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Lindy G Durrant - One of the best experts on this subject based on the ideXlab platform.
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a neoadjuvant adjuvant randomized trial of colorectal cancer patients vaccinated with an anti Idiotypic Antibody 105ad7 mimicking cd55
Clinical Cancer Research, 2006Co-Authors: Gustav J Ullenhag, Ian Spendlove, R A Robins, Nicholas F S Watson, Adrian A Indar, Mukul G Dube, Charles Maxwellarmstrong, J H Scholefield, Lindy G DurrantAbstract:Purpose: To assess the tolerability and effectiveness of 105AD7 vaccination in colorectal cancer patients. 105AD7 is a human anti-Idiotypic Antibody mimicking CD55, a glycoprotein, which is more than expressed on colorectal cancer cells and protects them from attack by complement. Experimental Design: Colorectal cancer patients ( n = 67) eligible for primary surgery were randomized to receive the anti-Idiotypic Antibody 105AD7±Bacillus Calmette-Guerin/alum or to no treatment (control group). The immunizations were given i.d./i.m. before surgery and continued for a period of 2 years. The patients were monitored in enzyme-linked immunospot (ELISPOT; γ-IFN), proliferation assay, and Luminex cytokine assays. Results: No serious adverse events were recorded. Of the 32 investigated immunized patients, 14 (44%) were considered to be responders in the ELISPOT assay. Induced proliferative responses were noted in 17 of 40 (43%) monitored patients. There was no correlation between the ELISPOT and proliferation assays. Luminex analyses revealed tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor responses not only to the vaccine but also toward the native antigen CD55 in 9 of 13 (69%) patients. Conclusions: Immune responses to vaccination were induced in a majority of monitored patients measured by ELISPOT and proliferation assay. The lack of correlation between the ELISPOT and proliferation assays may reflect the fact that the two methods measure different T-cell responses and highlights the importance of multiple readouts in evaluating a potential cancer vaccine. Responses to both the anti-idiotype and the CD55 antigen were measurable, adding support to the use of CD55 as a target in cancer treatment.
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a therapeutic human anti Idiotypic Antibody mimics cd55 in three distinct regions
European Journal of Immunology, 2000Co-Authors: Ian Spendlove, Vanessa Potter, Dale Christiansen, Bruce E Loveland, Lindy G DurrantAbstract:The human anti-Idiotypic Antibody 105AD7 was isolated from a colorectal cancer patient receiving the anti-tumor Antibody 791T/36 for radioimmuno-scintigraphy of liver metastases. We have mapped the binding site of 791T/36 to the first two small consensus repeat (SCR) domains of the complement regulatory protein (CD55) that is overexpressed by a wide range of solid tumors. Cloning of both antigen and anti-idiotype has identified the molecular basis of their mimicry. Amino acid homology has been identified between three complementarity-determining regions of 105AD7 and three regions of CD55 within the first two SCR domains. 791T/36 and anti-anti-Idiotypic (Ab3) polyclonal antibodies raised against 105AD7 showed specific binding to these peptides. The antibodies were also found to bind synergistically to combinations of these peptides, indicating cooperativity between the peptides in stabilizing Antibody binding. This also implies that the contact face on both CD55 antigen and 105AD7 is generated by the cooperation of several peptides positioned on two domains in each protein. Thus a human monoclonal anti-Idiotypic Antibody generated by a cancer patient is able to show both amino acid and structural homology with the complement regulatory protein CD55. These findings help identify the mechanism by which a human anti-Idiotypic Antibody is able to mimic a tumor-associated antigen and stimulate anti-tumor B and T cell responses.
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a neoadjuvant clinical trial in colorectal cancer patients of the human anti Idiotypic Antibody 105ad7 which mimics cd55
Clinical Cancer Research, 2000Co-Authors: Lindy G Durrant, R A Robins, Charles Maxwellarmstrong, D J Buckley, S Amin, Joseph C Carmichael, J H ScholefieldAbstract:Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-Idiotypic Antibody results in immune responses in 83% of patients with a permissive haplotype.
