Annals of Oncology Advance Access originally published online on November 25, 2005
Annals of Oncology 2006 17(3):437-442; doi:10.1093/annonc/mdj090
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© 2005 European Society for Medical Oncology
Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer
1 Royal Marsden Hospital, Sutton, Surrey, UK; 2 Titan Pharmaceuticals, South San Francisco, CA, USA; 3 Hematology and Oncology Services, New Orleans, LA, USA; 4 Guys Hospital, London, UK; 5 Leicester Royal Infirmary, Leicester, UK; 6 North Middlesex Hospital, Edmonton, UK; 7 Georgia Cancer Research Center, Decatur, GA, USA; 8 University of Aberdeen, Aberdeen, UK; 9 Weston Park Hospital NHS Trust, Sheffield, UK; 10 Newcastle General Hospital, Newcastle-upon-Tyne, UK; 11 Sharp Health Care, San Diego, CA, USA; 12 Columbus CCOP, Columbus, OH, USA; 13 Christie Hospital, Withington, UK; 14 University of California, San Diego, CA, USA; 15 City Hospital, Nottingham, UK
* Correspondence to: Dr. D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-86613156; Fax: +44-20-86439414; E-mail: david.cunningham{at}icr.ac.uk
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Abstract |
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Background: The monoclonal antibody 3H1 mimics the external structure of the carcinoembryonic antigen (CEA). It therefore has the potential, via the anti-idiotypic network, to stimulate immune responses to CEA that may benefit colorectal cancer patients.
Patients and methods: A total of 630 patients with previously untreated metastatic colorectal cancer were randomised in a 2:1 fashion to receive bolus 5-fluorouracil (5-FU) and leucovorin (LV) plus either 3H1 (n = 422) or placebo (n = 208).
Results: The addition of 3H1 to 5-FU and LV did not result in increased toxicity. Survival for the full intent-to-treat population was 14.7 months for the 3H1 arm and 15.2 months for the placebo arm (P = 0.80). Anti-CEA antibody responses were observed in 70% of patients treated with 3H1. Patients with a negative CEA response had a median survival of 8.3 months (95% CI 7.5–11.0) compared with patients with a strong response: median survival not reached (P <0.001).
Conclusion: 3H1 is safe and effectively induces immune responses to CEA. Addition of 3H1 to 5-FU and LV was not shown to improve overall patient outcomes. However, improved survival in patients developing anti-CEA responses to 3H1 are provocative and should be studied in further clinical trials.
Key words: anti-idiotype, antibody, carcinoembryonic antigen, response, colorectal
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The treatment of advanced colorectal cancer has improved significantly over the past decade. New cytotoxic agents as well as new monoclonal antibodies (mAb) have been shown to substantially improve patient outcomes in randomised trials. Nevertheless, the prognosis for patients with metastatic colorectal cancer remains relatively poor with median survivals for optimally treated patients of approximately 20 months [1
]. There is, therefore, a clear need for additional treatment strategies in order to improve outcomes further.
According to the anti-idiotype network theory, which was first postulated by Lindemann and Jerne, it should be possible to immunise a patient against a particular antigen by exposing that patient to an antibody (Ab2) which mimics the target antigen [2, 3]. Tumour-associated antigens (TAA) are usually weakly immunogenic; however, immune recognition may be improved by presenting the relevant antigen in a different molecular context, such as in combination with a murine antibody construct [4]. Immunisation with a TAA results in the stimulation of antibodies against the TAA, defined as Ab1. Immunisation using Ab1 will generate anti-idiotype antibodies against Ab1, defined as Ab2. Selected Ab2 molecules successfully mimic the three-dimensional structure of the original TAA. Immunisation of a human using murine Ab2 can induce production of anti-anti-idiotype antibodies (Ab3) which target not only the murine Ab2, but also the original TAA [5]. This approach, therefore, has the potential to enable immune recognition and target tumours via TAAs.
