The Experts below are selected from a list of 216 Experts worldwide ranked by ideXlab platform
Larry W. Kwak - One of the best experts on this subject based on the ideXlab platform.
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Vaccine therapy for B-cell lymphomas: next-generation strategies. Hematology Am Soc Hematol Educ Program. 2007: p
2007Co-Authors: Sattva S. Neelapu, Larry W. KwakAbstract:Active immunotherapy is a promising approach for the treatment of lymphomas. Immunization with the clonal tumor Immunoglobulin, Idiotype, expressed on the surface of B-cell malignancies was associated with induction of tumor-specific cellular and humoral immunity, molecular remissions, and prolonged disease-free survival in early clinical trials. Idiotype vaccination was also demonstrated to induce tumor-specific T-cell immunity in the absence of B cells following treatment with rituximab-containing chemo-therapy, suggesting that vaccines may be used in combination with rituximab. Three double-blind randomized phase 3 Idiotype vaccine trials are currently ongoing to definitively determine the clinical benefit of Idiotype vaccination in patients with lym
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Vaccine Therapy for B-Cell Lymphomas: Next-Generation Strategies
Hematology. American Society of Hematology. Education Program, 2007Co-Authors: Sattva S. Neelapu, Larry W. KwakAbstract:Active immunotherapy is a promising approach for the treatment of lymphomas. Immunization with the clonal tumor Immunoglobulin, Idiotype, expressed on the surface of B-cell malignancies was associated with induction of tumor-specific cellular and humoral immunity, molecular remissions, and prolonged disease-free survival in early clinical trials. Idiotype vaccination was also demonstrated to induce tumor-specific T-cell immunity in the absence of B cells following treatment with rituximab-containing chemotherapy, suggesting that vaccines may be used in combination with rituximab. Three double-blind randomized phase 3 Idiotype vaccine trials are currently ongoing to definitively determine the clinical benefit of Idiotype vaccination in patients with lymphoma. Novel second-generation lymphoma vaccines are in development to streamline the production of patient-specific cancer vaccines and show encouraging results in preclinical and pilot clinical studies. To enhance the clinical efficacy of active immunotherapy, future clinical trials are likely to use a combination strategy with the lymphoma vaccine to stimulate an antitumor T-cell response and the simultaneous suppression of immune regulatory pathways to augment the induced T-cell response.
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Immunotherapy of multiple myeloma
Seminars in hematology, 2001Co-Authors: Pier Adelchi Ruffini, Larry W. KwakAbstract:The failure of chemotherapy to cure a significant proportion of multiple myeloma (MM) patients and increasing knowledge of tumor immunology and MM biology have generated considerable interest in immunotherapy for this lethal disease. Immunotherapy for MM can be divided into three broad categories: passive antibody-mediated immunotherapy, active specific immunization (vaccination), and adoptive T-cell immunotherapy. Early clinical trials using anti-CD20 monoclonal antibodies (mAbs) have met with limited success so far but have also suggested that selected patient subgroups may benefit from this treatment. The availability of a truly tumor-specific antigen such as Immunoglobulin Idiotype, the recent demonstration that MM cells process and present Idiotype to T lymphocytes, and formal evidence of an antitumor effect of idiotypic vaccination in follicular lymphoma provide the framework for applying idiotypic vaccination in MM. The ability to generate ex vivo functional dendritic cells has made it possible to fuse them with patients' MM cells, thus producing a different type of customized vaccine. Dendritic cells are also a pivotal reagent to generate ex vivo MM-specific cytotoxic T lymphocytes (CTLs) to be reinfused into the patient for adoptive immunotherapy. This review summarizes achievements in MM immunotherapy based on data reported since 1998.