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clinical outcome of colorectal cancer patients treated with human monoclonal anti Idiotypic Antibody
International Journal of Cancer, 1994Co-Authors: G W L Denton, Lindy G Durrant, J D Hardcastle, E B Austin, H F Sewell, R A RobinsAbstract:A human monoclonal anti-Idiotypic Antibody (105AD7) has been developed which mimics a colorectal-tumour-associated antigen and induces cellular anti-colorectal tumour immune responses in animals. Thirteen patients with advanced colorectal cancer were immunized with 105AD7 and their survival was compared with that of a contemporary group of unimmunized patients with similar disease status. No toxicity related to anti-idiotype immunization was seen. Cellular responses to anti-Idiotypic immunization were indicated by lymphocyte proliferation to gp72-positive tumour cells, and production of interleukin-2; anti-tumour antibodies were not detected. Median survival following diagnosis of advanced disease of immunized patients was 12 months, compared with 4 months in unimmunized patients. The improved survival of immunized patients in this study without associated toxicity suggests that 105AD7 immunization may have considerable potential for immunotherapy of colorectal cancer. © Wiley-Liss, Inc.
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antitumor immune response and interleukin 2 production induced in colorectal cancer patients by immunization with human monoclonal anti Idiotypic Antibody
Cancer Research, 1991Co-Authors: R A Robins, G W L Denton, J D Hardcastle, E B Austin, Robert W Baldwin, Lindy G DurrantAbstract:Abstract The immunogenicity of human anti-Idiotypic Antibody has been investigated using a human monoclonal anti-Idiotypic Antibody (105AD7) which interacts with the binding site of 791T/36, a mouse monoclonal Antibody against gp72 antigen. This antigen is frequently expressed in gastrointestinal cancer; therefore, six patients with advanced colorectal cancer have been immunized with 105AD7 as an aluminum hydroxide gel precipitate in a phase I clinical study. Cryopreserved blood mononuclear cells were tested for in vitro proliferative responses by [3H]thymidine incorporation; plasma samples were tested by enzyme-linked immunosorbent assay for anti-anti-Idiotypic and antitumor antibodies, and for interleukin 2. Proliferative responses to gp72 positive tumor cells were seen in four of five patients tested; parallel in vitro responses to 105AD7 anti-Idiotypic Antibody were seen in most of these patients. Interleukin 2 was detected in the plasma of four of six patients after 105AD7 immunization, with peak levels up to 7 units/ml. No toxicity related to anti-idiotype immunization and no antitumor or anti-anti-idiotype antibodies were seen. This study shows that human monoclonal anti-idiotype 105AD7 is immunogenic in cancer patients, inducing cellular antitumor responses and interleukin 2 production. This suggests that human monoclonal anti-idiotype antibodies may have considerable potential for immunotherapy of human cancer.
R A Robins - One of the best experts on this subject based on the ideXlab platform.
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a neoadjuvant adjuvant randomized trial of colorectal cancer patients vaccinated with an anti Idiotypic Antibody 105ad7 mimicking cd55
Clinical Cancer Research, 2006Co-Authors: Gustav J Ullenhag, Ian Spendlove, R A Robins, Nicholas F S Watson, Adrian A Indar, Mukul G Dube, Charles Maxwellarmstrong, J H Scholefield, Lindy G DurrantAbstract:Purpose: To assess the tolerability and effectiveness of 105AD7 vaccination in colorectal cancer patients. 105AD7 is a human anti-Idiotypic Antibody mimicking CD55, a glycoprotein, which is more than expressed on colorectal cancer cells and protects them from attack by complement. Experimental Design: Colorectal cancer patients ( n = 67) eligible for primary surgery were randomized to receive the anti-Idiotypic Antibody 105AD7±Bacillus Calmette-Guerin/alum or to no treatment (control group). The immunizations were given i.d./i.m. before surgery and continued for a period of 2 years. The patients were monitored in enzyme-linked immunospot (ELISPOT; γ-IFN), proliferation assay, and Luminex cytokine assays. Results: No serious adverse events were recorded. Of the 32 investigated immunized patients, 14 (44%) were considered to be responders in the ELISPOT assay. Induced proliferative responses were noted in 17 of 40 (43%) monitored patients. There was no correlation between the ELISPOT and proliferation assays. Luminex analyses revealed tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor responses not only to the vaccine but also toward the native antigen CD55 in 9 of 13 (69%) patients. Conclusions: Immune responses to vaccination were induced in a majority of monitored patients measured by ELISPOT and proliferation assay. The lack of correlation between the ELISPOT and proliferation assays may reflect the fact that the two methods measure different T-cell responses and highlights the importance of multiple readouts in evaluating a potential cancer vaccine. Responses to both the anti-idiotype and the CD55 antigen were measurable, adding support to the use of CD55 as a target in cancer treatment.
