- Email: [email protected]
725. Emergency Use Regulatory Approval Process for Experimental Xenograft Vaccine
Cancer - Immunotherapy: Viral-Based Immune Modulation significantly prolongs the survival of mice with ip tumors. Effects appear to be due to a combination of oncolytic and immune effects. These promising results suggest that VSV.INFβ may be useful as a future therapy in patients with malignant mesothelioma.
725. Emergency Use Regulatory Approval Process for Experimental Xenograft Vaccine
Gladice Wallraven,1 Phillip B. Maples,1,2 John J. Nemunaitis.1,2,3,4 1 Mary Crowley Cancer Research Centers, Dallas, TX; 2Gradalis, Inc., Dallas, TX; 3Texas Oncology, P.A., Dallas, TX; 4Baylor Sammons Cancer Center, Dallas, TX. A 56 year old female patient with retroperitoneal leiomyosarcoma was at a life threatening stage of her disease. She was first diagnosed in October, 2001. She had been successfully palliated for several years following a series of surgical resections, chemotherapy and experimental drug treatment, however, recently she demonstrated progression of her disease. Rapid action was necessary and access to an experimental agent, TGF-β2 Antisense-GMCSF Gene Modified Autologous Xenograft Tumor Cell TAG Vaccine (“TAG vaccine”), was potentially able to be constructed via manufacturer, Gradalis, Inc. Patients with time constrained terminal diseases such as cancer may not have ready access to new treatments undergoing clinical development. Many patients and physicians are unaware of the Emergency Use IND regulation or believe that the approval process is too lengthy, cumbersome or complicated. We will illustrate the processes utilized to approve and permit emergency use treatment of a gene based product. A subject may qualify for a special exception to be filed with the FDA under an Investigational New Drug (IND) application entitled Emergency Use IND if either a) they do not meet the protocol eligibility criteria for an ongoing clinical trial or b) if no other standard or research therapies are available AND the situation does not allow time for routine IND submission. Unlike a Compassionate or Single Use IND, an Emergency Use IND is an expeditious process that allows for product shipment to be approved prior to a full IND filing. The communication to the FDA would be conducted via telephone or other rapid means. We will present the steps and issues involved in gaining an Emergency Use IND approval. Within a rapid timespan, the Emergency use trial was approved for this patient. In conclusion, the Emergency Use IND process is readily accessible when considering experimental gene transfer products. Although the clinical course of their diseases may not allow all the index patients to benefit from this process; those that do justify the effort.
726. Effect of Vaccine on Growth Suppression of Cancers and Hematopoietic Neoplasms by Total Body Irradiation and T Cell Depleted Bone Marrow Transplantation
Yucheng Tang,1 Yeon Hee Park,1 Tae Hae Han,1 Jonathan Maynard,1 Hakan Akbulut,1 Albert B. Deisseroth.1 1 Gene Therapy Program, Sidney Kimmel Cancer Center, San Diego, CA.
As chronological age advances, the ratio of antigen naïve T cells/ memory cells decreases and the response to vaccination diminishes. Multiple studies have shown that the percentage of individuals 55 years or older who develop a fully protective neutralizing antibody against influenza A following the yearly multivalent particle inactivated influenza vaccine is less than 20%. In addition, functional changes such as the reduction of the expression of CD40 ligand (CD40L) in activated CD4 T cells, have been discovered in mice and in human subjects of advanced chronological age. Since CD40L is essential for B cells and T cells to proliferate in response to an immunostimulatory signal, this defect could limit the response to vaccination. In order to design a vaccine strategy which circumvents these defects in the Molecular Therapy Volume 16, Supplement 1, May 2008 Copyright © The American Society of Gene Therapy
response in an aged test subject, we have linked the tumor associated antigen (TAA) to the extracellular domain (ecd) of the CD40L and embedded the TAA/ecdCD40L cDNA in a replication incompetent adenoviral vector. We have shown that the TAA/ecdCD40L released from the Ad-sig-TAA/ecdCD40L vector infected cells binds to the CD40 receptor on dendritic cells (DCs), and leads to presentation of the TAA on class I MHC by the DCs. The Ad-sig-TAA/ecdCD40L vector can overcome anergy in TAA.Tg mice, induce memory for over a year, and suppress the growth of TAA positive syngeneic tumor cell lines in TAA.Tg mice when TAA= rat Her-2-Neu (rH2N) and human MUC-1 (hMUC-1). Two sc injections of the TAA/ecdCD40L protein 14 days apart starting 7 days following the Ad-sig-TAA/ecdCD40L vector sc injection (we call this the TAA/ecdCD40L VPP vaccine) expands the magnitude of the increase of the antigen specific T cells and antibodies that is achievable by injection of the vector alone (TAA= rH2N, HPV E7, hMUC-1, tyrosinase related protein-2, and Bcr-Abl). Vaccination starting at 6 weeks of life can prevent the development of spontaneous mammary cancer at 6-8 months of life in 50% of vaccinated rH2N.Tg mice. The TAA/ecdCD40L VPP vaccine induces complete disappearance of established sc deposits of cancer and metastatic disease even in old mice. In order to test the effect of adding this vector prime-protein boost vaccine to total body irradiation and bone marrow transplantation, spleen cells were collected from TAA/ecdCD40L VPP vaccinated donor mice (TAA=HPV E7 or Bcr-Abl) and infused into recipient mice at 3 days following total body irradiation (TBI), and T cell depeleted bone marrow transplantation (TCDBMT) in mice in which TAA positive tumor cells was already growing. In addition, the recipient mice were also injected with the TAA/ecdCD40L vaccine approximately 3 weeks following the infusion of the spleen cells. We found that the vaccination increases the degree of suppression of the TAA positive tumor cells over that possible with TBI and TCDBMT alone. The FDA has given permission for patient entry of a phase I trial of this vaccine platform for recurrent carcinoma of the breast.
