction phase). Group S received two additional injections and group L five additional injections every 4 weeks (consolidation phase). Premedication before each single vaccination was not recommended. Treatment was performed on an outpatient basis.
patient evaluation
Patients were evaluated on a regular basis during every treatment and follow up. Before each vaccination all safety parameters were recorded according to the NCI-CTC criteria (CTC-Version 2.0 [19]). Additonally, full hematology, chemistry and CA125 measurement was performed.
Immune parameters were assessed in patients before starting the vaccination and before fifth and sixth abagovomab-application (short arm) or fifth, sixth, seventh, eighth and ninth application (long arm), respectively. For both groups, follow-up monitoring was performed at 2 and 6 weeks after the last injection.
detection of Ab3 and HAMA responses
Anti-allo- and anti-isotypic HAMA were determined by ELISA (Roche Diagnostics, Germany). HAMA response was termed positive if concentration exceeded 15 ng/ml. This concentration was chosen based on the detection limit and the sensitivity of the commercial HAMA assay kit used.
Determination of specific anti-anti-id antibodies (Ab3) was performed as described previously [16] including the following modifications: purified sera were allowed to bind to biotinylated anti-id abagovomab immobilized on streptavidin-coated microtiter plates (StreptaWell MTP, Roche Diagnostics, Germany) and bound Ab3 was detected with horseradish peroxidase-labelled rabbit anti-human IgG (Fc-specific, Dianova, Germany). Ab3 concentrations were determined using purified human Ab3 as standard. Ab3 responses were termed positive if concentration exceeded 1000 ng/ml. The cut-off for positive Ab3 response (>1000 ng/ml) was defined to exclude non-specific background staining which was observed in sera from healthy donors.
determination of CA125-specific antibodies (Ab1')
Microtiter plates were coated with 1000 U/ml purified CA125 antigen, blocked and incubated with pre- and postimmune sera of immunized patients. Anti-CA125 antibodies, so-called Ab1', were detected with anti-id mAb abagovomab, followed by incubation with HRP-labelled Fc-specific goat anti-mouse IgG (Dianova, Germany). Ab1' immunocomplexes (i.e. antibodies bound to circulating CA125) were measured after dissociation of the complexes by acid/heat treatment of patients' sera as described previously [17]. Ab1' antibody titers were defined as the highest dilution of sera with optical density at 405 nm (OD405) > 0.1 after subtracting background values.
detection of antigen-specific T cells
Frequencies of antigen-specific T cells were analyzed by cytokine flow cytometry in cryopreserved peripheral blood mononuclear cells (PBMC). PBMC were stimulated with 5000 U/ml CA125 antigen and co-stimulatory antibody CD28/CD49d (Becton Dickinson, Germany). Experimental controls included PBMC in the presence of co-stimulatory reagent without CA125 or with 5 µg/ml PHA (phytohemagglutinin) (Sigma Aldrich, Germany). Cultures were incubated at 37°C and 5% CO2 for a total of 18 h, adding 5 µg/ml Brefeldin A (Sigma, Germany) for the last 16 h. Activated cells were washed, permeabilized and subsequently stained with BD Fastimmune anti-hu-IFN FITC/CD69 PE/CD8 PerCP-Cy5/CD3 APC (Becton Dickinson, Germany). The percentage of IFN+/CD69+ T cells was determined using a FACS Calibur flow cytometer and CellQuestPro software (Becton Dickinson, Germany). Frequencies of IFN+/CD69+ T cells 
0.05% after subtracting background staining of the unstimulated control were regarded as CA125-specific. Immunological responders were defined as patients who demonstrated >2-fold increase of IFN-expressing T cells at least once during the study period.
statistical analyses
Based on clinical endpoint considerations, the sample size of this trial was set to 18 patients in each cohort, which was considered adequate for a preliminary assessment of safety, feasibility and tolerability of abagovomab. The first 18 consecutive patients enrolled were allocated to group L, the subsequent 18 to group S. No confirmative analyses were planned, all statistical analyses were merely exploratory. The drop-out rates due to toxicity and the humoral as well as cellular immune response rates in both cohorts were compared using Fisher's exact test with a two-sided alpha level of 0.05. Toxicity was measured by examining the frequency of grade 1–4 toxicities, graded according to the NCI-CTC (National Cancer Institute Common Toxicity Criteria) 2.0 and evaluated using the worst score over all cycles for each patient. Patients receiving at least one abagovomab injection were qualified for safety analysis. All statistical analyses were done with SAS (version 8.2; SAS Institute, Cary, NC).
