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TK Followed by Ganciclovir: Report of a Clinical Trial
ONCOLYTIC VIRUS AND SUICIDE GENE THERAPY FOR CANCER DU145 cells; 2.46 vs. 1.21 and 0.87 pmol/min/mg in PC3 cells), higher cytotoxicity was demonstrated with the cox2L vectors after exposure to 5-FC in both cell lines tested (IC50 of 13.1 and 21.4 nM for Adcox2LCDcox2LSSTr2 and Adcox2LSSTr2cox2LCD with DU145 cells, and 24.5 and 30.4 nM, respectively with PC3 cells). Conclusion. The combination of the therapeutic genes CD and SSTr2 with the cox2L promoter should provide specificity for tumor uptake of radiolabeled peptides that bind to SSTr2 and selective 5FC molecular chemotherapy, which are to be evaluated in metastatic prostate cancer models. Supported by DOD grant DAMD17-02-10001.
819. Gene Therapy for Retinoblastoma Using AdV/TK Followed by Ganciclovir: Report of a Clinical Trial Richard L. Hurwitz,1,2 Murali Chintagumpala,1 William F. Mieler,2 Evelyn Paysse,2 Milton Boniuk,2 Mary Y. Hurwitz,1 Patricia Chevez-Barrios,2,3 Texas Children’s Cancer Center, Center for Cell and Gene Therapy. 1 Pediatrics, Baylor College of Medicine, Houston, TX; 2 Ophthalmology, Baylor College of Medicine, Houston, TX; 3 Pathology, Baylor College of Medicine, Houston, TX. Objective: To determine the safety and assess the efficacy of using an intraocular injection of an adenoviral vector containing the herpes thymidine kinase gene (ADV/TK) followed by systemic administration of ganciclovir to treat refractory retinoblastoma. Methods: This was an IRB, RAC and FDA approved pilot study utilizing intrapatient dose escalation. All patients had bilateral retinoblastoma with only one functional eye containing measurable retinoblastoma that was refractory to standard therapies; enucleation was the imminent treatment. Each experimental treatment consisted of an injection of adenoviral vector via a single needle insertion through the cornea, iris, zonules, and into the vitreous and was confirmed by direct observation. Each injection was followed by 7 days of ganciclovir delivered intravenously every 12 hours. Vitreous seeds were treated by intravitreous injection adjacent to the site of disease. Results: Eight patients have been enrolled on the study. The first patient received a single injection of 108 vp AdV/TK and the next 3 patients received an initial injection of 109 vp followed by either one or 2 injections of 1010 vp. Two patients who received 1010 vp experienced mild intraocular inflammatory responses that were well-controlled with steroids. One patient who had numerous vitreous seeds developed vitreous contraction. One patient with vitreous seeds has had a complete response and is tumor free with excellent vision 22 months following the completion of therapy. Three patients were enucleated. The eyes of patients who were enucleated all contained necrotic tumor at and around the injection sites and marked decreases in the number of vitreous seeds. Three subsequent patients received an injection of 1010 vp followed by one to four injections of 1011 vp while a fourth received a single injection of 1011 vp. One patient was enucleated because of an increase in the number of vitreous opacities (seeds) after a total of one injection of 1010 vp and 4 injections of 1011 vp. Histopathologic examination revealed islands of inflammatory cells but no evidence of tumor. The other 3 patients (2 patients treated with one dose of 1010 vp and one dose of 1011 vp and one patient with a single dose of 1011 vp) achieved either a partial response and are being treated with standard therapies (one patient) or have achieved a complete response and are being observed for signs of recurrent disease (two patients). The major adverse event was moderate intraocular inflammation (responsive to steroids) seen in three patients treated with 1011 vp. There was no evidence of extraocular spread of tumor through the needle tract in any patient. Conclusions: AdV/TK followed by ganciclovir can be safely administered to children with retinoblastoma. Patients with vitreous S316
seeds, a complication particularly difficult to treat with standard therapies, appeared to respond. Suicide gene therapy may be able to contribute to the treatment of children with retinoblastoma.