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a neoadjuvant clinical trial in colorectal cancer patients of the human anti Idiotypic Antibody 105ad7 which mimics cd55
Clinical Cancer Research, 2000Co-Authors: Lindy G Durrant, R A Robins, Charles Maxwellarmstrong, D J Buckley, S Amin, Joseph C Carmichael, J H ScholefieldAbstract:Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-Idiotypic Antibody results in immune responses in 83% of patients with a permissive haplotype.
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clinical outcome of colorectal cancer patients treated with human monoclonal anti Idiotypic Antibody
International Journal of Cancer, 1994Co-Authors: G W L Denton, Lindy G Durrant, J D Hardcastle, E B Austin, H F Sewell, R A RobinsAbstract:A human monoclonal anti-Idiotypic Antibody (105AD7) has been developed which mimics a colorectal-tumour-associated antigen and induces cellular anti-colorectal tumour immune responses in animals. Thirteen patients with advanced colorectal cancer were immunized with 105AD7 and their survival was compared with that of a contemporary group of unimmunized patients with similar disease status. No toxicity related to anti-idiotype immunization was seen. Cellular responses to anti-Idiotypic immunization were indicated by lymphocyte proliferation to gp72-positive tumour cells, and production of interleukin-2; anti-tumour antibodies were not detected. Median survival following diagnosis of advanced disease of immunized patients was 12 months, compared with 4 months in unimmunized patients. The improved survival of immunized patients in this study without associated toxicity suggests that 105AD7 immunization may have considerable potential for immunotherapy of colorectal cancer. © Wiley-Liss, Inc.
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antitumor immune response and interleukin 2 production induced in colorectal cancer patients by immunization with human monoclonal anti Idiotypic Antibody
Cancer Research, 1991Co-Authors: R A Robins, G W L Denton, J D Hardcastle, E B Austin, Robert W Baldwin, Lindy G DurrantAbstract:Abstract The immunogenicity of human anti-Idiotypic Antibody has been investigated using a human monoclonal anti-Idiotypic Antibody (105AD7) which interacts with the binding site of 791T/36, a mouse monoclonal Antibody against gp72 antigen. This antigen is frequently expressed in gastrointestinal cancer; therefore, six patients with advanced colorectal cancer have been immunized with 105AD7 as an aluminum hydroxide gel precipitate in a phase I clinical study. Cryopreserved blood mononuclear cells were tested for in vitro proliferative responses by [3H]thymidine incorporation; plasma samples were tested by enzyme-linked immunosorbent assay for anti-anti-Idiotypic and antitumor antibodies, and for interleukin 2. Proliferative responses to gp72 positive tumor cells were seen in four of five patients tested; parallel in vitro responses to 105AD7 anti-Idiotypic Antibody were seen in most of these patients. Interleukin 2 was detected in the plasma of four of six patients after 105AD7 immunization, with peak levels up to 7 units/ml. No toxicity related to anti-idiotype immunization and no antitumor or anti-anti-idiotype antibodies were seen. This study shows that human monoclonal anti-idiotype 105AD7 is immunogenic in cancer patients, inducing cellular antitumor responses and interleukin 2 production. This suggests that human monoclonal anti-idiotype antibodies may have considerable potential for immunotherapy of human cancer.
J H Scholefield - One of the best experts on this subject based on the ideXlab platform.
