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Pennsylvania Mesothelioma Fact Sheet

While mesothelioma is a problem in all states, the specific incident rate for Pennsylvania is 1.4 / 100,000. This is above the average rate of 1.1 / 100,000. Click on the tabs below to find mesothelioma and asbestos research in PA, recent PA mesothelioma-related court cases, mesothelioma specialists in PA and potential asbestos hotspots in Pennsylvania.

Pennsylvania Mesothelioma Info

By clicking on the above tabs, you will find information on mesothelioma specific to the state of Pennsylvania

Pennsylvania Research and Clinical Trials

This is a partial list of scientific or medical grants in your state for research into mesothelioma and related illnesses.

Pennsylvania Doctors and Hospitals

This is a partial list of hospitals and physicians that reportedly treat mesothelioma patients in your state.

Pennsylvania Cases

This is a partial list of relevant court cases on mesothelioma in your state.

Disclaimer: Inclusion on this directory does not constitute endorsement by Cancer Monthly, Inc. All physicians who appear in this section do so based on their own expression of interest in the fields of mesothelioma treatment. Cancer Monthly, Inc. has not verified the competence, professional credentials, business practices or validity of the expressed interests of these physicians. Cancer Monthly makes no recommendation of any physician on this list and makes no suggestion that any such physician will cure or prevent any disease. Those consulting a physician on this list should approach the consultation exactly as they would with any other unknown physician.

Research

Abstract:The overall goal of this PO1 is to develop and evaluate approaches for gene therapy in the treatment of localized malignancies using malignant mesothelioma as the paradigm. Mesothelioma is an excellent candidate for the development of gene therapy because the disease is uniformly lethal with no effective therapies available, morbidity and mortality are the result of regional intrathoracic disease, and the tumor is localized to an anatomically defined space to which there is easy access. The rationale for this proposal comes from studies showing that tumor cells transduced with an adenoviral vector containing the Herpes Simplex thymidine kinase (HSVtk) gene are killed after exposure to the normally non-toxic anti-viral drug ganciclovir (GCV) and that a powerful “bystander effect” exists (i.e. uniform killing occurs even when only a small percentage of cells are transduced). Studies were extended to an animal model of human mesothelioma in which established mesothelioma tumors growing within the peritoneal cavity of immunodeficient mice were eradicated by intraperitoneal administration of the adeno-HSVtk vector followed by treatment with GCV. The grant consists of three projects and four cores. The goals of Project I are to develop new vectors based on adenovirus and adeno-associated virus expressing the HSVtk gene and to test these vectors for persistence and the development of immune response in animal models of mesothelioma. The goals of Project 2 are to test and optimize the “first generation” vector and the new vectors developed in Project 1 with regard to efficacy in the treatment of mesothelioma in animal models. The second focus of this project will be to study the mechanisms responsible for the efficacy of the HSVtk/GCV system in eradicating tumors. The goals of Project 3 are to use the vectors developed in Projects 1 and 2 to treat patients with malignant mesothelioma and to obtain information about the biologic effects of adenoviral vectors in the treatment of localized malignancy. A Phase I clinical trial is proposed using the first generation virus that will define the potential systemic, intrathoracic, and immunologic toxicities and determine a maximally tolerated dose. An important feature of this trial is a videothoracoscopic biopsy of pleural tumor after instillation of virus that will allow evaluation of gene transduction. These findings will form the basis of a Phase II clinical trial designed to evaluate possible efficacy. Using this information, the safety and efficacy of new viral vectors developed in Projects 1 and 2 will be tested in additional Phase I and II trials. The cores that support these projects include an Administrative Core, the Human Applications Laboratory (to make clinical grade viral vectors), a Cellular Morphology Core, and an Animal modeling and Toxicology Core.