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vaccination with syngeneic lymphoma derived Immunoglobulin Idiotype combined with granulocyte macrophage colony stimulating factor primes mice for a protective t cell response
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Larry W. Kwak, Howard A Young, Robin Pennington, Steve D WeeksAbstract:Abstract The Idiotype of the Ig expressed by a B-cell malignancy (Id) can serve as a unique tumor-specific antigen and as a model for cancer vaccine development. In murine models of Id vaccination, formulation of syngeneic Id with carrier proteins or adjuvants induces an anti-idiotypic antibody response. However, inducing a potent cell-mediated response to this weak antigen instead would be highly desirable. In the 38C13 lymphoma model, we observed that low doses of free granulocyte/macrophage colony-stimulating factor (GM-CSF) 10,000 units i.p. or locally s.c. daily for 4 days significantly enhanced protective antitumor immunity induced by s.c. Id-keyhole limpet hemocyanin (KLH) immunization. This effect was critically dependent upon effector CD4+ and CD8+ T cells and was not associated with any increased anti-idiotypic antibody production. Lymphocytes from spleens and draining lymph nodes of mice primed with Id-KLH plus GM-CSF, but not with Id-KLH alone, demonstrated significant proliferation to Id in vitro without any biased production of interferon gamma or interleukin 4 protein or mRNA. As a further demonstration of potency, 50% of mice immunized with Id-KLH plus GM-CSF on the same day as challenge with a large s.c. tumor inoculum remained tumor-free at day 80, compared with 17% for Id-KLH alone, when immunization was combined with cyclophosphamide. Taken together, these results demonstrate that GM-CSF can significantly enhance the immunogenicity of a defined self-antigen and that this effect is mediated exclusively by activating the T-cell arm of the immune response.
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Vaccination with syngeneic, lymphoma-derived Immunoglobulin Idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response.
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Larry W. Kwak, Howard A Young, Robin Pennington, Steve D WeeksAbstract:Abstract The Idiotype of the Ig expressed by a B-cell malignancy (Id) can serve as a unique tumor-specific antigen and as a model for cancer vaccine development. In murine models of Id vaccination, formulation of syngeneic Id with carrier proteins or adjuvants induces an anti-idiotypic antibody response. However, inducing a potent cell-mediated response to this weak antigen instead would be highly desirable. In the 38C13 lymphoma model, we observed that low doses of free granulocyte/macrophage colony-stimulating factor (GM-CSF) 10,000 units i.p. or locally s.c. daily for 4 days significantly enhanced protective antitumor immunity induced by s.c. Id-keyhole limpet hemocyanin (KLH) immunization. This effect was critically dependent upon effector CD4+ and CD8+ T cells and was not associated with any increased anti-idiotypic antibody production. Lymphocytes from spleens and draining lymph nodes of mice primed with Id-KLH plus GM-CSF, but not with Id-KLH alone, demonstrated significant proliferation to Id in vitro without any biased production of interferon gamma or interleukin 4 protein or mRNA. As a further demonstration of potency, 50% of mice immunized with Id-KLH plus GM-CSF on the same day as challenge with a large s.c. tumor inoculum remained tumor-free at day 80, compared with 17% for Id-KLH alone, when immunization was combined with cyclophosphamide. Taken together, these results demonstrate that GM-CSF can significantly enhance the immunogenicity of a defined self-antigen and that this effect is mediated exclusively by activating the T-cell arm of the immune response.
John M Timmerman - One of the best experts on this subject based on the ideXlab platform.
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Carrier protein conjugate vaccines: the "missing link" to improved antibody and CTL responses?
Human vaccines, 2009Co-Authors: John M TimmermanAbstract:There's still plenty "missing" from attempts to immunize against cancer and other pesky pathogens. Conjugation of weakly-immunogenic tumor-derived proteins or other pathogen-associated antigens to highly-immunogenic carrier proteins has long been utilized as a tool for improving immune responses. Such vaccines have recently been tested in phase 3 clinical trials targeting non-Hodgkin's B cell lymphoma. However, these vaccines, composed of tumor-specific Immunoglobulin ("Idiotype") protein linked to keyhole limpet hemocyanin using glutaraldehyde, largely failed to show efficacy. Yet substituting a sulfhydryl-based linker cleavable in lysosomes markedly augments the efficacy of these vaccines, offering heightened antibody and CTL responses. Could such conjugation strategies be the "missing link" needed in vaccines against pathogens requiring both antibodies and T cells for protection?
