The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ravi A Madan - One of the best experts on this subject based on the ideXlab platform.
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docetaxel alone or in combination with a therapeutic Cancer Vaccine panvac in patients with metastatic breast Cancer a randomized clinical trial
JAMA Oncology, 2015Co-Authors: Christopher R Heery, Mahsa Mohebtash, Philip M. Arlen, Ravi A Madan, Jennifer L Marte, Nuhad K Ibrahim, James L Murray, Kimberly B Koenig, Sheri Mcmahon, Seth M SteinbergAbstract:Importance Previous phase 1 and 2 trials of PANVAC, a poxviral-based Cancer Vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal Cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell–mediated killing. Objective The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast Cancer compared with docetaxel treatment alone. Design, Setting, and Participants Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast Cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. Main Outcomes and Measures The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P ≤ .10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. Results Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema ( P = .02, likely related to greater median number of docetaxel cycles) and injection-site reactions ( P P = .09). Conclusions and Relevance The results suggest that the combination of PANVAC with docetaxel in metastatic breast Cancer may provide a clinical benefit. This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. Trial Registration clinicaltrials.gov Identifier:NCT00179309
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
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prostvac vf a vector based Vaccine targeting psa in prostate Cancer
Expert Opinion on Investigational Drugs, 2009Co-Authors: Ravi A Madan, James W Hodge, Mahsa Mohebtash, Philip M. Arlen, James L GulleyAbstract:Prostvac is a prostate Cancer Vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector....
Patrick Midoux - One of the best experts on this subject based on the ideXlab platform.
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mRNA-based Cancer Vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes.
Cancer Gene Therapy, 2007Co-Authors: Michael Mockey, E Bourseau, V Chandrashekhar, Arabinda Chaudhuri, Sophie Lafosse, Bernhard Ryffel, Valerie F J Quesniaux, Chantal Pichon, Patrick MidouxAbstract:Immunization with mRNA encoding tumor antigen is an emerging Vaccine strategy for Cancer. In this paper, we demonstrate that mice receiving systemic injections of MART1 mRNA histidylated lipopolyplexes were specifically and significantly protected against B16F10 melanoma tumor progression. The originality of this work concerns the use of a new tumor antigen mRNA formulation as Vaccine, which allows an efficient protection against the growth of a highly aggressive tumor model after its delivery by intravenous route. Synthetic melanoma-associated antigen MART1 mRNA was formulated with a polyethylene glycol (PEG)ylated derivative of histidylated polylysine and L-histidine-(N,N-di-n-hexadecylamine)ethylamide liposomes (termed histidylated lipopolyplexes). Lipopolyplexes comprised mRNA/polymer complexes encapsulated by liposomes. The tumor protective effect was induced with MART1 mRNA carrying a poly(A) tail length of 100 adenosines at an optimal dose of 12.5 microg per mouse. MART1 mRNA lipopolyplexes elicited a cellular immune response characterized by the production of interferon-gamma and the induction of cytotoxic T lymphocytes. Finally, the anti-B16 response was enhanced using a formulation containing both MART1 mRNA and MART1-LAMP1 mRNA encoding the antigen targeted to the major histocompatibility complex class II compartments by the lysosomal sorting signal of LAMP1 protein. Our results provide a basis for the development of mRNA histidylated lipopolyplexes for Cancer Vaccine.
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mrna based Cancer Vaccine prevention of b16 melanoma progression and metastasis by systemic injection of mart1 mrna histidylated lipopolyplexes
Cancer Gene Therapy, 2007Co-Authors: Michael Mockey, E Bourseau, V Chandrashekhar, Arabinda Chaudhuri, Sophie Lafosse, Bernhard Ryffel, Valerie F J Quesniaux, Chantal Pichon, Patrick MidouxAbstract:mRNA-based Cancer Vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes
Christopher R Heery - One of the best experts on this subject based on the ideXlab platform.