727. AdCD40LGene Therapy for Bladder Carcinoma – A Phase I/IIa Trial
Angelica Loskog,1 Camilla Lindqvist,1 Moa Fransson,1 Sara Mangsbo,1 Truls Gårdmark,2 Per-Uno Malmström,2 Thomas H. Tötterman.1 1 Clinical Immunology Division, Uppsala University, Uppsala, Sweden; 2Department of Urology, Uppsala University Hospital, Uppsala, Sweden. Background: Bladder cancer is sensitive for immunotherapy as exemplified by local bacillus Calmette-Guérin therapy (BCG). However, BCG is not effective in refractory disease and better alternatives are warranted. We are developing immunostimulating gene therapy for bladder cancer by transferring the CD40L gene into the tumor milieu. CD40L is a potent stimulator of systemic immunity and may therefore be effective in both local and invasive disease. Further, local expression of CD40L may induce apoptosis in nearby CD40+ tumor cells. Materials and Methods: Five bladder cancer patients (grade 3) scheduled for radical cystectomy due to invasive tumor growth were enrolled in Phase I. The CD40L expressing adenoviral vector was instilled into the bladder cavity. To facilitate viral uptake, bladders were prewashed with Clorpactin®WCS-90. The patients underwent 3 repeated cycles of gene therapy one week apart. The first 3 patients received 1x10e11 vector particles/treatment and the 2 last patients 1x10e12 particles/treatment. Patients were monitored for toxicity, transgene expression, immunological effects and tumor status. Phase IIa will begin in February 2008 and will include 9-12 recurrent Ta patients in cohorts of 3. Ta (noninvasive) patients will be enrolled to allow tumor monitoring. Results: AdCD40L therapy was well tolerated without any toxicity related to the gene transfer. Adenoviral vector and transgene expression could be detected in S271
725. Emergency Use Regulatory Approval Process for Experimental Xenograft Vaccine
Gladice Wallraven,1 Phillip B. Maples,1,2 John J. Nemunaitis.1,2,3,4 1 Mary Crowley Cancer Research Centers, Dallas, TX; 2Gradalis, Inc., Dallas, TX; 3Texas Oncology, P.A., Dallas, TX; 4Baylor Sammons Cancer Center, Dallas, TX. A 56 year old female patient with retroperitoneal leiomyosarcoma was at a life threatening stage of her disease. She was first diagnosed in October, 2001. She had been successfully palliated for several years following a series of surgical resections, chemotherapy and experimental drug treatment, however, recently she demonstrated progression of her disease. Rapid action was necessary and access to an experimental agent, TGF-β2 Antisense-GMCSF Gene Modified Autologous Xenograft Tumor Cell TAG Vaccine (“TAG vaccine”), was potentially able to be constructed via manufacturer, Gradalis, Inc. Patients with time constrained terminal diseases such as cancer may not have ready access to new treatments undergoing clinical development. Many patients and physicians are unaware of the Emergency Use IND regulation or believe that the approval process is too lengthy, cumbersome or complicated. We will illustrate the processes utilized to approve and permit emergency use treatment of a gene based product. A subject may qualify for a special exception to be filed with the FDA under an Investigational New Drug (IND) application entitled Emergency Use IND if either a) they do not meet the protocol eligibility criteria for an ongoing clinical trial or b) if no other standard or research therapies are available AND the situation does not allow time for routine IND submission. Unlike a Compassionate or Single Use IND, an Emergency Use IND is an expeditious process that allows for product shipment to be approved prior to a full IND filing. The communication to the FDA would be conducted via telephone or other rapid means. We will present the steps and issues involved in gaining an Emergency Use IND approval. Within a rapid timespan, the Emergency use trial was approved for this patient. In conclusion, the Emergency Use IND process is readily accessible when considering experimental gene transfer products. Although the clinical course of their diseases may not allow all the index patients to benefit from this process; those that do justify the effort.
726. Effect of Vaccine on Growth Suppression of Cancers and Hematopoietic Neoplasms by Total Body Irradiation and T Cell Depleted Bone Marrow Transplantation
Yucheng Tang,1 Yeon Hee Park,1 Tae Hae Han,1 Jonathan Maynard,1 Hakan Akbulut,1 Albert B. Deisseroth.1 1 Gene Therapy Program, Sidney Kimmel Cancer Center, San Diego, CA.