Carcinoembryonic antigen (CEA) is a 180 kD cell-surface expressed glycoprotein antigen, which is present in a number of adenocarcinomas including colorectal cancer [6]. The gene sequence and three-dimensional structure of CEA have been described [7]. CEA is a member of the immunoglobulin superfamily and has cell adhesion properties as well as other less clearly defined roles [8]. 3H1 is a murine anti-idiotype mAb (Ab2), which mimics the external structure of CEA [9]. CeaVac® (3H1 adsorbed to aluminum hydroxide, Titan Pharmaceuticals Inc, South San Francisco, CA) was originally generated in BALB/c mice against the antibody 8019 (Ab1), which in turn targets the CEA antigen. It is administered by subcutaneous injection while adsorbed to an adjuvant, aluminium hydroxide.
3H1 has been shown to generate strong immune responses in patients treated in combination with chemotherapy. In one study, 32 patients with resected Dukes' B, C and D (including incompletely resected Dukes' D) colorectal cancer were treated with 3H1 alone (18 patients) or 3H1 plus 5-fluorouracil (5-FU) based chemotherapy (14 patients) [10]. All patients in this study developed high-titre immunoglobulin G and T-cell immune responses to CEA; the addition of chemotherapy did not appear to modify this response.
In order to determine clinical efficacy in patients with metastatic disease, a large randomised study was initiated to compare 5-FU/leucovorin (LV) plus 3H1 to 5-FU/LV plus placebo in patients with previously untreated advanced colorectal cancer.
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patients and methods |
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patient eligibility
Patients with histologically or cytologically verified adenocarcinoma of the colon or rectum that was metastatic were eligible if they had never received therapy other than surgery for advanced disease. Other criteria for inclusion were: measurable or evaluable disease; non-measurable/evaluable disease following surgical metastasectomy, prior adjuvant therapy was allowed if treatment was completed at least 6 months prior to trial entry; age between 18 and 75 years; life expectancy of at least 4 months; Eastern Co-operative Group (ECOG) performance status of 0 or 1; bilirubin <2.0 mg/dl (<34.2 µmol/l) and AST <3x the upper limit of normal (ULN) (liver metastases <5x ULN); creatinine <2.0 mg/dl (<176.8 µmol/l); hemoglobin >10 g/dl; platelets >100 000/mm3; leucocytes >4000/mm3; absolute neutrophils >1500/mm3; normal or subclinically significant electrocardiogram.
Exclusion criteria were: previous exposure to murine mAb; sensitivity to rodent proteins; active infection; any immunodeficiency disorder; immunisation or immunomodulatory therapy within 30 days of study entry; malnutrition; history of colitis or inflammatory bowel disease; pancreatitis within the previous 10 years; known central nervous system metastasis; psychiatric or addictive disorders; celiac disease; familial cancer syndromes; use of systemic corticosteroids or immunosuppressants within 45 days of study entry; pregnancy or lactation. All sexually active subjects were required to use an acceptable method of contraception.
This study was performed in accordance with the Declaration of Helsinki. The protocol was reviewed and approved by the Institutional Review Board at each site prior to commencement of the study. All patients gave written informed consent to participate in this study.
study design
This was a phase III double-blind, randomised placebo-controlled study of 3H1 or placebo in combination with 5-FU/LV. Patients were prospectively stratified according to disease site (colon or rectum) and treatment centre location (US or non-US). Randomisation to 3H1 or placebo was performed in a 2:1 ratio. All patients received 5-FU/LV according to the Mayo Clinic schedule. The primary end point was overall survival. Secondary end points were time to disease progression, tumour response, immunologic response and safety profile in eligible patients. The study was conducted at 53 centres in the USA and Europe following approval by the Institutional Review Board/Ethics Committee at each institution.
treatment plan
All patients received intravenous LV 20 mg/m2 over 2 min followed by bolus 5-FU 425 mg/m2 each day for 5 consecutive days. Treatment was repeated every 4–5 weeks.