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docetaxel alone or in combination with a therapeutic Cancer Vaccine panvac in patients with metastatic breast Cancer a randomized clinical trial
JAMA Oncology, 2015Co-Authors: Christopher R Heery, Mahsa Mohebtash, Philip M. Arlen, Ravi A Madan, Jennifer L Marte, Nuhad K Ibrahim, James L Murray, Kimberly B Koenig, Sheri Mcmahon, Seth M SteinbergAbstract:Importance Previous phase 1 and 2 trials of PANVAC, a poxviral-based Cancer Vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal Cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell–mediated killing. Objective The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast Cancer compared with docetaxel treatment alone. Design, Setting, and Participants Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast Cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. Main Outcomes and Measures The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P ≤ .10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. Results Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema ( P = .02, likely related to greater median number of docetaxel cycles) and injection-site reactions ( P P = .09). Conclusions and Relevance The results suggest that the combination of PANVAC with docetaxel in metastatic breast Cancer may provide a clinical benefit. This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. Trial Registration clinicaltrials.gov Identifier:NCT00179309
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
Renee N Donahue - One of the best experts on this subject based on the ideXlab platform.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients.
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phase i trial of a yeast based therapeutic Cancer Vaccine gi 6301 targeting the transcription factor brachyury
Cancer immunology research, 2015Co-Authors: Christopher R Heery, Harpreet B Singh, Myrna Rauckhorst, Italia Grenga, Timothy C Rodell, William L. Dahut, Philip M. Arlen, Renee N Donahue, Jennifer L Marte, Ravi A MadanAbstract:The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) Vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic Cancer Vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.
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dual effects of a targeted small molecule inhibitor cabozantinib on immune mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a Cancer Vaccine
Journal of Translational Medicine, 2014Co-Authors: Anna R Kwilas, Dana T Aftab, Andressa Ardiani, Renee N Donahue, James W HodgeAbstract:Background: Growing awareness of the complexity of carcinogenesis has made multimodal therapies for Cancer increasingly compelling and relevant. In recent years, immunotherapy has gained acceptance as an active therapeutic approach to Cancer treatment, even though Cancer is widely considered an immunosuppressive disease. Combining immunotherapy with targeted agents that have immunomodulatory capabilities could significantly improve its efficacy. Methods: We evaluated the ability of cabozantinib, a receptor tyrosine kinase inhibitor, to modulate the immune system in vivo as well as alter the phenotype of tumor cells in vitro in order to determine if this inhibitor could act synergistically with a Cancer Vaccine. Results: Our studies indicated that cabozantinib altered the phenotype of MC38-CEA murine tumor cells, rendering them more sensitive to immune-mediated killing. Cabozantinib also altered the frequency of immune sub-populations in the periphery as well as in the tumor microenvironment, which generated a more permissive immune environment. When cabozantinib was combined with a poxviral-based Cancer Vaccine targeting a self-antigen, the combination significantly reduced the function of regulatory T cells and increased cytokine production from effector T cells in response to the antigen. These alterations to the immune landscape, along with direct modification of tumor cells, led to markedly improved antitumor efficacy. Conclusions: These studies support the clinical combination of cabozantinib with immunotherapy for the treatment of Cancer.
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dual effects of a targeted small molecule inhibitor cabozantinib on immune mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a Cancer Vaccine
Journal of Translational Medicine, 2014Co-Authors: Anna R Kwilas, Dana T Aftab, Andressa Ardiani, Renee N Donahue, James W HodgeAbstract:Growing awareness of the complexity of carcinogenesis has made multimodal therapies for Cancer increasingly compelling and relevant. In recent years, immunotherapy has gained acceptance as an active therapeutic approach to Cancer treatment, even though Cancer is widely considered an immunosuppressive disease. Combining immunotherapy with targeted agents that have immunomodulatory capabilities could significantly improve its efficacy. We evaluated the ability of cabozantinib, a receptor tyrosine kinase inhibitor, to modulate the immune system in vivo as well as alter the phenotype of tumor cells in vitro in order to determine if this inhibitor could act synergistically with a Cancer Vaccine. Our studies indicated that cabozantinib altered the phenotype of MC38-CEA murine tumor cells, rendering them more sensitive to immune-mediated killing. Cabozantinib also altered the frequency of immune sub-populations in the periphery as well as in the tumor microenvironment, which generated a more permissive immune environment. When cabozantinib was combined with a poxviral-based Cancer Vaccine targeting a self-antigen, the combination significantly reduced the function of regulatory T cells and increased cytokine production from effector T cells in response to the antigen. These alterations to the immune landscape, along with direct modification of tumor cells, led to markedly improved antitumor efficacy. These studies support the clinical combination of cabozantinib with immunotherapy for the treatment of Cancer.