Tags: Gene Therapy, Mesothelioma

  • Followup Grant: 5P01CA066726-03
  • Followup Grant: 5P01CA066726-04
  • Followup Grant: 3P01CA066726-04S1
  • Followup Grant: 2P01CA066726-05A1
  • Followup Grant: 5P01CA066726-06
  • Followup Grant: 5P01CA066726-07
  • Followup Grant: 5P01CA066726-08
  • Followup Grant: 5P01CA066726-02

Abstract:The broad, long-term objective of this project is to discover acquired genetic alterations in human malignant mesothelioma. The proposed investigations emphasize three prominent sites of chromosomal deletion (9p21-p22, 1p21-p22, and 6q15-q2l) documented in malignant mesothelioma, each of which is also a frequent site of allelic loss in a variety of more common malignancies such as breast cancer. This project proposes to analyze the role of the putative tumor suppressor gene p16/MTS1/CDK4- inhibitor, located in 9p21-p22, in malignant mesothelioma and determine whether other genes from this chromosomal region are also altered in these tumors. Mesothelioma cell lines displaying homozygous deletions of 9p21-p22 that do not overlap the p16 locus will be examined to determine if another candidate tumor suppressor gene(s) is involved in these cases. An emphasis will be placed on studies of primary tumor tissues to determine whether p16 or a neighboring locus is the critically altered 9p21-p22 gene in malignant mesothelioma. This project also proposes to positionally clone and characterize the putative tumor suppressor gene located in 1p21-p22. Other fine deletion mapping studies will define molecularly the critically deleted segment in 6q15-q21, in preparation for the eventual cloning of the putative tumor suppressor gene(s) located in this region. In addition, differential messenger RNA display and a combination of comparative genomic hybridization and loss of heterozygosity analyses will be employed to identify other recurrent genetic changes contributing to the pathogenesis of malignant mesothelioma.

Tags: Carcinoma, Cytogenetics, Mesothelioma, Molecular Genetics, Neoplasm /cancer Genetics Allele, Chromosome Deletion, Genetic Mapping, Messenger Rna, Molecular Oncology, Neoplasm /cancer Invasiveness, Pathology, Tumor Suppressor Gene Human Tissue, Laboratory Mouse, Northern Blotting, Polymerase Chain Reaction, Tissue /cell Culture, Transfection

  • Followup Grant: 5R01CA045745-10
  • Followup Grant: 5R01CA045745-11
  • Followup Grant: 5R01CA045745-12
  • Followup Grant: 5R01CA045745-09

Abstract: The goals of project 3 are to develop novel therapeutic approaches for the treatment of localized malignancy, such as mesothelioma, and to obtain important information about the biology of adenovirus-mediated gene transfer in cancer therapy. Malignant mesothelioma, a tumor arising from the lining of the pleural or peritoneal mesothelial cells, is characterized by aggressive local, rather than distant, spread for its attendant morbidity and mortality and mortality and is extremely resistant to treatment despite aggressive multimodality therapy. Studies by others using packaging cells secreting a retrovirus containing the Herpes Simplex thymidine kinase (HSVtk) gene followed by treatment of animals with the anti-viral drug ganciclovir (GCV) have demonstrated brain tumor regression. Recently completed studies show that injection of an adenovirus vector containing the HSVtk gene (Ad.RSVtk) followed by treatment with GCV can eradicate established human mesothelioma tumors growing with the peritoneal cavity of immunodeficient mice. These results suggest that administration of HSVtk/GCV using adenovirus may be efficacious in patients with this disease, as well as in other forms of cancer where localized spread is detrimental (i.e. brain tumor, ovarian cancer, leptomeningeal-metastasis, bladder carcinoma). Malignant mesothelioma thus represents an ideal “model” tumor system in which to test this hypothesis and to obtain valuable information about the biology of adenovirus-based gene therapy for localized malignancy in humans. After toxicity studies have been completed in animals, a Phase i clinical trial will begin in which patients with mesothelioma will be given intrapleural administration of Ad.RSVtk followed by treatment with GCV for 14 days. This study will define the potential systemic, intrathoracic, and immunologic toxicities and determine the maximal tolerated dose. An important feature of this protocol includes a videothoracoscopic biopsy of tumor three days after virus instillation that will allow the amount of gene transduction within the cells of the tumor and the type of immune response generated to be determined histologically. It is hypothesized that specific histologic featrues (including degree of fibrosis and vascularity, degree of expression of vitronectin receptor, and degree of immune response generated) will correlate with the efficiency and efficacy of the Ad.RSVtk/GCV system in mesothelioma patients with less extensive “non-bulky” disease. Using this information, the safety and efficacy of new viral vectors developed in Projects 1 and 2 will be tested in additional Phase I and Phase II clinical trials.