Patients randomised to 3H1 were treated with 2.0 mg (1 ml) monoclonal antibody 3H1 adsorbed to aluminium hydroxide adjuvant. Patients randomised to placebo received 1 ml aluminium hydroxide suspended in normal saline. Either 3H1 or placebo was administered intradermally every 2 weeks for the first four doses. Subsequent doses were administered subcutaneously every 4 weeks for 23 additional injections. Blinded 3H1/placebo treatment was given until disease progression, after which blinded treatment could continue for up to 2 additional years at the discretion of the principal investigator.
patient evaluation
Medical history, physical examination, laboratory studies, tumour evaluation, chest radiography and electrocardiography were performed within 30 days prior to study drug administration. Women of child-bearing potential had to have a negative serum pregnancy test during this time. Further laboratory tests including a coagulation panel, serum CEA level, and antibody assays were obtained prior to study drug administration on day 1.
Safety assessments were performed each time a patient received 3H1 or placebo. The severity of adverse events was graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0. Radiological tumour evaluations were performed at week 10, then every 8 weeks thereafter until disease progression. Serum CEA levels and antibody assays were performed at 10 and 14 weeks, then every 12 weeks subsequently.
Complete tumour response (CR) was defined as complete disappearance of all detectable lesions with no new lesions. Partial response (PR) was defined as 
50% decrease in the sum of products of the largest perpendicular diameters of all measurable lesions compared with baseline. Progressive disease (PD) was defined as 50% increase in the sum of the product of the largest bidimensional measurements of at least one measurable lesion; or 100% increase in the size of any lesion (including non-measurable); or appearance of a new lesion. Stable disease (SD) included all patients not meeting the definitions of CR, PR or PD.
immunologic evaluation
Antibody responses to 3H1 (Ab3 response) and to CEA were assessed by radioimmuno-inhibition assays as described. A positive response was considered to be 46% inhibition in the anti-3H1 assay and 52% inhibition in the anti-CEA assay. These cut-off values were established based on the lowest limit of quantitation of the assays. Blood was collected for antibody assays at baseline, weeks 10 and 14 and every 12 weeks thereafter. Patients who had baseline and at least one subsequent evaluation were considered evaluable for immune response. A random sample of 51 placebo-treated patients was compared with the 3H1-treated patients. The magnitude of anti-CEA immune response was defined as follows: negative (<52% inhibition at all serum dilutions); weak (52% inhibition at serum dilution 
40); moderate (52% inhibition at serum dilution >40 and 160); strong (52% inhibition at serum dilution >160).
statistical considerations
The primary end point was overall survival. A sample size of 561 patients [2:1 ratio of 3H1 (374) to placebo (167)] was required to detect a 50% increase in survival in 3H1 recipients with 80% power and a type 1 error of 0.05 (two-sided). A total sample size of 623 patients was utilized in order to allow for 10% of patients not completing at least six doses of study drug. Overall survival was calculated from randomisation to death.
Primary analysis was conducted when all patients had at least 1 year of follow-up. Survival analyses were performed on the intent-to-treat as well as the protocol-specified modified intent-to-treat population (mITT), which consisted of patients who received at least six doses of study drug. The rationale for the mITT population was that it was expected that patients would need at least six doses of 3H1 to generate an immune response. Exploratory efficacy analyses were based on the full intent-to-treat population and other populations. All patients who received the study drug were included in the safety analysis.
Statistical analyses were performed using PC SAS, version 8.2. Continuous data (other than time to event data) were evaluated using analysis of variance (ANOVA)/analysis of covariance (ANCOVA) models using PROC GLM in SAS. The models included the terms for treatment and strata. For the analysis of proportions, the Cochran–Mantel–Haenszel (CMH) test was used to compare 3H1 with placebo adjusted for strata. In the modelling of categorical data, logistic regression models were employed using PROC LOGISTIC in SAS. Summary descriptive statistics including N, mean, standard deviation, median and range (minimum, maximum) were used for continuous variables and frequencies and percentages for categorical variables. Time to event analyses were summarised using Kaplan–Meier estimations. Censored observations and confidence intervals for the estimated median times were summarised as well. Cox proportional hazards regression models were used to identify the other significant prognostic stratification variables and interactions. All statistical tests were two-sided, with type I error rates of 5%. All confidence intervals were constructed at the 95% confidence level.