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
Thirty-eight patients were recruited by 10 centers between July 2003 and April 2004. Two patients were excluded: one patient withdrew consent and one patient had progressive disease before the first vaccination. From the total of 36 eligible patients, the first 18 (50%) patients were assigned to receive the long arm (nine injections), the second 18 (50%) patients to the short arm (six injections). Figure 1 shows the trial profile.
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Patient characteristics are shown in Table 1. The age distributions in the two treatment arms differed significantly (P = 0.001) with a mean of 52.5 (±11.6) and 65.3 (±7.9) years in groups S and L, respectively. There were no significant differences with regard to ECOG (Eastern Cooperative Oncology Group) and FIGO-stage distribution at primary diagnosis between both treatment arms.
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treatment compliance
A total of 230 vaccinations were applied, 126 (55%) in group L and 104 (45%) in group S. The short schedule was completed as planned in 16 (89%) patients and the long schedule in eight (44%) patients. Seventeen (94%) patients from each group received the initial four injections every 2 weeks. In group L, 13 (72%) patients received at least six injections, followed by 10 (56%), nine (50%) and eight (44%) patients who received at least seven, eight or nine injections, respectively (Figure 1). In group S, premature termination occurred due to one patient's withdrawal (6%) and one patient's progressive disease (6%). Premature termination in group L occurred due to progressive disease in eight (44%) and due to death as a result of progressive disease in two (11%) patients.
toxicity
Hematologic toxicities did not exceed grade 2 and were presumably related to the disease and prior cytotoxic treatment rather than the vaccination with abagovomab (Table 2).
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Non-hematologic toxicities were usually mild and transient (Table 3). The most common toxicity related to the vaccine was grade 1/2 local injection site reaction which occurred in 15 (83%) patients of group L and 15 (83%) patients of group S. All other non-hematologic toxicities were rare. No treatment-limiting toxicities were observed in either group.
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Ab3 assessment
There were no significant differences between the two vaccination schedules with regard to Ab3-induction (Figure 2). At baseline, two patients of group L had low Ab3 titers (1.2 µg/ml and 1.9 µg/ml), while none of the patients in group S tested positive for Ab3. In group S, 17 (94.4%) patients were Ab3-positive at least once after vaccination. The patient for whom a positive Ab3 is not documented had progressive disease after three injections. In group L 16 (88.8%) patients were Ab3-positive at least once during Ab3 assessments. Of those for whom a positive Ab3 was not measured, one died after two injections and one had progressive disease after four injections. Neither of them was tested for Ab3, thus resulting in 100% of Ab3-positivity for all tested patients in both groups. Ab3-induction set on during the vaccination period and increased during the course of treatment with the maximum at 6 weeks follow-up in both groups (Figure 2). The median Ab3 titer 6 weeks after the last injection tended to be higher in group L, with 359.6 µg/ml (range: 98.9–988.7), than in group S, with 209.6 µg/ml (range: 8.6–618.9), but this difference was not statistically significant (P = 0.0556).
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HAMA assessment
HAMA was evaluable in 16 (88.8%) and 17 (94.4%) patients in groups L and S, respectively. The reasons for non-evaluation were the same as mentioned for Ab3 assessment. HAMA was positive in 17 (100%) patients of group S and 15 (93.8%) patients of group L at least once during the study period. The two schedules did not show any significant differences with regard to HAMA titers (Figure 3). HAMA titer increased steadily in both groups during the study period. Maximum titers were reached 6 weeks after the last injection in both treatment arms. Median titer at 6 weeks follow-up was 8.1 µg/ml (range: 1.4–184.9) in group L and 2.0 µg/ml (range: 0.017–13.2) in group S (P = 0.1006).
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assessment of CA125-specific antibodies (Ab1')
CA125-specific antibodies (Ab1'), including circulating Ab1' immunocomplexes, could be detected in 13 patients in the short arm and six patients in the long arm, respectively (Table 4). A comparison of short versus long arm indicated that the percentage of patients with CA125-specific antibody response is not further amplified by increasing the number of applications.
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CA125-specific cellular immune response
Twelve (66.7%) patients in group L and 17 (94.4%) patients in group S were evaluable for cellular immune response. Again, two (11.1%) patients in group L and one (5.6%) patient in group S were not evaluable due to progressive disease prior to the assessment. Additionally, four (22.2%) patients of group L were not evaluable for cellular IFN
-expression due to a lack of stimulation of baseline PBMC samples with mitogen as positive control.
A >2-fold increase of IFN-expressing CA125-specific CD8+ T cells at least once during the course of immunization was observed in nine (75%) patients of group L and three (17.6%) of group S (P = 0.006). The incidence of IFN-positive CD8+ T cells in the blood samples of these patients ranged from 0.05% to 1.98% and 0.14% to 0.58% in groups L and S, respectively (Table 5).