820. Phase I Study of Replication-Competent Adenovirus-Mediated Double Suicide Gene Therapy in Combination with Three-Dimensional Conformal Radiation Therapy for the Treatment of Locally Aggressive Prostate Cancer Svend O. Freytag,1 Hans Stricker,1 Jan Pegg,1 Dell Paielli,1 Summer Xia,1 Steve Brown,1 Jae Ho Kim.1 1 Radiation Oncology and Urology, Henry Ford Health System, Detroit, MI. Adenovirus-mediated suicide gene therapy may hold much promise in the treatment of human cancer. Although originally conceived as a monotherapy, we were the first to propose using suicide gene therapy as a means to improve the effectiveness of radiation therapy. We have developed a novel, trimodal approach that utilizes a lytic, replication-competent adenovirus (Ad5-CD/ TKrep) to selectively and efficiently deliver a CD/HSV-1 TK fusion gene to tumors. Our preclinical studies have demonstrated that the Ad5-CD/TKrep virus itself, via its cytolytic activity, has potent anti-tumor activity. The efficacy of Ad5-CD/TKrep viral therapy can be enhanced significantly by invoking the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems, which render malignant cells sensitive to specific pharmacological agents, and importantly, sensitizes them to radiation. Our preclinical work led to the first FDA-approved clinical trial (BB-IND 8436) in which a replicationcompetent virus was used to deliver a therapeutic gene to humans. This trial was completed in 2001 with excellent results. As a followup to this trial, we evaluated the safety and efficacy of our viral oncolytic/double suicide gene therapy approach in combination with three-dimensional conformal radiation therapy (3DCRT) in patients with newly diagnosed, intermediate to high risk prostate cancer (BB-IND 9852). Fifteen patients received a single intraprostatic injection (1012 vp) of the replication-competent Ad5-CD/TKrep virus followed by one to three weeks of 5-FC (150 mg/kg/day) and valganciclovir vGCV (1,800 mg/day) prodrug therapy and standard dose (70 Gy) 3DCRT. The primary endpoint was toxicity six weeks after completion of 3DCRT. The trial has been completed with excellent results. There were no dose-limiting toxicities and the maximum tolerated dose duration of the 5-FC + vGCV prodrug therapy was not defined. Ninety three percent (93%) of the adverse events observed were grade 1/2 in severity and there were no serious adverse events. Prostate biopsies obtained at 2, 3 and 4 weeks postinjection demonstrated that CD/HSV-1 TK transgene expression can persist in the prostate for at least 3 weeks. Our early analyses have indicated that PSA response and post-treatment prostate biopsy results are better than what would be expected for patients receiving standard dose 3DCRT alone. Based on these encouraging results, a randomized, two-arm, prospective Phase II study has been planned using a second-generation adenovirus that, in preclinical models, is markedly more efficacious than the prototype Ad5-CD/ TKrep virus. Our work continues to give us hope that gene therapy may demonstrate value in the clinic, particularly when combined with conventional cancer therapies such as radiation therapy.
Molecular Therapy Vol. 7, No. 5, May 2003, Part 2 of 2 Parts
Copyright ® The American Society of Gene Therapy
819. Gene Therapy for Retinoblastoma Using AdV/TK Followed by Ganciclovir: Report of a Clinical Trial Richard L. Hurwitz,1,2 Murali Chintagumpala,1 William F. Mieler,2 Evelyn Paysse,2 Milton Boniuk,2 Mary Y. Hurwitz,1 Patricia Chevez-Barrios,2,3 Texas Children’s Cancer Center, Center for Cell and Gene Therapy. 1 Pediatrics, Baylor College of Medicine, Houston, TX; 2 Ophthalmology, Baylor College of Medicine, Houston, TX; 3 Pathology, Baylor College of Medicine, Houston, TX. Objective: To determine the safety and assess the efficacy of using an intraocular injection of an adenoviral vector containing the herpes thymidine kinase gene (ADV/TK) followed by systemic administration of ganciclovir to treat refractory retinoblastoma. Methods: This was an IRB, RAC and FDA approved pilot study utilizing intrapatient dose escalation. All patients had bilateral retinoblastoma with only one functional eye containing measurable retinoblastoma that was refractory to standard therapies; enucleation was the imminent treatment. Each experimental treatment consisted of an injection of adenoviral vector via a single needle insertion through the cornea, iris, zonules, and into the vitreous and was confirmed by direct observation. Each injection was followed by 7 days of ganciclovir delivered intravenously every 12 hours. Vitreous seeds were treated by intravitreous injection adjacent to the site of disease. Results: Eight patients have been enrolled on the study. The first patient received a single injection of 108 vp AdV/TK and the next 3 patients received an initial injection of 109 vp followed by either one or 2 injections of 1010 vp. Two patients who received 1010 vp experienced mild intraocular inflammatory responses that were well-controlled with steroids. One patient who had numerous vitreous seeds developed vitreous contraction. One patient with vitreous seeds has had a complete response and is tumor free with excellent vision 22 months following the completion of therapy. Three patients were enucleated. The eyes of patients who were enucleated all contained necrotic tumor at and around the injection sites and marked decreases in the number of vitreous seeds. Three subsequent patients received an injection of 1010 vp followed by one to four injections of 1011 vp while a fourth received a single injection of 1011 vp. One patient was enucleated because of an increase in the number of vitreous opacities (seeds) after a total of one injection of 1010 vp and 4 injections of 1011 vp. Histopathologic examination revealed islands of inflammatory cells but no evidence of tumor. The other 3 patients (2 patients treated with one dose of 1010 vp and one dose of 1011 vp and one patient with a single dose of 1011 vp) achieved either a partial response and are being treated with standard therapies (one patient) or have achieved a complete response and are being observed for signs of recurrent disease (two patients). The major adverse event was moderate intraocular inflammation (responsive to steroids) seen in three patients treated with 1011 vp. There was no evidence of extraocular spread of tumor through the needle tract in any patient. Conclusions: AdV/TK followed by ganciclovir can be safely administered to children with retinoblastoma. Patients with vitreous S316
seeds, a complication particularly difficult to treat with standard therapies, appeared to respond. Suicide gene therapy may be able to contribute to the treatment of children with retinoblastoma.