Tags:Drug Screening /evaluation, Gene Therapy, Human Therapy Evaluation, Mesothelioma, Neoplasm /cancer Therapy Cellular Immunity, Clinical Trial, Cytotoxicity, Dosage, Drug Adverse Effect, Ganciclovir, Genetic Transduction, Humoral Immunity, Neoplasm /cancer Immunology, Oncogene, Virus Protein, Vitronectin Adeno Associated Virus Group, Biopsy, Cell Mediated Lymphocytolysis Test, Histopathology, Human Subject, Transfection

  • Followup Grant: 5P01CA066726-040003

Abstract: The overall goals of Project 2 are 1) to study the mechanisms responsible for the efficacy of the HSVtk/GCV system in eradicating tumors and 2) to optimize and further characterize the treatment of malignant mesothelioma using the Herpes Simplex thymidine kinase (HSVtk) gene carried in recombinant viral vectors. Preliminary data indicate that administration of a “first generation” adenovirus (Ad) vector containing the Herpes Simplex thymidine kinase (HSV) gene driven from a Rous Sarcoma Virus(RSV) promoter (Ad.RSVtk), in conjunction with the antiviral drug gancichovir (GCV), can eradicate established tumor in a model of human malignant mesothelioma growing within the peritoneal cavity of immunodeficient mice. This process appears to depend on a powerful “bystander effect” whereby only a relatively small percentage of cells need to be transduced with the Ad.RSVtk gene. These experiments suggest that this system may be of efficacy in treating certain human cancers, such as malignant mesothelioma and others that grow in defined anatomic spaces. Before such a goal is reached, however, a number of important questions about the mechanisms by which tumor eradication is effected , the optimal mode of delivery, and the role of the immune system must be answered. In addition, it will be critical to optimize the system by evaluating the ability of improved viral vectors containing HSVtk\generated in Project 1 to treat tumor. A major focus of this proposal will be to study possible mechanisms by which the HSVtk/GCV system eradicates tumor. Experiments examining the role of the role of the immune system, vascular system, and gap junctional transfer of toxic metabolites will be conducted. The treatment of malignant mesothelioma using the first generation Ad.RSVtk vector will be further characterized and optimized by developing and evaluating models of pleural mesothelioma in immunodeficient (nude) rats and immunocompetent animals (Fischer rat). Finally, the efficacy of second generation adenoviruses containing HSVtk and newly developed viral vectors containing hSVtk generated in Project 1 in treating models of mesothelioma in immunodeficient and immunocompetent animals will be studied. The information gained about he mechanisms and optimization of the HSVtk/GCV system and the testing of new vectors designed in Project 1 (i.e. adeno- associated virus) will be critical in designing and implementing new clinical trials in Project 3.

Tags: Herpes Simplex Disease, Drug Screening /evaluation, Gene Therapy, Mesothelioma, Neoplasm /cancer Therapy, Nonhuman Therapy Evaluation, Thymidine Kinase, Transfection Vector Rous Sarcoma Virus, Disease Model, Ganciclovir, Gene Expression, Genetic Promoter Element, Genetic Transduction, Prodrug Adeno Associated Virus Group, Laboratory Mouse, Laboratory Rat, Polymerase Chain Reaction