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results |
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patient characteristics
There were 630 patients enrolled between December 1998 and July 2001. Four hundred and twenty-two patients were randomized to 3H1 and 208 to placebo. Fifteen patients did not receive protocol therapy; therefore 615 patients were available for safety analysis. The treatment arms were well balanced with respect to baseline characteristics (Table 1). Overall, patients had received minimal therapy other than surgery prior to study enrolment, with less than 25% having received prior adjuvant chemotherapy.
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Patients in the 3H1 arm received treatment for a median of 31 weeks while patients in the placebo arm received treatment for a median of 27 weeks. The median number of cycles of 5-FU/LV was five for both treatment arms. A total of 444 patients received at least six doses of 3H1 or placebo and constituted the mITT group.
efficacy
There was no significant difference in survival or time to progression between 3H1 and placebo-treated patients in the ITT population. Survival was 14.7 months (95% CI 13.4–16.1) for the 3H1 arm and 15.2 months (95% CI 13.1–16.8) for the placebo arm (P = 0.80) (Figure 1). Survival analysis using the protocol-specified mITT population, revealed a median survival of 19.1 months (95% CI 16.3–21.3) for the 3H1 arm and 17.1 months (95% CI 15.3–19.2) for the placebo arm (P = 0.13), log rank test. An exploratory analysis of patients who received eight doses showed a median survival of 21.3 months (95% CI 19.2–22.3) for the 3H1 arm (n = 251) and 18.5 months (95% CI 16.4–20.2) for the placebo arm (n = 125; P = 0.038) (Figure 2).
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No significant difference was observed between the treatment arms with regards to tumour response. Sixteen per cent of patients treated with 3H1 and 5-FU/LV and 13% of patients treated with placebo and 5-FU/LV achieved a CR or PR (P = 0.3).
After disease progression, 49.8% of 3H1 patients and 46.6% of placebo patients received second-line chemotherapy (P = ns). Irinotecan was the most commonly administered treatment, given to 36.7% of 3H1 patients and 36.1% of placebo patients.
immunologic assessments
Three hundred and forty-three 3H1-treated patients and 208 placebo patients were evaluable for assessment of CEA immune response. Antibody responses were evaluated in all 343 3H1 patients and in a random sample of 51 placebo patients. Sixty-three per cent of 3H1 patients had a positive anti-anti-Id response (Ab3) and 70% had detectable anti-CEA antibodies. Eighteen per cent of placebo patients had a positive Ab3 response and none developed anti-CEA antibodies (P < 0.001).
Patients (n = 102) with a negative CEA response (<52% CEA-inhibition at all dilutions) had a median survival of 8.3 months (95% CI 7.5–11.0 months). Patients (n = 108) with a weak response (52% CEA-inhibition at serum dilution 40) had a median survival of 15.8 months (95% CI 13.9–19.3 months). Patients (n = 91) with a moderate response (52% CEA-inhibition at serum dilution >40 and 160) had a median survival of 20.0 months (95% CI 16.3–23.8 months). Patients (n = 42) with a strong response (52% CEA inhibition serum dilution 160) had a median survival of 28.2 months (95% CI 24.6 to upper limit not reached). The differences in survival were statistically significant (P < 0.001) (Figure 3).
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adverse events
3H1 was well tolerated and the adverse event profile, when administered with 5-FU/LV, was similar to that of bolus 5-FU/LV alone. Table 2 summarizes the most frequent (
5% of patients) grade 3/4 adverse events. Injection site reaction and injection site granuloma were more frequently observed in patients treated with 3H1 (Table 3). However, only 1.7% of patients receiving 3H1 experienced grade 3 injection site reactions. No hypersensitivity, allergic reactions or serum sickness in response to 3H1 were observed.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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This large randomised phase III trial demonstrates that the combination of 5-FU/LV and 3H1 is well tolerated compared with 5-FU/LV alone; and induces strong anti-CEA antibody responses in patients with previously untreated metastatic colorectal cancer. There was no significant difference in overall survival between the two treatment arms. Tumour response rates in both arms were similar and were consistent with previous studies of bolus 5-FU/LV [11
]. There was no increase in overall toxicity in patients treated with 3H1 and 5-FU/LV compared with those treated with placebo and 5-FU/LV. Less than 2% of patients experienced grade 3 injection site reactions in each arm. Other observed adverse events were consistent with the known toxicity profile of 5-FU/LV. Only 2% of patients discontinued study treatment due to a drug-related adverse event.