820. Phase I Study of Replication-Competent Adenovirus-Mediated Double Suicide Gene Therapy in Combination with Three-Dimensional Conformal Radiation Therapy for the Treatment of Locally Aggressive Prostate Cancer Svend O. Freytag,1 Hans Stricker,1 Jan Pegg,1 Dell Paielli,1 Summer Xia,1 Steve Brown,1 Jae Ho Kim.1 1 Radiation Oncology and Urology, Henry Ford Health System, Detroit, MI. Adenovirus-mediated suicide gene therapy may hold much promise in the treatment of human cancer. Although originally conceived as a monotherapy, we were the first to propose using suicide gene therapy as a means to improve the effectiveness of radiation therapy. We have developed a novel, trimodal approach that utilizes a lytic, replication-competent adenovirus (Ad5-CD/ TKrep) to selectively and efficiently deliver a CD/HSV-1 TK fusion gene to tumors. Our preclinical studies have demonstrated that the Ad5-CD/TKrep virus itself, via its cytolytic activity, has potent anti-tumor activity. The efficacy of Ad5-CD/TKrep viral therapy can be enhanced significantly by invoking the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems, which render malignant cells sensitive to specific pharmacological agents, and importantly, sensitizes them to radiation. Our preclinical work led to the first FDA-approved clinical trial (BB-IND 8436) in which a replicationcompetent virus was used to deliver a therapeutic gene to humans. This trial was completed in 2001 with excellent results. As a followup to this trial, we evaluated the safety and efficacy of our viral oncolytic/double suicide gene therapy approach in combination with three-dimensional conformal radiation therapy (3DCRT) in patients with newly diagnosed, intermediate to high risk prostate cancer (BB-IND 9852). Fifteen patients received a single intraprostatic injection (1012 vp) of the replication-competent Ad5-CD/TKrep virus followed by one to three weeks of 5-FC (150 mg/kg/day) and valganciclovir vGCV (1,800 mg/day) prodrug therapy and standard dose (70 Gy) 3DCRT. The primary endpoint was toxicity six weeks after completion of 3DCRT. The trial has been completed with excellent results. There were no dose-limiting toxicities and the maximum tolerated dose duration of the 5-FC + vGCV prodrug therapy was not defined. Ninety three percent (93%) of the adverse events observed were grade 1/2 in severity and there were no serious adverse events. Prostate biopsies obtained at 2, 3 and 4 weeks postinjection demonstrated that CD/HSV-1 TK transgene expression can persist in the prostate for at least 3 weeks. Our early analyses have indicated that PSA response and post-treatment prostate biopsy results are better than what would be expected for patients receiving standard dose 3DCRT alone. Based on these encouraging results, a randomized, two-arm, prospective Phase II study has been planned using a second-generation adenovirus that, in preclinical models, is markedly more efficacious than the prototype Ad5-CD/ TKrep virus. Our work continues to give us hope that gene therapy may demonstrate value in the clinic, particularly when combined with conventional cancer therapies such as radiation therapy.
Molecular Therapy Vol. 7, No. 5, May 2003, Part 2 of 2 Parts
Copyright ® The American Society of Gene Therapy