  • Followup Grant: 5P01CA066726-040002
  • Followup Grant: 3P01CA066726-04S10002

Abstract: The broad, long-term objective of this project is to enhance markedly the understanding of the biological and clinical implications of chromosome alterations in human non-small cell lung cancer (NSCLC) and mesothelioma, two neoplasms for which the current cytogenetic data base is relatively sparse. Karyologic investigations will be performed on a series of tumors from patients with NSCLC or mesothelioma, with emphasis on analyses of untreated primary tumors. This project proposes to identify recurrent chromosome abnormalities in these tumors and correlate the genetic alterations with important clinicopathologic features such as tumor cell phenotype, disease stage, subsequent metastatic behavior, and survival. Long-term tumor cultures and cell lines will be established, and the possibility that specific chromosome alterations correlate with various biological parameters such as spontaneous metastatic ability and in vitro invasiveness in these cell lines will be explored. An inherent component of the overall goal of this project is the evaluation of newer tumor cell culture methods, growth of tumor cell xenografts in athymic mice, and “interphase cytogenetics” techniques (using fluorescence in situ hybridization) to enhance karyologic investigations in these tumors. The molecular and functional characterization of several recurrent sites of chromosome loss previously identified cytogenetically in NSCLC and mesothelioma is also proposed. The frequency of loss of heterozygosity at specific chromosomal sites that have been implicated as “hot spots” for apparently unbalanced structural rearrangements in NSCLC will be determined. Furthermore, the incidence and minimal region of overlap of allelic loss on chromosome regions 1p, 3p, and 22q in mesothelioma will also be investigated. Results of karyotypic analysis of these same tumors will be used to assist in the interpretation of the loss of heterozygosity data. Finally, this project proposes to examine whether tumorigenicity of mesothelioma cell lines exhibiting loss of lp, 3p, or 22q can be suppressed or modulated by microcell-mediated transfer of one or more normal homologs of these chromosomes.

Tags: Cytogenetics, Lung Neoplasm, Mesothelioma, Neoplasm /cancer Genetics Chromosome Disorder, Cytodiagnosis, Karyotype, Metastasis, Molecular Oncology, Neoplasm /cancer Diagnosis, Neoplasm /cancer Invasiveness, Neoplastic Cell Athymic Mouse, Histochemistry /cytochemistry, Human Tissue From Nonrelated Source, Immunocytochemistry, In Situ Hybridization, Neoplasm /cancer Transplantation, Nucleic Acid Probe, Restriction Fragment Length Polymorphism, Tissue /cell Culture

  • Followup Grant: 5R01CA045745-05
  • Followup Grant: 7R01CA045745-03

Abstract: The broad, long-term objective of this project is to enhance markedly the understanding of the biological and clinical implications of chromosome alterations in human non-small cell lung cancer (NSCLC) and mesothelioma, two neoplasms for which the current cytogenetic data base is relatively sparse. Karyologic investigations will be performed on a series of tumors from patients with NSCLC or mesothelioma, with emphasis on analyses of untreated primary tumors. This project proposes to identify recurrent chromosome abnormalities in these tumors and correlate the genetic alterations with important clinicopathologic features such as tumor cell phenotype, disease stage, subsequent metastatic behavior, and survival. Long-term tumor cultures and cell lines will be established, and the possibility that specific chromosome alterations correlate with various biological parameters such as spontaneous metastatic ability and in vitro invasiveness in these cell lines will be explored. An inherent component of the overall goal of this project is the evaluation of newer tumor cell culture methods, growth of tumor cell xenografts in athymic mice, and “interphase cytogenetics” techniques (using fluorescence in situ hybridization) to enhance karyologic investigations in these tumors. The molecular and functional characterization of several recurrent sites of chromosome loss previously identified cytogenetically in NSCLC and mesothelioma is also proposed. The frequency of loss of heterozygosity at specific chromosomal sites that have been implicated as “hot spots” for apparently unbalanced structural rearrangements in NSCLC will be determined. Furthermore, the incidence and minimal region of overlap of allelic loss on chromosome regions 1p, 3p, and 22q in mesothelioma will also be investigated. Results of karyotypic analysis of these same tumors will be used to assist in the interpretation of the loss of heterozygosity data. Finally, this project proposes to examine whether tumorigenicity of mesothelioma cell lines exhibiting loss of lp, 3p, or 22q can be suppressed or modulated by microcell-mediated transfer of one or more normal homologs of these chromosomes.

Tags: Cytogenetics, Lung Neoplasm, Mesothelioma, Neoplasm /cancer Genetics Chromosome Disorder, Cytodiagnosis, Karyotype, Metastasis, Molecular Oncology, Neoplasm /cancer Diagnosis, Neoplasm /cancer Invasiveness, Neoplastic Cell Athymic Mouse, Histochemistry /cytochemistry, Human Tissue, Immunocytochemistry, In Situ Hybridization, Neoplasm /cancer Transplantation, Nucleic Acid Probe, Restriction Fragment Length Polymorphism, Tissue /cell Culture