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enhanced immune stimulation by a therapeutic lymphoma tumor antigen vaccine produced in insect cells involves mannose receptor targeting to antigen presenting cells
Vaccine, 2009Co-Authors: David J Betting, Xi Y Mu, Kamran Kafi, Desmond Mcdonnel, Francisco Rosas, Daniel P Gold, John M TimmermanAbstract:Abstract Therapeutic vaccination of lymphoma patients with tumor-specific Immunoglobulin (Idiotype, Id) coupled to the carrier protein keyhole limpet hemocyanin (Id-KLH) is undergoing clinical investigation, and methods to improve the immunogenicity of these and other protein tumor antigen vaccines are being sought. Id proteins can be produced via tumor-myeloma hybridomas or recombinant methods in mammalian, bacteria, or insect cells. We now demonstrate that terminal mannose residues, characteristic of recombinant proteins produced in insect cells, yield Id proteins with significantly enhanced immunostimulatory properties compared to Id proteins derived from mammalian cells. Recombinant baculovirus-infected insect cell-derived Id showed higher binding to and activation of human dendritic cells mediated by mannose receptors. In vivo , insect cell-derived Id elicited higher levels of tumor-specific CD8 + cytotoxic T lymphocyte (CTL) and improved eradication of pre-established murine lymphoma. Insect cell and mammalian Id generated similar levels of tumor-specific antibodies, showing no impairment in antibody responses to native tumor antigen despite the glycoslylation differences in the immunogen. Combining insect cell production and maleimide-based KLH conjugation offered the highest levels of anti-tumor immunity. Our data comparing sources of recombinant Id protein tumor antigens used in therapeutic cancer vaccines demonstrate that insect cell-derived antigens can offer several immunologic advantages over proteins derived from mammalian sources.
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Tumor-specific recombinant Idiotype immunisation after chemotherapy as initial treatment for follicular non-Hodgkin lymphoma
Leukemia & lymphoma, 2009Co-Authors: John M Timmerman, Debra K Czerwinski, Wenkai Weng, Julie M. Vose, Diane E. Ingolia, Martha Mayo, Dan W. Denney, Ronald LevyAbstract:Tumor-specific variable regions of the clonal Immunoglobulin (Idiotype, Id) expressed by B cell non-Hodgkin lymphoma (NHL) can be targeted by active immunotherapy. We conducted a phase I/II trial to determine the safety and immunogenicity of a patient-specific, recombinant, mammalian cell-derived Id protein conjugated to keyhole limpet hemocyanin (Id-KLH; MyVax® personalised immunotherapy) in 22 patients with follicular NHL in first remission after chemotherapy. Subjects received five subcutaneous immunisations with MyVax® plus locally administered granulocyte-macrophage colony-stimulating factor (GM-CSF). Among 21 evaluable patients, 62% mounted Id-specific immune responses. Evoked anti-Id antibodies recognised both recombinant Id and native Id, and could specifically stain autologous tumor cells. At median follow-up of more than 6 years, median progression-free survival is 38 months. Immunisation of follicular lymphoma patients with MyVax® Id-KLH is safe and patients often mount tumor-specific immune responses. These results form the basis of a pivotal phase 3 trial of MyVax® in follicular NHL.
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Therapeutic Lymphoma Idiotype Vaccine Generated in Insect Cells Results in Mannose Receptor Targeting and Enhanced Immune Activation.
Blood, 2007Co-Authors: David J Betting, Kamran Kafi, Desmond Mcdonnel, Francisco Rosas, Daniel P Gold, John M TimmermanAbstract:Treatment of lymphoma patients with tumor-specific Immunoglobulin (Idiotype, Id) coupled to the immunogenic carrier protein keyhole limpet hemocyanin (Id-KLH) has shown promising results in phase 2 clinical trials. However, vaccines fail to elicit anti-Id immune responses in some patients, thus prompting the search for ways to improve the immunogenicity of Id-KLH vaccines. Current Id vaccine trials utilize tumor-specific Id proteins secreted by tumor-myeloma hybridomas, or recombinant Id proteins produced in mammalian lymphoid cells, bacteria, or insect cells. We now provide evidence that terminal mannose carbohydrate structures, characteristic of recombinant proteins produced in insect cells, lead to Id proteins with significantly enhanced immunostimulatory properties compared to Id proteins derived from mammalian sources. Monocyte-derived human dendritic cells (DCs) were incubated with fluorescently labeled Id proteins produced in insect or mammalian cell cultures. Insect cell-derived Id demonstrated substantially higher binding to DCs compared to the Id from a mammalian source by flow cytometry, and only the insect cell Id showed reduced binding when the DCs were preincubated with mannose receptor inhibitors. These results