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Phase I/II Trial of Intravenous NDV-HUJ Oncolytic Virus in Recurrent Glioblastoma Multiforme
Abstract
We undertook a Phase I/II trial in patients with apparent recurrent glioblastoma multiforme (GBM) based on imaging studies to determine the safety and tumor response of repetitive intravenous administration of NDV-HUJ, the oncolytic HUJ strain of Newcastle disease virus. The first part of the study utilized an accelerated intrapatient dose-escalation protocol with one-cycle dosage steps of 0.1, 0.32, 0.93, 5.9, and 11 billion infectious units (BIU) of NDV-HUJ (1 BIU = 1
10<SUP minmax_bound="true">9</SUP> EID<SUB minmax_bound="true">50</SUB> 50% egg infectious dose) followed by three cycles of 55 BIU. Virus was administered by intravenous infusion over 15 min. In the second part, patients received three cycles of 11 BIU. All patients without progressive disease were maintained with two doses of 11 BIU iv weekly. Eleven of the 14 enrolled patients (11?58 years, Karnofsky performance scale 50?90%) received treatment. Toxicity was minimal with Grade I/II constitutional fever being seen in 5 patients. Maximum tolerated dose was not achieved. Anti-NDV hemagglutinin antibodies appeared within 5?29 days. NDV-HUJ was recovered from blood, saliva, and urine samples and one tumor biopsy. One patient achieved a complete response. Intravenous NDV-HUJ is well tolerated. The findings of good tolerability and encouraging responses warrant the continued evaluation of NDV-HUJ in GBM, as well as other cancers.
Introduction
Primary malignant gliomas are among the most lethal and difficult forms of cancer. Of these glioblastoma multiforme (GBM) is the most rapidly growing and most challenging<SUP minmax_bound="true">1</SUP>. Despite improvements, the outcome for GBM patients has not changed significantly over the past 30 years<SUP minmax_bound="true">2</SUP>. With maximal conventional therapy, survival is approximately 14 months from time of diagnosis and about 30 weeks from the time of recurrence<SUP minmax_bound="true">3</SUP>. Recent advances in the understanding of brain tumor biology have led to the development of novel therapeutic approaches<SUP minmax_bound="true">4,5</SUP>, including oncolytic virotherapy<SUP minmax_bound="true">6,7,8</SUP>. Viruses, particularly adenovirus<SUP minmax_bound="true">9,10</SUP> and HSV<SUP minmax_bound="true">11,12</SUP>, have been engineered to deliver therapeutic genes, while other viruses<SUP minmax_bound="true">13,14,15</SUP> have been utilized without engineering for their innate cytotoxic effects.
Among the nonengineered oncolytic viruses, Newcastle disease virus (NDV)<SUP minmax_bound="true">16</SUP> has a long history as a broad-spectrum oncolytic agent that can destroy tumor cells and stimulate the immune system<SUP minmax_bound="true">17,18,19,20,21,22,23,24,25</SUP>. NDV is a single-stranded RNA virus, whose natural host is poultry. The 73-T<SUP minmax_bound="true">26</SUP>, MTH68<SUP minmax_bound="true">27</SUP>, and PV701 (MK107)<SUP minmax_bound="true">28,29</SUP> strains of NDV have been the subject of several clinical studies. NDV-PV701 has recently been evaluated in a Phase I study of patients with advanced solid tumors; however, patients with CNS tumors were excluded from this study<SUP minmax_bound="true">29</SUP>. Anecdotal responses to MTH68 in malignant glioma have been reported<SUP minmax_bound="true">27</SUP>.
NDV strains that are not pathogenic to poultry (lentogenic) have also been shown to kill cancer cells<SUP minmax_bound="true">24</SUP> but possibly by different mechanisms<SUP minmax_bound="true">17</SUP>. Infection of tumor cells by lentogenic NDV generates several innate danger signals leading to apoptosis. The lentogenic Ulster strain of NDV has been combined with various tumor cells as a tumor vaccine for different cancers, including GBM<SUP minmax_bound="true">30</SUP>, but the use of a lentogenic NDV strain alone in oncolytic virotherapy has not been evaluated. HUJ is a new lentogenic strain of NDV (NDV-HUJ) that has a selective cytopathogenicity for human and animal cancer cell lines (L. Rasooly, E. Ovin, N. Hooshi, and E. Galun, unpublished results; Z. Zakay-Rones and A. Panet, unpublished results).
We here present the first clinical evaluation of a lentogenic NDV strain administered systemically and the first evaluation of any NDV strain in GBM patients. We evaluated patients with recurrent GBM in a single-site, open-label Phase I/II study of NDV-HUJ.
(for entire article, see link above)
.