  • Followup Grant: 3R01CA045745-05S1

Abstract: The broad, long-term objective of this project is to enhance markedly the understanding of the biological and clinical implications of chromosome alterations in human non-small cell lung cancer (NSCLC) and mesothelioma, two neoplasms for which the current cytogenetic data base is relatively sparse. Karyologic investigations will be performed on a series of tumors from patients with NSCLC or mesothelioma, with emphasis on analyses of untreated primary tumors. This project proposes to identify recurrent chromosome abnormalities in these tumors and correlate the genetic alterations with important clinicopathologic features such as tumor cell phenotype, disease stage, subsequent metastatic behavior, and survival. Long-term tumor cultures and cell lines will be established, and the possibility that specific chromosome alterations correlate with various biological parameters such as spontaneous metastatic ability and in vitro invasiveness in these cell lines will be explored. An inherent component of the overall goal of this project is the evaluation of newer tumor cell culture methods, growth of tumor cell xenografts in athymic mice, and “interphase cytogenetics” techniques (using fluorescence in situ hybridization) to enhance karyologic investigations in these tumors. The molecular and functional characterization of several recurrent sites of chromosome loss previously identified cytogenetically in NSCLC and mesothelioma is also proposed. The frequency of loss of heterozygosity at specific chromosomal sites that have been implicated as “hot spots” for apparently unbalanced structural rearrangements in NSCLC will be determined. Furthermore, the incidence and minimal region of overlap of allelic loss on chromosome regions 1p, 3p, and 22q in mesothelioma will also be investigated. Results of karyotypic analysis of these same tumors will be used to assist in the interpretation of the loss of heterozygosity data. Finally, this project proposes to examine whether tumorigenicity of mesothelioma cell lines exhibiting loss of lp, 3p, or 22q can be suppressed or modulated by microcell-mediated transfer of one or more normal homologs of these chromosomes.

Tags: Cytogenetics, Lung Neoplasm, Mesothelioma, Neoplasm /cancer Genetics Chromosome Disorder, Cytodiagnosis, Karyotype, Metastasis, Molecular Oncology, Neoplasm /cancer Diagnosis, Neoplasm /cancer Invasiveness, Neoplastic Cell Athymic Mouse, Histochemistry /cytochemistry, Human Tissue, Immunocytochemistry, In Situ Hybridization, Neoplasm /cancer Transplantation, Nucleic Acid Probe, Restriction Fragment Length Polymorphism, Tissue /cell Culture

Abstract: DESCRIPTION (provided by applicant): This application is the second revision of the second competitive renewal of a P01 whose goal was to develop and evaluate approaches for gene therapy in the treatment of localized malignancies, using malignant mesothelioma (MM) as the paradigm. The original P01 evaluated the use of a suicide gene (HSVtk) delivered by an adenoviral (Ad) vector. 34 patients were treated with minimal toxicity and clear cut evidence of superficial gene transfer. There were two long-term survivors whose responses appear to have been due to anti-tumor immune reactions. This led to a redirection of the project to immuno-gene therapy of thoracic malignancies using an adenovirus (Ad) expressing the cytokine Interferon-beta. A Phase 1 trial of intrapleural Ad.lFNbeta for patients with MM and malignant pleural effusions was completed: evidence of anti-tumor immune responses and clinical responses were observed. This new proposal is a highly interlinked group of three projects and three cores. Each component has the same overall goal: to develop effective clinical approaches using immuno- and/or immuno-gene therapy for the treatment of thoracic malignancies. The unifying scientific theme of the P01 is that effective immunotherapy will require interventions at multiple points in the generation of an anti-tumor response. This Project will continue and extend the ongoing clinical trials using Ad.lFNbeta aimed at patients with mesothelioma. This will include a small Phase 1 trial using multiple dosing and Phase 2 trials combining immunotherapy, chemotherapy, and surgery. The second Project will continue to conduct preclinical studies to support the clinical trials. Aims will focus on approaches to augment immunotherapy using inhibitors of immunosuppression, chemotherapy, and vascular disrupting agents. The third Project will develop adoptive immunotherapy for mesothelioma using genetically modified lymphocytes engineered to target the tumor antigen Mesothelin. Core A will continue to supply administrative support. The existing Pathology and Translational Service Cores will be merged into a new Core B entitled the “Tissue Acquisition, Sample Processing, and Pathology Core”. Core C will continue to provide biostatistical and data management services. All projects will also make use of a newly established Penn Cancer Center Human Immunology Core for immune analyses. This project should provide new treatment options for patients with malignant mesothelioma who have few current therapeutic options.