demonstrated that the insect cell-derived Id resulted in better targeting to DCs compared to the mammalian Id. When insect cell-derived Id proteins were coupled to KLH using glutaraldehyde and co-cultured with immature human DCs, increased expression of CD80 and CCR7 was observed by flow cytometry, indicating DC maturation. Upregulation of these markers was blocked by pre-treatment with anti-mannose receptor antibody. In tumor therapy studies, mice with 4-day established A20 murine B cell lymphoma were treated with 3 weekly injections of Id-KLH plus GM-CSF and followed for survival. A20 bearing mice treated with Id-KLH containing insect cell-derived A20 Id displayed improved survival compared with mice treated with hybridoma-derived A20 Id-KLH (61% vs. 46%, respectively). Anti-Id antibodies against A20 murine B cell lymphoma were assessed by ELISA following Id-KLH immunization. Both insect and mammalian sources of Id generated similar levels of anti-Id antibodies, showing no impairment in antibody responses due to the differences in glycoslylation. Anti-A20 cytotoxic T lymphocyte (CTL) activity was measured in splenic T cells from Id-KLH-immunized mice. Here, induction of CD8+ CTLs by insect cell-derived A20 Id-KLH was significantly greater than CTL induction following immunization with hybridoma-derived A20 Id-KLH (P=0.0061). To determine the importance of the T cell response in A20 tumor killing in vivo, mice were depleted of CD4+ and CD8+ T cell subsets, challenged with A20 tumor, and then vaccinated 4 days later as in the experiment above. Mice depleted of CD8+ T cells all succumbed to tumor demonstrating a critical role for CD8+ T cells in A20 tumor eradication. In conclusion, our data comparing sources of recombinant Id protein tumor antigens used in therapeutic cancer vaccines suggest that post-translational modifications, namely terminal mannose residues, can significantly influence the immunological properties and eventual therapeutic efficacy of the product.
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Superior T Cell and Humoral Immunity Generated Against B Cell Lymphomas Using a Sulfhydryl-Based Idiotype Carrier Protein Conjugation Method.
Blood, 2006Co-Authors: David J Betting, Sara A. Hurvitz, Kamran Kafi, Alireza Abdollahi-fard, John M TimmermanAbstract:Therapeutic vaccination of lymphoma patients with tumor-specific Immunoglobulin (Idiotype, Id) chemically-coupled to the highly immunogenic foreign carrier protein keyhole limpet hemocyanin (Id-KLH) has shown promising results in phase I/II clinical trials, and phase III trials are underway. However, many patients fail to mount anti-Id immune responses. Traditionally Id is coupled to KLH using glutaraldehyde (glut), which crosslinks via lysine, cysteine, tyrosine and histidine residues. Maleimide (mal) crosslinks only via cysteine sulfhydryl groups, thus limiting the potential for epitope destruction, and potentially allowing more efficient lysosomal processing in antigen presenting cells. The murine B cell lymphoma A20 was reported to be unresponsive to vaccination with glut/Id-KLH. We hypothesized that Id epitopes might be damaged by glut, but preserved using the more specificmal conjugation method. Id proteins were partially reduced to generate free sulfhydryl groups, and reacted with mal-activated KLH. Mice with 4-day established A20 lymphoma were vaccinated with 3 weekly glut/Id-KLH or mal/Id-KLH plus GM-CSF. As previously reported, tumor eradication was uncommon in glut/Id-KLH-treated mice (8–25%), with no statistical advantage over control-treated mice. In contrast, tumor was eradicated in 33–66% of mice vaccinated with mal/Id-KLH, with tumor free-survival being highly significant compared to control mice (p=0.0001) and glut/Id-KLH-vaccinated mice (p=0.0084). Combined vaccination with glut/Id-KLH+mal/Id-KLH did not improve survival over mal/Id-KLH alone (p=0.99). KLH conjugated to an irrelevant antibody did not result in any long-term survivors when challenged with A20. The length of time Id and KLH were allowed to conjugate with glut showed a statistically significant time dependence that affected survival (highest 58%) and anti-Id titers, while mal conjugation showed no such time dependence, and gave superior protection (83%). Mice vaccinated with A20 mal/Id-KLH generated 14-fold higher anti-Id antibody titers compared to glut/Id-KLH, and had superior survival after lethal tumor challenge (58% vs. 25%, respectively). A20 immune sera stained A20 cells via FACS analysis and the dominant isotype was shown to be IgG1 by ELISA. Adoptive transfer of high titer A20 anti-Id immune sera resulted in no protective advantage compared to naive sera indicating antibodies are not the dominant protective mechanism against A20. Depletion of CD8+ T cells demonstrated their critical role in A20 tumor eradication (p
Ronald Levy - One of the best experts on this subject based on the ideXlab platform.