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a neoadjuvant adjuvant randomized trial of colorectal cancer patients vaccinated with an anti Idiotypic Antibody 105ad7 mimicking cd55
Clinical Cancer Research, 2006Co-Authors: Gustav J Ullenhag, Ian Spendlove, R A Robins, Nicholas F S Watson, Adrian A Indar, Mukul G Dube, Charles Maxwellarmstrong, J H Scholefield, Lindy G DurrantAbstract:Purpose: To assess the tolerability and effectiveness of 105AD7 vaccination in colorectal cancer patients. 105AD7 is a human anti-Idiotypic Antibody mimicking CD55, a glycoprotein, which is more than expressed on colorectal cancer cells and protects them from attack by complement. Experimental Design: Colorectal cancer patients ( n = 67) eligible for primary surgery were randomized to receive the anti-Idiotypic Antibody 105AD7±Bacillus Calmette-Guerin/alum or to no treatment (control group). The immunizations were given i.d./i.m. before surgery and continued for a period of 2 years. The patients were monitored in enzyme-linked immunospot (ELISPOT; γ-IFN), proliferation assay, and Luminex cytokine assays. Results: No serious adverse events were recorded. Of the 32 investigated immunized patients, 14 (44%) were considered to be responders in the ELISPOT assay. Induced proliferative responses were noted in 17 of 40 (43%) monitored patients. There was no correlation between the ELISPOT and proliferation assays. Luminex analyses revealed tumor necrosis factor-α and granulocyte macrophage colony-stimulating factor responses not only to the vaccine but also toward the native antigen CD55 in 9 of 13 (69%) patients. Conclusions: Immune responses to vaccination were induced in a majority of monitored patients measured by ELISPOT and proliferation assay. The lack of correlation between the ELISPOT and proliferation assays may reflect the fact that the two methods measure different T-cell responses and highlights the importance of multiple readouts in evaluating a potential cancer vaccine. Responses to both the anti-idiotype and the CD55 antigen were measurable, adding support to the use of CD55 as a target in cancer treatment.
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a neoadjuvant clinical trial in colorectal cancer patients of the human anti Idiotypic Antibody 105ad7 which mimics cd55
Clinical Cancer Research, 2000Co-Authors: Lindy G Durrant, R A Robins, Charles Maxwellarmstrong, D J Buckley, S Amin, Joseph C Carmichael, J H ScholefieldAbstract:Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-Idiotypic Antibody results in immune responses in 83% of patients with a permissive haplotype.
Hakan Mellstedt - One of the best experts on this subject based on the ideXlab platform.
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t cell receptor bv gene usage in colorectal carcinoma patients immunised with recombinant ep cam protein or anti Idiotypic Antibody
Cancer Immunology Immunotherapy, 2005Co-Authors: Szilvia Mosolits, Katja Markovic, Jan Fagerberg, Janerik Frodin, Mohammadreza Rezvany, Shahryar Kiaii, Hakan Mellstedt, Mahmood JedditehraniAbstract:The tumour-associated antigen, Ep-CAM, is over-expressed in colorectal carcinoma (CRC). In the present study, a recombinant Ep-CAM protein or a human anti-Idiotypic Antibody (anti-Id) mimicking Ep-CAM, either alone or in combination, was used for vaccination of CRC patients (n=9). GM-CSF was given as an adjuvant cytokine. A cellular immune response was assessed by measuring anti-Ep-CAM lymphoproliferation, IFN-γ production (ELISPOT) and by analysing the TCR BV gene usage within the CD4+ and CD8+ T-cell subsets followed by CDR3 fragment analysis. A proliferative and/or IFN-γ T-cell response was induced against the Ep-CAM protein in eight out of nine patients, and against Ep-CAM-derived peptides in nine out of nine patients. Analysis of the TCR BV gene usage showed a significantly higher usage of BV12 family in CD4+ T cells of patients both before and after immunisation than in those of healthy control donors (p<0.05). In the CD8+ T-cell subset, a significant (p<0.05) increase in the BV19 usage was noted in patients after immunisation. In individual patients, a number of TCR BV gene families in both CD4+ and CD8+ T cells were over-expressed mainly in post-immunisation samples. Analysis of the CDR3 length polymorphism revealed a higher degree of clonality in post-immunisation samples than in pre-immunisation samples. In vitro stimulation with Ep-CAM protein confirmed the expansion of anti-Ep-CAM T-cell clones. The results indicate that immunisation with the Ep-CAM protein and/or anti-Id entails the induction of an anti-Ep-CAM T-cell response in CRC patients, and suggest that BV19+ CD8+ T cells might be involved in a vaccine-induced immune response.