Tags: Gene Therapy, Mesothelioma, Pharmacogenetics Biotechnology

  • Followup Grant: 5P01CA066726-12
  • Followup Grant: 2P01CA066726-10A2
  • Followup Grant: 5P01CA066726-13

Abstract: DESCRIPTION (provided by applicant): The National Mesothelioma Virtual Bank (NMVB) for Translational Research has created and maintains a national virtual patient registry and research resource bank. To date the NMVB has made available over 400 unique cases to share with the research community. NMVB now proposes to expand their innovative resources through a cooperative working group that broadly shares their mesothelioma research tools. The NMVB database is used for clinical and outcomes data collection related to each research resource (serum, plasma, tissue, pleural effusions, tissue microarrays, whole slide images, proteomic/genomic data and other resources – see specific aim 1). Each NMVB partner will be responsible for the data entry and updates into the registry for each of their research resources on a web based database developed in Pittsburgh which has its foundation in tools from the NCI Cancer Biomedical Informatics Grid (caBIG) effort. The registry has been established and managed by the University of Pittsburgh team in collaboration with New York University, the University of Pennsylvania and the Meso Foundation via a CDC NIOSH cooperative agreement. We intend to significantly expand the network to include the National Functional Genomics Center and the Cooperative Human Tissue Network, as well as other organizations who are interested in sharing their research resources. In addition to actively publicizing the availability of this resource to prospective users in the research community, the Meso Foundation will collaborate with the NMVB to develop a virtual patient registry (see specific aim 2) that will allow researchers to access the patients affected by mesothelioma for clinical and translational research studies. Meso Foundation is well positioned to do this and can capitalize on its deep linkages to the patient advocacy community to create a dialogue with this deeply vested population. Marketing, outreach and evaluation of the NMVB’s impact on translational research will be accomplished by partnering with the Meso Foundation (see specific aim 3). In summary, we intend to continue to expand our network to at least 1200 cases for translational research as well as develop a unique patient registry for recruiting those afflicted with mesothelioma. This expansion of the NMVB will provide unique and innovative tools to aid in the prevention, early detection and treatment of this uniformly fatal disease.

Tags: There Are No Thesaurus Terms On File For This Project.

  • Followup Grant: 5U24OH009077-04

Abstract: The treatment of malignant mesothelioma (MPM) remains inadequate. New therapies, such as gene therapy or immuno-gene therapy, are desperately needed. This Project is based on a previous series of Phase I clinical trials using recombinant, replication-deficient adenoviral (Ad) vectors containing the Herpes Simplex Thymidine Kinase (HSVtk) gene in 34 MPM patients. Significant intratumoral HSVtk gene transfer was achieved and some radiographic and clinical responses were noted, including 2 patients who had durable complete responses in delayed fashion, highly suggestive of anti-tumor immune responses. On this basis, the focus of laboratory and clinical work was shifted to genetic immunotherapy of thoracic malignancies. Based on strong preclinical data, a new Phase I clinical trial using a single dose of intrapleural adenoviral interferon beta (Ad.lFN-beta) for patients with MPM and malignant pleural effusions (MPE) was conducted. The approach was safe and a number of immunologic responses, as well as clinical responses were observed. The goal of this Project is to continue and extend these clinical trials aimed at patients with mesothelioma. In the first aim, a Phase 1 trial will be conducted to assess the safety, toxicity profile, immune responses, and clinical effect of two intrapleural doses of Ad.lFN-beta for patients with MPE/MPM. Specific Aims 2 and 3 will consist of Phase 2 clinical trials testing approaches in patients with MPM that were developed from our preclinical studies to augment efficacy. Aim 2 will determine the efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta as neo-adjuvant therapy in combination with surgical debulking and adjuvant COX-2 inhibitors in patients with MPM. Aim 3 will determine the efficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta in combination with chemotherapy and adjuvant COX-2 inhibitors in patients with MPM. In Aim 4, investigators will begin the steps needed to develop an adoptive immunotherapy trial using genetically engineering T-lymphocytes reactive against mesothelin for patients with mesothelioma and other tumors expressing this tumor antigen after preclinical optimization.