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escherichia coli based production of a tumor Idiotype antibody fragment tetanus toxin fragment c fusion protein vaccine for b cell lymphoma
Protein Expression and Purification, 2011Co-Authors: Kedar G Patel, Ronald Levy, Shoshana Levy, James R SwartzAbstract:The unique Immunoglobulin Idiotype expressed on the surface of B lymphoma cells can be used as an effective antigen in tumor-specific vaccines when fused to immunostimulatory proteins and cytokines. A DNA vaccine encoding for an Idiotype antibody single chain Fv (scFv) fragment fused to the Tetanus Toxin Fragment C (TTFrC) has been shown to induce protective anti-tumor responses. Protein-based strategies may be more desirable since they provide greater control over dosage, duration of exposure, and in vivo distribution of the vaccine. However, production of fusion protein vaccines containing complex disulfide bonded Idiotype antibodies and antibody-derived fragments is challenging. We use an Escherichia coli-based cell-free protein synthesis platform as well as high-level expression of E. coli inclusion bodies followed by refolding for the rapid generation of an antibody fragment - TTFrC fusion protein vaccine. Vaccine proteins produced using both methods were shown to elicit anti-tumor humoral responses as well as protect from tumor challenge in an established B cell lymphoma mouse model. The development of technologies for the rapid production of effective patient-specific tumor Idiotype-based fusion protein vaccines provides opportunities for clinical application.
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escherichia coli based production of a tumor Idiotype antibody fragment tetanus toxin fragment c fusion protein vaccine for b cell lymphoma
Protein Expression and Purification, 2011Co-Authors: Kedar G Patel, Ronald Levy, Patrick P Ng, Shoshana Levy, James R SwartzAbstract:The unique Immunoglobulin Idiotype expressed on the surface of B lymphoma cells can be used as an effective antigen in tumor-specific vaccines when fused to immunostimulatory proteins and cytokines. A DNA vaccine encoding for an Idiotype antibody single chain Fv (scFv) fragment fused to the Tetanus Toxin Fragment C (TTFrC) has been shown to induce protective anti-tumor responses. Protein-based strategies may be more desirable since they provide greater control over dosage, duration of exposure, and in vivo distribution of the vaccine. However, production of fusion protein vaccines containing complex disulfide bonded Idiotype antibodies and antibody-derived fragments is challenging. We use an Escherichia coli-based cell-free protein synthesis platform as well as high-level expression of E. coli inclusion bodies followed by refolding for the rapid generation of an antibody fragment - TTFrC fusion protein vaccine. Vaccine proteins produced using both methods were shown to elicit anti-tumor humoral responses as well as protect from tumor challenge in an established B cell lymphoma mouse model. The development of technologies for the rapid production of effective patient-specific tumor Idiotype-based fusion protein vaccines provides opportunities for clinical application.
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Novel Anti-CD19/Idiotype Bispecific Diabody Vaccine for B-Cell Lymphoma.
Blood, 2009Co-Authors: Patrick P Ng, Kedar G Patel, Shoshana Levy, James R Swartz, Alejandro Virrueta, Ronald LevyAbstract:Abstract 2712 Poster Board II-688 The unique Immunoglobulin Idiotype (Id) on B-cell lymphoma is an excellent target for a “custom-made” vaccine therapy for individual patients. Previous studies have shown that vaccine-induced anti-Id humoral responses are effective in protecting mice from the aggressive 38C13 lymphoma. Therefore, we explore a novel strategy of direct activation of Id-specific B cells using a bispecific diabody containing the Id variable fragments (Fv) of 38C13, and those of an anti-CD19 monoclonal antibody. This molecule is designed to cross-link the Id-specific B cell receptor to the CD19/CD21/CD81 co-stimulatory complex, an interaction that has been shown to lower the activation threshold of B cells and result in a dramatic increase in antibody production. The αCD19/Id diabody is a 52 kDa heterodimer of two single chain Fv9s (scFv), αCD19VH-38C13VL and 38C13VH -αCD19VL, held together by non-covalent interactions between the cognate VH and VL domains. It was produced in an E. coli extract-based Cell-Free Protein Synthesis (CFPS) System developed by our group, which has been used successfully to rapidly produce cytokine-Id fusion vaccines in previous studies. Within 2 hours, the two diabody scFv9s were co-expressed and self-assembled in vitro. The heterodimer product was purified by metal affinity chromatography. Correct folding was confirmed by a flow cytometry assay in which the diabody bound simultaneously to the CD19 on the surface of B cells and also to an anti-38C13 Id antibody labeled with FITC. Most importantly, as a vaccine the αCD19/Id diabody generated a robust anti-Id IgG response comparable to that induced by 38C13 IgM conjugated to the carrier protein keyhole limpet hemocyanin (KLH). Diabody vaccinated mice also showed improved survival compared to control groups when both were challenged with a lethal dose of tumor. Further optimization of the therapeutic efficacy and the development of improved methods for the rapid and economical production of αCD19/Id diabody by the CFPS technology may make it possible to use individualized diabody-based therapy as a frontline treatment, before the use of toxic chemotherapy and radiation therapy. Disclosures: No relevant conflicts of interest to declare.