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vaccination with ep cam protein or anti Idiotypic Antibody induces th1 biased response against mhc class i and ii restricted ep cam epitopes in colorectal carcinoma patients
Clinical Cancer Research, 2004Co-Authors: Szilvia Mosolits, Katja Markovic, Jan Fagerberg, Janerik Frodin, Lena Virving, Carl G M Magnusson, Michael Steinitz, Hakan MellstedtAbstract:Purpose: The tumor-associated antigen Ep-CAM (epithelial cell adhesion molecule) is overexpressed in colorectal carcinoma (CRC). The aim of the present study was to evaluate and compare the safety and immunogenicity of a recombinant Ep-CAM protein and a human anti-Idiotypic Antibody (anti-Id) mimicking Ep-CAM. Experimental Design: Patients with resected American Joint Committee on Cancer stages II–IV CRC without remaining macroscopic disease received intradermal/subcutaneous injections of Ep-CAM (400 μg/dose; n = 7) or anti-Id (500 μg/dose; n = 6) at weeks 0, 2, and 6 in combination with granulocyte macrophage colony-stimulating factor (75 μg/day, for 4 consecutive days). Results: Adverse reactions were mild (grade I–II). All patients immunized with the Ep-CAM protein produced Ep-CAM–specific IgG antibodies, predominantly IgG1 and IgG3 subclasses, whereas no humoral response was induced by the anti-Id vaccine. All patients, with one exception in each group, mounted an Ep-CAM–specific proliferative T-cell response. The immune response was more rapid, potent, and protracted after Ep-CAM in comparison with anti-Id vaccination. Interferon-γ-secreting cells (ELISPOT) were detected in both immunization groups against the Ep-CAM protein as well as various Ep-CAM–derived MHC class I- and II-restricted peptides. Flow cytometry analysis showed that Ep-CAM–specific interferon-γ- and perforin-producing cells predominantly resided within CD8 + CD56 − and CD8 dim CD56 + T cells. Conclusions: Ep-CAM protein in combination with granulocyte macrophage colony-stimulating factor induced a long-lasting, Th1-biased humoral and cellular immune response compared with anti-Id. Ep-CAM–specific T cells and natural killer-like T cells responding in a MHC class I- and II-restricted manner were also induced. Vaccination with Ep-CAM protein may warrant further investigation as a novel therapeutic approach to CRC.
Silke Reinartz - One of the best experts on this subject based on the ideXlab platform.
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the anti Idiotypic Antibody abagovomab in patients with recurrent ovarian cancer a phase i trial of the ago ovar
Annals of Oncology, 2006Co-Authors: J Pfisterer, Silke Reinartz, A Du Bois, Jalid Sehouli, S Loibl, Alexander Reuss, U Canzler, A Belau, C Jackisch, R KimmigAbstract:Abstract 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). IFNγ-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.
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vaccination of patients with advanced ovarian carcinoma with the anti idiotype aca125 immunological response and survival phase ib ii
Clinical Cancer Research, 2004Co-Authors: Silke Reinartz, Patrick Giffels, H Schlebusch, Siegmund Kohler, Karl Krista, Kirsten Renke, Jens Huober, Volker Mobus, Rolf Kreienberg, Andreas DuboisAbstract:Purpose: A Phase I/IIb multicenter study was conducted to evaluate the safety and immunogenicity of the anti-Idiotypic Antibody vaccine ACA125 that functionally imitates the tumor antigen CA125 in 119 patients with advanced ovarian carcinoma. A preliminary report on the initial 42 patients demonstrated safety and immunogenicity. Experimental Design: Using the complete intention-to-treat population ( n = 119) who received a mean of 9.7 ACA125 applications, survival was analyzed with respect to immunological responses. Results: In 81 patients (68.1%), a specific anti-anti-Idiotypic Antibody (Ab3) response could be induced. Additionally, the development of CA125-specific antibodies (Ab1′) and Antibody-dependent cell-mediated cytotoxicity of CA125-positive tumor cells was observed in 50.4% and 26.9% of patients, respectively. The median survival of all patients was 19.4 months (range, 0.5–56.1 months). Ab3-positive patients showed a significantly longer survival (median, 23.4 months; P Conclusions: Although the uncontrolled design of this study prevents definitive conclusions with respect to subgroups, the data support a relationship between Ab3 response and survival time. Thus, the need for further randomized, controlled clinical trials to establish efficacy of the vaccine ACA125 seems to be indicated.