As with previous studies, vaccination with 3H1 resulted in the generation of high titre anti-CEA responses in a majority of patients [12]. There appeared to be an association between the strength of the humoral response and survival in 3H1-treated patients. Given the lack of overall survival improvement in the 3H1 arm compared with the placebo arm, it remains unclear whether a stronger anti-CEA immune response actually improved survival, or whether stronger immune responses to 3H1 occurred in patients with a better intrinsic prognosis. The trend towards improved survival with a greater number of 3H1 versus placebo doses may suggest that generation by 3H1 of anti-CEA immune response is a factor in improved survival. A small study in patients with ovarian carcinoma has previously demonstrated an association between immune response to an anti-idiotype monoclonal antibody ACA125 and survival [12]. Of 42 patients treated, 28 patients had an immune response; these patients survived 19.9 ± 13.1 months compared with 5.3 ± 4.3 months for non-responders (P < 0.0001).
There are a number of potential reasons for the inability to achieve survival improvement with the addition of 3H1 to 5-FU/LV despite the development of anti-CEA responses. These include decreased cellular immune function in patients with metastatic disease and high tumour volume leading to inadequate penetration of immune effector cells. Another possibility is that duration of 3H1 treatment may have been too short to impact on survival. The use of modern chemotherapy combinations such as oxaliplatin/5-FU/leucovorin (FOLFOX) or irinotecan/5-FU/leucovorin (FOLFIRI) is associated with longer progression-free survival compared with 5-FU/LV and therefore would have allowed longer and possibly more efficacious durations of 3H1 therapy. While our study was not statistically powered to detect small differences in survival, the Kaplan–Meier curves do not suggest that the lack of survival difference was due to a lack of power.
Other approaches to CEA vaccination have involved recombinant CEA-vaccinia or avipox virus vaccines either with or without co-stimulatory factors. Preclinical studies demonstrated strong anti-CEA antibody responses, as well as anti-tumour activity in xenograft models [13]. In a phase I study of 56 patients with metastatic CEA-positive cancer (mostly colorectal cancer), patients were treated with one of eight schedules of vaccinia and/or fowlpox CEA vaccine in combination with a triad of co-stimulatory molecules ± GM-CSF [14]. Of 30 evaluable patients who completed at least four vaccinations, 21 achieved stable disease, some of whom remained progression-free for up to 16 months. The treatment was well tolerated, with skin reactions, fever and chills being the predominant toxicities. No immune response data are available at present.
Selection of the target antigen for anti-idiotypic treatment of colorectal cancer may be critical, as cell-mediated antitumour effects may vary according to the selected antigen. Therefore, other antigens have been evaluated for the purposes of anti-idiotypic strategies. In 35 patients with colorectal cancer scheduled for surgery, CD55 was targeted with the anti-idiotypic antibody 105AD7 both before and after surgical resection [15]. Immune response in the form of infiltration of helper T cells and NK cells in the resected tumours was observed, particularly in patients expressing HLA-DR1, DR3 and DR7. Encouraging relapse-free survival was reported in the 14 patients with Dukes' C tumours, with 64% remaining relapse-free at a median follow-up of 4.5 years. However, randomised survival data is required to determine if CD55 is a superior target for anti-idiotypic therapy compared with CEA.
Anti-idiotype vaccination in other epithelial tumours has been explored in several clinical studies. Non-randomised clinical trials using anti-idiotype antibodies have demonstrated the induction of specific IgG responses against ganglioside antigens such as GD2 and Neu-Gc-GM3 in melanoma and breast cancer, respectively [16–18]. Again, randomised survival data is required to confirm the encouraging results from these trials.