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CD4+ CA125-specific T cells with a >2-fold increase of IFN
-expression could be observed in seven (58.3%) and five (29.4%) patients of groups L and S, respectively (P = 0.148). The incidence of IFN-overexpressing CD4+ T cells ranged from 0.07% to 0.58% in group L and 0.05% to 0.75% in group S (Table 5). No consistent correlation between induction of Ab3 responses and frequencies of CA125-specific CTL and T helper cells could be observed in patients receiving either six or nine applications (Figure 4). Despite existing Ab3 responses in all patients, the time course of T cell responses varied in individuals regardless of the treatment schedule. Some patients developed increasing CA125-specific cytotoxic T-lymphocytes (CTL) and T helper cell responses, which decreased during the follow-up period (Figure 4A). In other cases, T cell responses were only temporarily detected during vaccination (Figure 4B).
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Figure 5 shows an example of cytokine flow cytometry. Dot blots show CD69+IFN
+ CTL and T helper cells of CA125-stimulated PBMC compared with unstimulated controls. Before vaccination, PBMC stimulated with CA125 did not show increased IFN expression compared with unstimulated control. In contrast, after six injections a significant increase of intracellular IFN expression over background was observed in CTL and T helper cells.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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CA125 is overexpressed by the majority of ovarian cancers, and various antibody-based CA125-directed immunotherapeutical approaches have induced specific immune responses [3–5]. However, recent results from a randomized phase III trial with the human monoclonal antibody directed against CA125 failed to show a clinical benefit in a first-line consolidation setting [20]. The reason might be the low immunogenicity of CA125 as target for monoclonal antibodies.
This lack of antigenicity could be overcome by an anti-idiotypic vaccination approach. A previous phase Ib/II study showed that i.m. vaccination with abagovomab induced CA125-specific humoral and cellular immune responses which were correlated to improved survival in recurrent ovarian cancer [17]. However, the design was uncontrolled, the patient population heterogeneous and the study period exceeded several years. Therefore, no definitive conclusions could be drawn from that trial.
With regard to practical considerations concerning the large scale use within phase III trials, the i.m. application route seems to be more uncomfortable for patients than the s.c. administration. Thus, the present study evaluated two s.c. vaccination schedules of different lengths with 2 mg abagovomab. The 2 mg dose was chosen on the basis of previous results from phase I and I/IIb studies with i.m. injection of abagovomab [16, 17, 21].
The primary endpoint of this trial was the drop-out rate due to toxicity as overall measure of feasibility. There were no toxicity-related limitations in either group indicating s.c. administration of abagovomab to be safe and feasible. This is in line with previous reports using i.m. injection [16, 17]. Premature termination occurred more often in the long arm group, but the reasons could be clearly allocated to progressive disease.
Toxicity did not differ significantly between the two groups. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Other toxicities were usually mild and transient or presumably related to either the disease or prior treatment. Interestingly, abagovomab s.c. did not aggravate toxicities like hemato- or neurotoxicity which might impair attempts at maintenance therapy after completion of first-line therapy.
Humoral immune response in terms of Ab3 or HAMA induction did not differ between the two groups and was seen in 100% of evaluable patients at least once during the study period, most occurring by the time of the fourth injection. Ab3 and HAMA titers increased steadily during the study period and tended to be higher for patients in the long arm. This observation bares certain limitations of this study, since the total observation period differed between both treatment arms. At present, critical titers for clinical efficacy are not yet defined and a correlation between the number of applications and the maximum Ab3 reactivity or absolute Ab3 titers and clinical benefit have not been reported [16, 17]. Another interesting observation was the induction of CA125-specific Ab1' antibodies in at least a subset of patients in both vaccination arms. This is in accordance with previous studies which have demonstrated that the development of CA125-specific antibodies after abagovomab application occurs only in a subpopulation of Ab3 responders [16, 17]. Interestingly, the majority of patients who continued the vaccination schedule also developed CA125-specific antibody responses. Thus, it might be considered that Ab1' responses could possibly have an impact on the clinical outcome, which has already been observed in previous trials [17].
Data on comparative studies with respect to the ideal administration route of anti-idiotypic vaccinations are rare. Durrant et al. suggested, with another anti-id antibody, that s.c. administration could increase immunogenicity [22]. Nevertheless, preliminary results indicated no differences in immunogenicity of abagovomab s.c. or i.m. in a phase I trial [23]. In accordance with our results, the authors observed an overall Ab3 response rate of 100% regardless of the administration route [23]. In contrast, the rate of Ab3 responders ranged between 67% and 68% after i.m. injection of abagovomab [16, 17]. The reason for this difference may partly be explained by the fact that previous studies included patients receiving fewer than four injections; these patients were excluded from analysis in the present study.