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immunological consolidation of ovarian carcinoma recurrences with monoclonal anti idiotype Antibody aca125 immune responses and survival in palliative treatment see the biology behind k a foon and m bhattacharya chatterjee are solid tumor anti idiotype vaccines ready for prime time clin cancer res 7 1112 1115 2001
Clinical Cancer Research, 2001Co-Authors: Uwe Wagner, Silke Reinartz, Patrick Giffels, H Schlebusch, Siegmund Kohler, Kirsten Renke, Jens Huober, Volker Mobus, H J Biersack, Rolf KreienbergAbstract:The aim of the present study was to assess whether the induction of specific immune responses by vaccination with the murine monoclonal anti-Idiotypic Antibody ACA125, which imitates the tumor-associated antigen CA125, has a positive influence on the survival of patients with recurrent ovarian carcinoma. Forty-two patients with platinum-pretreated recurrences were included in a clinical Phase I/II trial of consolidation in third-line therapy. Patients initially received four immunizations with 2 mg of alum-precipitated anti-idiotype ACA125 every 2 weeks and then monthly applications. No serious allergic reactions could be detected within a maximal control period of 56 months. Hyperimmune sera of 27 of 42 patients (64.2%) showed increased concentrations of human antimouse antibodies. Specific anti-anti-Idiotypic antibodies as a marker for induced immunity were detected in 28 of 42 patients (66.7%). The survival of the whole ACA125-treated collective of patients after a mean of 12.6 Antibody applications was 14.9 +/- 12.9 months. The survival of patients with a positive immune response was 19.9 +/- 13.1 months in contrast with 5.3 +/- 4.3 months in those patients without detectable anti-CA125 immunity (P < 0.0001). According to these results, vaccination with a suitable anti-Idiotypic Antibody offers an effective way to induce specific immunity against a primarily nonimmunogenic tumor antigen such as CA125 and is associated with a positive impact on the survival of patients with recurrent ovarian cancer with few side effects, which warrants a Phase III trial for ovarian cancer patients after primary therapy.
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immunological properties of a single chain fragment of the anti Idiotypic Antibody aca125
Cancer Immunology Immunotherapy, 2000Co-Authors: Silke Reinartz, Uwe Wagner, Patrick Giffels, Ursula Gruenn, H Schlebusch, Diethelm WallwienerAbstract:Vaccination with anti-Idiotypic antibodies has been described as a promising concept for treatment of several malignant diseases. The murine monoclonal anti-Idiotypic Antibody ACA125 imitates a specific epitope of the tumor-associated antigen CA125 expressed by 80% of ovarian carcinomas. In the first clinical trial it could be shown that mAb ACA125 is able to elicit anti-anti-Idiotypic antibodies (Ab3) with anti-CA125 specificity in patients with advanced ovarian cancer. In order to improve the capabilities of anti-idiotype vaccines we generated a genetically engineered single-chain fragment (scFv) ACA125 composed of heavy- and light-chain variable regions connected by a flexible linker. The antigenicity of scFv ACA125 was demonstrated by immunizing rats i.p. with scFv or complete mAb in complete/incomplete Freund's adjuvants (CFA/IFA) or precipitated by aluminium hydroxide. Negative control groups included applications of irrelevant mouse IgG or adjuvants alone. Anti-anti-Idiotypic antibodies (Ab3) directed against the mAb ACA125 as well as specific anti-CA125 antibodies (Ab1') could be detected in all animals treated with scFv in CFA/IFA. Nevertheless, Antibody titers were lower than when the complete mAb ACA 125 was used. Suprisingly, an increase of specificity could not be observed in scFv-immunized animals, which had been expected because of the lack of heavy- and light-chain constant regions that could raise rather unspecific anti-isotypic and anti-allotypic rat anti-(mouse Ig) antibodies (RAMA). In contrast, the RAMA responses detected in these rats were even stronger than those following immunization with complete mAb ACA125. In conclusion, the anti-Idiotypic scFv ACA125 alone cannot improve the immunogenic features of the corresponding mAb, but provides a useful tool for the further development of genetic vaccines.