As chronological age advances, the ratio of antigen naïve T cells/ memory cells decreases and the response to vaccination diminishes. Multiple studies have shown that the percentage of individuals 55 years or older who develop a fully protective neutralizing antibody against influenza A following the yearly multivalent particle inactivated influenza vaccine is less than 20%. In addition, functional changes such as the reduction of the expression of CD40 ligand (CD40L) in activated CD4 T cells, have been discovered in mice and in human subjects of advanced chronological age. Since CD40L is essential for B cells and T cells to proliferate in response to an immunostimulatory signal, this defect could limit the response to vaccination. In order to design a vaccine strategy which circumvents these defects in the Molecular Therapy Volume 16, Supplement 1, May 2008 Copyright © The American Society of Gene Therapy
response in an aged test subject, we have linked the tumor associated antigen (TAA) to the extracellular domain (ecd) of the CD40L and embedded the TAA/ecdCD40L cDNA in a replication incompetent adenoviral vector. We have shown that the TAA/ecdCD40L released from the Ad-sig-TAA/ecdCD40L vector infected cells binds to the CD40 receptor on dendritic cells (DCs), and leads to presentation of the TAA on class I MHC by the DCs. The Ad-sig-TAA/ecdCD40L vector can overcome anergy in TAA.Tg mice, induce memory for over a year, and suppress the growth of TAA positive syngeneic tumor cell lines in TAA.Tg mice when TAA= rat Her-2-Neu (rH2N) and human MUC-1 (hMUC-1). Two sc injections of the TAA/ecdCD40L protein 14 days apart starting 7 days following the Ad-sig-TAA/ecdCD40L vector sc injection (we call this the TAA/ecdCD40L VPP vaccine) expands the magnitude of the increase of the antigen specific T cells and antibodies that is achievable by injection of the vector alone (TAA= rH2N, HPV E7, hMUC-1, tyrosinase related protein-2, and Bcr-Abl). Vaccination starting at 6 weeks of life can prevent the development of spontaneous mammary cancer at 6-8 months of life in 50% of vaccinated rH2N.Tg mice. The TAA/ecdCD40L VPP vaccine induces complete disappearance of established sc deposits of cancer and metastatic disease even in old mice. In order to test the effect of adding this vector prime-protein boost vaccine to total body irradiation and bone marrow transplantation, spleen cells were collected from TAA/ecdCD40L VPP vaccinated donor mice (TAA=HPV E7 or Bcr-Abl) and infused into recipient mice at 3 days following total body irradiation (TBI), and T cell depeleted bone marrow transplantation (TCDBMT) in mice in which TAA positive tumor cells was already growing. In addition, the recipient mice were also injected with the TAA/ecdCD40L vaccine approximately 3 weeks following the infusion of the spleen cells. We found that the vaccination increases the degree of suppression of the TAA positive tumor cells over that possible with TBI and TCDBMT alone. The FDA has given permission for patient entry of a phase I trial of this vaccine platform for recurrent carcinoma of the breast.
727. AdCD40LGene Therapy for Bladder Carcinoma – A Phase I/IIa Trial
Angelica Loskog,1 Camilla Lindqvist,1 Moa Fransson,1 Sara Mangsbo,1 Truls Gårdmark,2 Per-Uno Malmström,2 Thomas H. Tötterman.1 1 Clinical Immunology Division, Uppsala University, Uppsala, Sweden; 2Department of Urology, Uppsala University Hospital, Uppsala, Sweden. Background: Bladder cancer is sensitive for immunotherapy as exemplified by local bacillus Calmette-Guérin therapy (BCG). However, BCG is not effective in refractory disease and better alternatives are warranted. We are developing immunostimulating gene therapy for bladder cancer by transferring the CD40L gene into the tumor milieu. CD40L is a potent stimulator of systemic immunity and may therefore be effective in both local and invasive disease. Further, local expression of CD40L may induce apoptosis in nearby CD40+ tumor cells. Materials and Methods: Five bladder cancer patients (grade 3) scheduled for radical cystectomy due to invasive tumor growth were enrolled in Phase I. The CD40L expressing adenoviral vector was instilled into the bladder cavity. To facilitate viral uptake, bladders were prewashed with Clorpactin®WCS-90. The patients underwent 3 repeated cycles of gene therapy one week apart. The first 3 patients received 1x10e11 vector particles/treatment and the 2 last patients 1x10e12 particles/treatment. Patients were monitored for toxicity, transgene expression, immunological effects and tumor status. Phase IIa will begin in February 2008 and will include 9-12 recurrent Ta patients in cohorts of 3. Ta (noninvasive) patients will be enrolled to allow tumor monitoring. Results: AdCD40L therapy was well tolerated without any toxicity related to the gene transfer. Adenoviral vector and transgene expression could be detected in S271