At present little is known about the clinical impact of cellular immune responses after anti-id vaccination. A previous study indicated that antibody-dependent cellular cytotoxicity (ADCC) could be induced by vaccination with abagomovab in some patients, but the impact of ADCC on survival in recurrent ovarian cancer patients was less striking in comparison to humoral immune responses and, therefore, was not the subject of immune response monitoring in the present study [17].
Another interesting cellular effector mechanism is the induction of T-cell responses. CA125-specific T-cell responses have been shown to correlate with prolonged survival after vaccination of recurrent ovarian cancer patients with a monoclonal anti-CA125 antibody [5]. However, data on T-cell responses after anti-id vaccination are rare and the prognostic significance is still unknown [24, 25]. Several mechanisms may be suggested for the generation of tumor-specific T-cell immunity after anti-id vaccination. Based on the structural mimicry between anti-id and the corresponding tumor antigen, anti-id vaccines could contain immunogenic peptides recognized by T cells. Indeed, peptides for a defined epitope of high molecular weight melanoma-associated antigen could be identified in the murine anti-id vaccine MELIMMUNE. These peptides were able to induce tumor-specific CTLs with lytic capacity [26, 27]. Additionally, HAMA is supposed to be a potent mediator of cellular cytotoxicity by binding to the anti-id antibody with subsequent endocytosis by antigen-presenting cells [28]. An alternative is the formation of immunocomplexes between circulating tumor antigen and induced anti-anti-id antibodies resulting in improved antigen uptake by antigen-presenting cells and development of specific T-cell responses. In this study, CA125-specific T-cell responses could be detected in at least a subset of patients in both groups. Evaluation of T-cell responses showed a significant advantage for the induction of CA125-specific CD8+ T-cells in the long arm, while induction of CD4+ T-cells did not differ significantly between the two schedules. Since the number of evaluable patients was lower in the long arm group this might indicate improved CD8-response after longer vaccination. However, the absolute number of patients was low and differed between the two treatment arms. Another limitation is the larger probability for the detection of cellular response in the long arm group due to the longer study period with the probability of three additional assessments. Nevertheless, these results do indicate that abagomovab has the potential to induce CA125-specific cytotoxic and helper T-cell responses.
Recently, two randomized phase III trails have been conducted with anti-id antibodies: Bec2 in patients with small-cell lung cancer and 3H1 in patients with colorectal cancer [29, 30]. Unfortunately, neither vaccine had any impact on the overall outcome of patients, but a trend towards improved survival was seen in patients developing specific humoral immune responses. In light of these results, the clinical potential of anti-id vaccines could be regarded as questionable, but there are several reasons that should be discussed. The success of anti-id vaccines depends on the nature of the individual anti-id antibody in terms of structural mimicry between anti-id/antigen and the presence of immunogenic peptides in the anti-id sequence. The immune response rate after Bec2 immunization was significantly lower compared to our study, indicating an improved immunogenicity of abagovomab. The 3H1 vaccine was combined with chemotherapy, which could have negatively influenced relevant cellular immune functions. A potential impact of tumor-specific immunity was not investigated in these studies, thus a comparison with immunogenic features of abagovomab remains elusive.
Conclusively, s.c. application of abagovomab seems to be safe and tolerable irrespective of the length of the vaccination schedule. The tendency for higher AB3 titers and improved CA125-specific cellular cytotoxicity might indicate that longer vaccination should be preferred as the experimental arm in future phase III trials.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The authors thank all participating patients and centers, the staff at the study office Kiel of the AGO-OVAR (S. Eichner, K. Fiering, A. Krüger, M. Schulze, G. Voß), the staff at the statistical department of AGO-OVAR at the KKS Marburg, and the study monitors. This study was supported by Cellcontrol AG, Germany. AGO-OVAR received grants and study drugs to perform the present trial. The study was designed, performed and analyzed independently by the AGO-OVAR. AGO-OVAR as well as the principal investigator had full access to all data in the study and had final responsibility for the decision to submit for publication.
Important parts of this final analysis were presented at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO) [31], the 14th International Meeting of the European Society of Gynaecological Oncology (ESGO) 2005 [32] and the 13th European Cancer Conference 2005 (ECCO) [33].
Received for publication January 25, 2006. Revision received May 26, 2006. Accepted for publication May 30, 2006.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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