Tags: Birth, Clinical Trial, Clinical Trial Phase I, Gene, Gene Therapy, Immune Response, Mesothelioma, Neoplasm /cancer

  • Followup Grant: 5P01CA066726-120004
  • Followup Grant: 5P01CA066726-130004

Abstract: DESCRIPTION: (Applicant’s Description) The short term goals of this project are to develop new strategies to augment HSVtk therapy and to test these new systems in well characterized animal models of mesothelioma. The long term goals are to move the most promising of these new approaches into phase I clinical trials for mesothelioma. The first specific aim will be to develop and evaluate adenoviruses containing “improved” versions of HSV/k. Two hypotheses will be tested: (1) mutant versions of HSVtk with increased affinity and/or improved kinetics will augment tumor killing efficacy and (2) a chimeric HSVtk/VP22 fusion protein will augment tumor killing efficacy due to the ability of the VP22 protein (a tegument protein produced by Herpes Simplex Virus) to transfer from transduced to non-transduced cells. Accordingly, Ad vectors containing mutant HSVtk’s with augmented ability to phosphorylate ganciclovir and containing a chimeric transgene consisting of HSVtk coupled to the HSV-VP22 protein will be produced and tested. The second specific aim will be to develop and evaluate replication-competent adenoviral vectors expressing HSVtk. Two hypotheses will be tested: (1) use of replicating vectors (even if only 1 or 2 rounds of replication occur) will be able to deliver transgene to a larger number of tumor cells and thus enhance efficacy and (2 ) adenoviral vectors in which a tumor-associated promoter regulates EIA expression will confer replication selectivity in the appropriate tumor cells. A fully replicative virus containing the HSVtk gene inserted into the E3 region will be produced and studied. In addition, Ad mutants that replicate selectively in tumors will be constructed and tested. This will be accomplished by disrupting the normal Ad EIA promoter region and inserting tumor-selective promoters into this region. The third Specific Aim will be to evaluate the use of specific cytokines to augment HSVtk/GCV efficacy. The hypothesis that immune augmentation can increase the efficacy of HSVt/dGCV gene therapy will be tested. Intracavitary Ad. HSVtk therapy will be combined with intracavitary injection of specific cytokines that are commercially available and have been shown to have some efficacy in mesothelioma (IL-2, Interferon-cq and interferon-7). In addition, investigators from this Project will work closely with investigators from this Project to provide the animals models needed for their pharmacokinetic and imaging studies.

Tags: Drug Screening /evaluation, Ganciclovir, Gene Therapy, Mesothelioma, Neoplasm /cancer Therapy, Nonhuman Therapy Evaluation, Transfection /expression Vector Disease /disorder Model, Gene Expression, Genetic Transduction, Interferon, Interleukin 2, Neoplasm /cancer Immunotherapy, Pharmacogenetics, Prodrug Adenoviridae, Alphaherpesvirinae, Biotechnology, Laboratory Mouse, Laboratory Rat, Polymerase Chain Reaction, Thymidine Kinase

  • Followup Grant: 5P01CA066726-070002
  • Followup Grant: 5P01CA066726-080002
  • Followup Grant: 5P01CA066726-090002

Abstract: DESCRIPTION (provided by applicant): The proposed Mesothelioma Virtual Bank (MVB) for Translational Research will create and maintain infrastructure to support a national virtual patient registry and tissue bank. MVB proposes to create and maintain a set of resources through a cooperative working group that will make available their independent stores of mesothelioma tissue for public access. MVB will use a centralized internet-based database or registry modeled after the virtual tissue bank registry created by the Pennsylvania Cancer Alliance Bioinformatics Consortium (PCABC, see http://pcabc.upmc.edu). The MVB registry will be used for data recording and collection related to each tissue sample (serum, tissue or DMA). Each participating institution will be responsible for the data entry and updates into the registry for each of their samples. The registry will be established and managed by the University of Pittsburgh team in collaboration with, and guidance from the CDC and NIOSH via this cooperative agreement. Marketing and outreach efforts of the MVB will be accomplished by partnering with Translating Research Across Communities (TRAC). In addition to actively publicizing the availability of this resource to prospective users in the research community, TRAC will capitalize on its deep linkages to the Patient Advocacy Community to create a dialogue with this deeply vested population. Education and direct involvement of this Community will garner general as well as fiscal support for the MVB that will be necessary to sustain the tissue bank, informatics tools and patient registry staff critical to the long term viability of this important program.