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Tumor-specific recombinant Idiotype immunisation after chemotherapy as initial treatment for follicular non-Hodgkin lymphoma
Leukemia & lymphoma, 2009Co-Authors: John M Timmerman, Debra K Czerwinski, Wenkai Weng, Julie M. Vose, Diane E. Ingolia, Martha Mayo, Dan W. Denney, Ronald LevyAbstract:Tumor-specific variable regions of the clonal Immunoglobulin (Idiotype, Id) expressed by B cell non-Hodgkin lymphoma (NHL) can be targeted by active immunotherapy. We conducted a phase I/II trial to determine the safety and immunogenicity of a patient-specific, recombinant, mammalian cell-derived Id protein conjugated to keyhole limpet hemocyanin (Id-KLH; MyVax® personalised immunotherapy) in 22 patients with follicular NHL in first remission after chemotherapy. Subjects received five subcutaneous immunisations with MyVax® plus locally administered granulocyte-macrophage colony-stimulating factor (GM-CSF). Among 21 evaluable patients, 62% mounted Id-specific immune responses. Evoked anti-Id antibodies recognised both recombinant Id and native Id, and could specifically stain autologous tumor cells. At median follow-up of more than 6 years, median progression-free survival is 38 months. Immunisation of follicular lymphoma patients with MyVax® Id-KLH is safe and patients often mount tumor-specific immune responses. These results form the basis of a pivotal phase 3 trial of MyVax® in follicular NHL.
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Anti-Idiotype Antibody Response after Vaccination Correlates with Better Overall Survival in Follicular Lymphoma.
Blood, 2007Co-Authors: Robert Tibshirani, Behnaz Taidi, Debra Czerwinski, Ronald LevyAbstract:Abstract Purpose Immunoglobulin Idiotype (Id) is a clonal marker expressed by B cells. Lymphoma B cells express a unique Id which serves as an ideal target for immunotherapy. It has been shown that induction of anti-Id immune response through vaccination is associated with many clinical benefits, including tumor regression, molecular remission, and prolonged progression free survival (PFS). However, it is unknown if induced immune response is an independent predictor for overall survival (OS). Patients and Methods We analyzed 91 patients who were uniformly treated with CVP followed by Idiotype vaccination as the first-line therapy. The induction of anti-Id immune response was evaluated and correlated with OS. Univariate and multivariate analyses were applied to select independent factors that predicted OS. Results: Those patients who achieved a CR/CRu to CVP chemotherapy or produced anti-Id antibody after vaccination had longer survival than those who did not. At 10 years, OS was 90% and 68% for patients with or without a CR/CRu after CVP (p = 0.024); 90% and 69% for patients with or without tumor-specific antibody production, respectively (p = 0.027). In contrast, generation of anti-Id cellular response did not correlate with OS. Furthermore, CR/CRu to CVP and generation of anti-Id antibody response were the only two independent factors among those tested that were correlated with longer survival. Conclusion: Generation of anti-Id antibody after active immunotherapy is an independent predictor for better OS in follicular lymphoma.
Steve D Weeks - One of the best experts on this subject based on the ideXlab platform.