Nicole F Steinmetz - One of the best experts on this subject based on the ideXlab platform.
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heterologous prime boost enhances the antitumor immune response elicited by plant virus based Cancer Vaccine
Journal of the American Chemical Society, 2019Co-Authors: Sourabh Shukla, Hema Masarapu, Chao Wang, Nicole F SteinmetzAbstract:New Cancer Vaccine strategies are required to vanquish the self-tolerance and elicit robust immune responses against tumor-associated antigens and/or neoantigens. Contemporary approaches in nanomedicine center on the use of a single nanocarrier modified with multiple copies of multiple different functional domains, e.g., epitopes for Vaccines. Therefore, we set out to develop a combinatorial approach toward the next-generation concept of epitope delivery: a prime-boost strategy in which the same epitope is delivered using different nanocarriers. We tested this concept in the setting of HER2+ breast Cancer. We synthesized HER2-based Cancer Vaccines using three icosahedral plant viruses as carriers and evaluated the immune response as a result of repetitive, homologous immunization using BALB/c mice. Two of the Vaccines induced a Th2-predominant response and the other a Th1-predominant response. To enhance the immunogenicity of the Vaccines, we developed a heterologous prime-boost strategy with each of the ...
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heterologous prime boost enhances the antitumor immune response elicited by plant virus based Cancer Vaccine
Journal of the American Chemical Society, 2019Co-Authors: Sourabh Shukla, Hema Masarapu, Chao Wang, Nicole F SteinmetzAbstract:New Cancer Vaccine strategies are required to vanquish the self-tolerance and elicit robust immune responses against tumor-associated antigens and/or neoantigens. Contemporary approaches in nanomedicine center on the use of a single nanocarrier modified with multiple copies of multiple different functional domains, e.g., epitopes for Vaccines. Therefore, we set out to develop a combinatorial approach toward the next-generation concept of epitope delivery: a prime-boost strategy in which the same epitope is delivered using different nanocarriers. We tested this concept in the setting of HER2+ breast Cancer. We synthesized HER2-based Cancer Vaccines using three icosahedral plant viruses as carriers and evaluated the immune response as a result of repetitive, homologous immunization using BALB/c mice. Two of the Vaccines induced a Th2-predominant response and the other a Th1-predominant response. To enhance the immunogenicity of the Vaccines, we developed a heterologous prime-boost strategy with each of the ...
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heterologous prime boost enhances the antitumor immune response elicited by plant virus based Cancer Vaccine
Journal of the American Chemical Society, 2019Co-Authors: Hui Cai, Sourabh Shukla, Hema Masarapu, Chao Wang, Nicole F SteinmetzAbstract:New Cancer Vaccine strategies are required to vanquish the self-tolerance and elicit robust immune responses against tumor-associated antigens and/or neoantigens. Contemporary approaches in nanomedicine center on the use of a single nanocarrier modified with multiple copies of multiple different functional domains, e.g., epitopes for Vaccines. Therefore, we set out to develop a combinatorial approach toward the next-generation concept of epitope delivery: a prime-boost strategy in which the same epitope is delivered using different nanocarriers. We tested this concept in the setting of HER2+ breast Cancer. We synthesized HER2-based Cancer Vaccines using three icosahedral plant viruses as carriers and evaluated the immune response as a result of repetitive, homologous immunization using BALB/c mice. Two of the Vaccines induced a Th2-predominant response and the other a Th1-predominant response. To enhance the immunogenicity of the Vaccines, we developed a heterologous prime-boost strategy with each of the Vaccines administered only once, yielding higher titers of HER2-specific immunoglobulins and increasing the toxicity of the antisera toward Cancer cells. The prime-boost also induced a Th1-predominant response. An in vivo tumor challenge showed that the prime-boost regimen reduced tumor growth and improved survival in mice. This novel strategy to elicit robust immune responses against weakly immunogenic antigens in principle could be broadly applicable to Cancers and other diseases.