In conclusion, this randomised study has demonstrated the safety and tolerability of 3H1 administration in combination with 5-FU/LV in patients with previously untreated metastatic colorectal cancer. Induction of anti-CEA humoral responses was observed, although there was no statistically significant difference in overall survival between the two treatment arms. Patients who received a sufficient number of 3H1 doses to generate an antibody response appeared to have improved survival. Due to the delayed nature of immune responses, and the possible negative effect of bulky metastatic disease, the best models for 3H1 treatment may be in patients with fully resected primary or metastatic colorectal cancer. Trials of 3H1 immunisation are ongoing in these disease settings.
Received for publication September 19, 2005. Revision received October 24, 2005. Accepted for publication October 24, 2005.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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1. Punt CJA. New options and old dilemmas in the treatment of patients with advanced colorectal cancer. Ann Oncol 2004; 15: 1453–1459.
2. Lindenmann J. Speculations on idiotypes and homobodies. Ann Immunol (Paris) 1973; 124: 171–184.[Medline]
3. Jerne NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974; 125C: 373–389.
4. Lutzky J, Gonzalez-Angulo AM, Orzano JA. Antibody-based vaccines for the treatment of melanoma. Semin Oncol 2002; 29: 462–470.[CrossRef][Web of Science][Medline]
5. Foon KA, Bhattacharya-Chatterjee M. Are solid tumor anti-idiotype vaccines ready for prime time? Commentary re: U. Wagner et al., Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. Clin Cancer Res 2001; 7: 1154–1162.
6. Gold P, Freedman SO. Demonstration of tumor-specific antigens in human colonic carcinomata by immunological tolerance and absorption techniques. J Exp Med 1965; 121: 439–462.[Abstract]
7. Zimmermann W, Ortlieb B, Friedrich R et al. Isolation and characterization of cDNA clones encoding the human carcinoembryonic antigen reveal a highly conserved repeating structure. Proc Natl Acad Sci USA 1987; 84: 2960–2964.
8. Paxton RJ, Mooser G, Pande H et al. Sequence analysis of carcinoembryonic antigen: identification of glycosylation sites and homology with the immunoglobulin supergene family. Proc Natl Acad Sci USA 1987; 84: 920–924.
9. Bhattacharya-Chatterjee M, Mukerjee S, Biddle W et al. Murine monoclonal anti-idiotype antibody as a potential network antigen for human carcinoembryonic antigen. J Immunol 1990; 145: 2758–2765.[Abstract]
10. Foon KA, John WJ, Chakraborty M et al. Clinical and immune responses in resected colon cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. J Clin Oncol 1999; 17: 2889–2895.
11. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1992; 10: 896–903.[Abstract]
12. Wagner U, Kohler S, Reinartz S et al. Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. Clin Cancer Res 2001; 7: 1154–1162.
13. Kantor J, Irvine K, Abrams S et al. Antitumor activity and immune responses induced by a recombinant carcinoembryonic antigen-vaccinia virus vaccine. J Natl Cancer Inst 1992; 84: 1084–1091.
14. Marshall JL, Arlen PM, Rizvi N. A phase I study of sequential vaccinations with fowlpox-CEA (6D)-Tricom (B7/ICAM/LFA3) alone, and in combination with vaccinia-CEA (6D)-Tricom and GM-CSF in patients with CEA expressing carcinomas. Proc Am Soc Clin Oncol 2002; 21: Abstr 24
15. Durrant LG, Maxwell-Armstrong C, Buckley D et al. A neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, which mimics CD55. Clin Cancer Res 2000; 6: 422–430.
16. Foon KA, Lutzky J, Baral RN et al. Clinical and immune responses in advanced melanoma patients immunized with an anti-idiotype antibody mimicking disialoganglioside GD2. J Clin Oncol 2000; 18: 376–384.
17. Diaz A, Alfonso M, Alonso R et al. Immune responses in breast cancer patients immunized with an anti-idiotype antibody mimicking NeuGc-containing gangliosides. Clin Immunol 2003; 107: 80–89.[CrossRef][Web of Science][Medline]
18. Reece DE, Foon KA, Chatterjee MB et al. Use of the anti-idiotype breast cancer vaccine 11D10 in conjunction with autologous stem cell transplantation in patients with metastatic breast cancer. Clin Breast Cancer 2003; 3 (Suppl 4): S152–S157.
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