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vaccination with syngeneic lymphoma derived Immunoglobulin Idiotype combined with granulocyte macrophage colony stimulating factor primes mice for a protective t cell response
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Larry W. Kwak, Howard A Young, Robin Pennington, Steve D WeeksAbstract:Abstract The Idiotype of the Ig expressed by a B-cell malignancy (Id) can serve as a unique tumor-specific antigen and as a model for cancer vaccine development. In murine models of Id vaccination, formulation of syngeneic Id with carrier proteins or adjuvants induces an anti-idiotypic antibody response. However, inducing a potent cell-mediated response to this weak antigen instead would be highly desirable. In the 38C13 lymphoma model, we observed that low doses of free granulocyte/macrophage colony-stimulating factor (GM-CSF) 10,000 units i.p. or locally s.c. daily for 4 days significantly enhanced protective antitumor immunity induced by s.c. Id-keyhole limpet hemocyanin (KLH) immunization. This effect was critically dependent upon effector CD4+ and CD8+ T cells and was not associated with any increased anti-idiotypic antibody production. Lymphocytes from spleens and draining lymph nodes of mice primed with Id-KLH plus GM-CSF, but not with Id-KLH alone, demonstrated significant proliferation to Id in vitro without any biased production of interferon gamma or interleukin 4 protein or mRNA. As a further demonstration of potency, 50% of mice immunized with Id-KLH plus GM-CSF on the same day as challenge with a large s.c. tumor inoculum remained tumor-free at day 80, compared with 17% for Id-KLH alone, when immunization was combined with cyclophosphamide. Taken together, these results demonstrate that GM-CSF can significantly enhance the immunogenicity of a defined self-antigen and that this effect is mediated exclusively by activating the T-cell arm of the immune response.
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Vaccination with syngeneic, lymphoma-derived Immunoglobulin Idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response.
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Larry W. Kwak, Howard A Young, Robin Pennington, Steve D WeeksAbstract:Abstract The Idiotype of the Ig expressed by a B-cell malignancy (Id) can serve as a unique tumor-specific antigen and as a model for cancer vaccine development. In murine models of Id vaccination, formulation of syngeneic Id with carrier proteins or adjuvants induces an anti-idiotypic antibody response. However, inducing a potent cell-mediated response to this weak antigen instead would be highly desirable. In the 38C13 lymphoma model, we observed that low doses of free granulocyte/macrophage colony-stimulating factor (GM-CSF) 10,000 units i.p. or locally s.c. daily for 4 days significantly enhanced protective antitumor immunity induced by s.c. Id-keyhole limpet hemocyanin (KLH) immunization. This effect was critically dependent upon effector CD4+ and CD8+ T cells and was not associated with any increased anti-idiotypic antibody production. Lymphocytes from spleens and draining lymph nodes of mice primed with Id-KLH plus GM-CSF, but not with Id-KLH alone, demonstrated significant proliferation to Id in vitro without any biased production of interferon gamma or interleukin 4 protein or mRNA. As a further demonstration of potency, 50% of mice immunized with Id-KLH plus GM-CSF on the same day as challenge with a large s.c. tumor inoculum remained tumor-free at day 80, compared with 17% for Id-KLH alone, when immunization was combined with cyclophosphamide. Taken together, these results demonstrate that GM-CSF can significantly enhance the immunogenicity of a defined self-antigen and that this effect is mediated exclusively by activating the T-cell arm of the immune response.
Bjarne Bogen - One of the best experts on this subject based on the ideXlab platform.
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peripheral t cell tolerance as a tumor escape mechanism deletion of cd4 t cells specific for a monoclonal Immunoglobulin Idiotype secreted by a plasmacytoma
European Journal of Immunology, 1996Co-Authors: Bjarne BogenAbstract:: Tumors could escape an immune attack by inducing peripheral T cell tolerance. To test this, T cell receptor (TCR)-transgenic mice were injected with plasmacytoma cells secreting a highly tumor-specific antigen, a monoclonal Immunoglobulin (Ig), for which the transgene-encoded TCR is specific. The TCR recognizes a third hypervariable region idiotypic (Id) peptide of the Ig, presented by a class II molecule on host antigen-presenting cells. The TCR-transgenic mice have previously been shown to be protected against an Id+ plasmacytoma challenge. In the present experiments, the protection was deliberately overwhelmed by subcutaneous injection of large numbers of plasmacytoma cells. Such tumor mice, chronically exposed to increasing amounts of monoclonal Ig, delete Id-specific CD4+ T cells in their peripheral lymphoid organs and in the tumor. The residual CD4+ cells express endogenous, rather than transgene-encoded TCR alpha chains. Peripheral deletion, functional T cells unresponsiveness, and thymocyte deletion are all first detected at the same serum concentration of monoclonal Ig, approximately 50 micrograms/ml (0.3 microM), and become more and more profound as the tumor burden increases. The results suggest that peripheral T cell tolerance to Id could be a tumor escape mechanism in patients with B cell malignancies. In addition, the findings have implications for T cell tolerance to Ig V regions in normal individuals.