Phase I/II Trial of Intravenous NDV-HUJ Oncolytic Virus in Recurrent Glioblastoma Multiforme
Abstract
We undertook a Phase I/II trial in patients with apparent recurrent glioblastoma multiforme (GBM) based on imaging studies to determine the safety and tumor response of repetitive intravenous administration of NDV-HUJ, the oncolytic HUJ strain of Newcastle disease virus. The first part of the study utilized an accelerated intrapatient dose-escalation protocol with one-cycle dosage steps of 0.1, 0.32, 0.93, 5.9, and 11 billion infectious units (BIU) of NDV-HUJ (1 BIU = 1
10<SUP minmax_bound="true">9</SUP> EID<SUB minmax_bound="true">50</SUB> 50% egg infectious dose) followed by three cycles of 55 BIU. Virus was administered by intravenous infusion over 15 min. In the second part, patients received three cycles of 11 BIU. All patients without progressive disease were maintained with two doses of 11 BIU iv weekly. Eleven of the 14 enrolled patients (11?58 years, Karnofsky performance scale 50?90%) received treatment. Toxicity was minimal with Grade I/II constitutional fever being seen in 5 patients. Maximum tolerated dose was not achieved. Anti-NDV hemagglutinin antibodies appeared within 5?29 days. NDV-HUJ was recovered from blood, saliva, and urine samples and one tumor biopsy. One patient achieved a complete response. Intravenous NDV-HUJ is well tolerated. The findings of good tolerability and encouraging responses warrant the continued evaluation of NDV-HUJ in GBM, as well as other cancers.Introduction
Primary malignant gliomas are among the most lethal and difficult forms of cancer. Of these glioblastoma multiforme (GBM) is the most rapidly growing and most challenging<SUP minmax_bound="true">1</SUP>. Despite improvements, the outcome for GBM patients has not changed significantly over the past 30 years<SUP minmax_bound="true">2</SUP>. With maximal conventional therapy, survival is approximately 14 months from time of diagnosis and about 30 weeks from the time of recurrence<SUP minmax_bound="true">3</SUP>. Recent advances in the understanding of brain tumor biology have led to the development of novel therapeutic approaches<SUP minmax_bound="true">4,5</SUP>, including oncolytic virotherapy<SUP minmax_bound="true">6,7,8</SUP>. Viruses, particularly adenovirus<SUP minmax_bound="true">9,10</SUP> and HSV<SUP minmax_bound="true">11,12</SUP>, have been engineered to deliver therapeutic genes, while other viruses<SUP minmax_bound="true">13,14,15</SUP> have been utilized without engineering for their innate cytotoxic effects.
Among the nonengineered oncolytic viruses, Newcastle disease virus (NDV)<SUP minmax_bound="true">16</SUP> has a long history as a broad-spectrum oncolytic agent that can destroy tumor cells and stimulate the immune system<SUP minmax_bound="true">17,18,19,20,21,22,23,24,25</SUP>. NDV is a single-stranded RNA virus, whose natural host is poultry. The 73-T<SUP minmax_bound="true">26</SUP>, MTH68<SUP minmax_bound="true">27</SUP>, and PV701 (MK107)<SUP minmax_bound="true">28,29</SUP> strains of NDV have been the subject of several clinical studies. NDV-PV701 has recently been evaluated in a Phase I study of patients with advanced solid tumors; however, patients with CNS tumors were excluded from this study<SUP minmax_bound="true">29</SUP>. Anecdotal responses to MTH68 in malignant glioma have been reported<SUP minmax_bound="true">27</SUP>.
NDV strains that are not pathogenic to poultry (lentogenic) have also been shown to kill cancer cells<SUP minmax_bound="true">24</SUP> but possibly by different mechanisms<SUP minmax_bound="true">17</SUP>. Infection of tumor cells by lentogenic NDV generates several innate danger signals leading to apoptosis. The lentogenic Ulster strain of NDV has been combined with various tumor cells as a tumor vaccine for different cancers, including GBM<SUP minmax_bound="true">30</SUP>, but the use of a lentogenic NDV strain alone in oncolytic virotherapy has not been evaluated. HUJ is a new lentogenic strain of NDV (NDV-HUJ) that has a selective cytopathogenicity for human and animal cancer cell lines (L. Rasooly, E. Ovin, N. Hooshi, and E. Galun, unpublished results; Z. Zakay-Rones and A. Panet, unpublished results).
We here present the first clinical evaluation of a lentogenic NDV strain administered systemically and the first evaluation of any NDV strain in GBM patients. We evaluated patients with recurrent GBM in a single-site, open-label Phase I/II study of NDV-HUJ.
(for entire article, see link above)
.