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Thymic selection of Immunoglobulin Idiotype specific T-cells.
Thymus, 1994Co-Authors: Zlatko Dembic, Siegfried Weiss, Bjarne BogenAbstract:The thymus is the major site for differentiation and maturation of developing T-cells. The diversity in the T-cell repertoire is generated during ontogeny by rearrangements of T-cell receptor gene segments that encode clonally distributed receptors. Most of the newly produced thymocytes that bear alpha beta TCR die in the thymus as a consequence of at least two selective processes. Those that can react to self MHC antigens survive (positive selection), but only if the binding affinity for the same or other self MHC (probably complexed with self peptides) molecules is not too high (negative selection). As a result, each T-cell that has acquired functional competence in the thymus should have a certain degree of self-MHC specificity. Our comprehension of thymic development has been aided by the study of transgenic mice that bear functionally rearranged TCR or Ig lambda light chain genes. To study positive selection we analyzed transgenic mice with alpha beta TCR genes isolated from a T-cell clone specific for an idiotypic peptide of lambda 2(315) (a mutant of the lambda 2 Ig chain) bound to the E(d) MHC class II molecule. The results suggest that positive selection of some thymocytes might be weak, reminiscent of a 'struggle for survival', since the selected population was small and had high levels of transgenic receptor and coreceptor (CD4) molecules. The thymic tolerance mechanism was also investigated using a combination of both TCR and lambda 2(315) transgenic mice. The clonal deletion of Id specific thymocytes was influenced by the production site as well as the concentration of the lambda 2(315) antigen. In conclusion, the interaction avidity of a single thymocyte, which is important for selective processes, might be affected by the expression levels of each interacting component: TCR, CD4 or CD8 and MHC molecule and self antigen.
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Clonal deletion ofspecific thymocytes byan Immunoglobulin Idiotype
1993Co-Authors: Bjarne Bogen, Zlatko Dembic, Siegfried WeissAbstract:antigen-presenting cells (APC). Toexplorethis possibility,wehave examined if a circulatory self antigen, immuno-globulin (Ig), can induce clonal deletion of specificthymocytes.Ig is a class of self antigens of particular significancebecause their variable (V) regions have highly diversifiedidiotypic (Id) determinants thought to be important inimmune regulation (Jerne, 1974). It has recently becomeclearthatIdiotypescanberecognizednotonlybyantibodies,but also by MHC-restricted T cells. Thus, Ig can beendocytosed andprocessedbyAPC,followedbypresenta-tion ofshort Id-peptides to MHCclass II molecule-restricted
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Clonal deletion of specific thymocytes by an Immunoglobulin Idiotype.
The EMBO journal, 1993Co-Authors: Bjarne Bogen, Zlatko Dembic, Siegfried WeissAbstract:We have investigated whether Immunoglobulin can induce clonal deletion of thymocytes by employing two strains of transgenic mice. One strain is transgenic for an alpha/beta T cell receptor (TCR) which recognizes a processed idiotypic peptide of the lambda 2(315) light chain variable region, bound to the I-Ed class II major histocompatibility complex molecule. The other mouse strain is transgenic for the lambda 2(315) gene. Double transgenic offspring from a TCR-transgenic female mated with a lambda 2(315) transgenic male exhibit a pronounced clonal deletion of CD4+CD8+ thymocytes. Analysis of neonates from the reciprocal (lambda 2(315)-transgenic female x TCR-transgenic male) cross suggests that the deletion in double transgenic offspring most likely is caused by lambda 2(315) produced within the thymus rather than by maternally derived IgG, lambda 2(315). Nevertheless, IgG, lambda 2(315) can cause deletion of CD4+CD8+ thymocytes when injected in large amounts intraperitoneally into either adult or neonatal TCR-transgenic mice. Deletion is evident 48 and 72 h after injection, but by day 7 the thymus has already regained its normal appearance. A serum concentration of several hundred microgram/ml is required for deletion to be observed. Therefore, the heterogeneous Idiotypes of serum Ig are probably each of too low concentration to cause thymocyte deletion in normal animals.