Tags: Mesothelioma, Patient /disease Registry, Tissue Resource /registry Internet, Cooperative Study, Informatics, Occupational Health /safety Clinical Research, Human Data, Human Tissue

  • Followup Grant: 5U19OH009077-02

Abstract: Applications of gene therapy for the treatment of cancer hold tremendous promise. The potential effectiveness of cancer gene therapies depends, in part, on the efficiency and specificity of therapeutic gene transfer. One strategy that may be effective despite the current limitations of somatic gene transfer is the treatment of local disease by in vivo gene transfer of HSVTK. The concept is to transfer the HSVTK gene into a subpopulation of malignant cells rendering them and adjacent non-transduced cells sensitive to the drug gangciclovir. We will focus on animal and clinical models of mesothelioma to study and evaluate this strategy. This project will develop and evaluate the methods of gene transfer that will be required for successful gene therapies for mesothelioma based on HSVTK bystander approach. Gene transfer by recombinant adenoviruses and recombinant adeno associated viruses (AAV) will be evaluated. A variety of recombinant adenoviruses will be constructed that vary with respect to structure and function of the viral gene loci that have been retained in the recombinant. Our preliminary studies indicate that subtle differences in recombinant adenoviral structure can translate into significant changes in biology with respect ot replicative capacity, immunogenicity, and transgene persistence. The use of recombinant AAV will also be evaluated. This family of recombinant viruses has the advantage of conferring longer and more stable transgene expression with less immunogenicity. Both vector systems will be evaluated in several animal models of mesothelioma with respect to biological issues of 1) efficiency of gene transfer within the tumor, 2) specificity of gene transfer, 3) stability of gene trans, 4) immune responses to the target cells, and 4) associated pathology. This project will collaborate closely with Project II by providing HSVTK adenovirus and AAV technology as well, in addition to delineating the immune components that contribute to the bystander effect.

Tags: Drug Design /synthesis /production, Gene Therapy, Neoplasm /cancer Therapy, Nonhuman Therapy Evaluation, Transfection Vector Cellular Immunity, Disease Model, Genetic Promoter Element, Humoral Immunity, Neoplasm /cancer Immunology, Recombinant Dna Adenoviridae, Adeno Associated Virus Group, Laboratory Rat, Molecular Cloning

  • Followup Grant: 5P01CA066726-040001
  • Followup Grant: 3P01CA066726-04S10001

Abstract: DESCRIPTION: (Applicant’s Description) An initial phase I Clinical Trial was performed using an E1/E3-deleted adenoviral vector containing the Herpes Simplex Thymidine Kinase (HSVtk) gene in 26 patients with unresectable malignant mesothelioma. The results demonstrated that intratumoral HSVtk gene transfer was possible at high titers of vector, but was primarily limited to the superficial cell layers immediately below the pleural space. At current doses of this vector and with large tumors, gene transfer is thus not likely to be effective from a therapeutic standpoint. The primary goals of this project are 1) to optimize gene therapy approaches before proposing to move on to phase II trials, 2) evaluate new imaging techniques to assess therapeutic efficacy and gene transfer in collaboration with another Project optimize ganciclovir administration in collaboration with another Project to test new therapeutic approaches. To achieve these goals, five specific aims are proposed. In the first aim, the phase I clinical trial dose escalation trial will be continued using an E1/E4-deleted adenoviral vector (H5.001RSV.tk). This El/E4 “third generation” adenoviral vector appears to be less hepatotoxic and has a much lower incidence of recombination allowing it to be produced at a substantially lower cost. In addition, information will be collected about the validity of PET-labeled 18F-GCV. In the second aim, a phase I clinical trial of intrapleural Ad.tk after tumor debulking will be performed in order to maximize the vector: tumor cell ratio and improve gene transfer efficiency. In addition, this protocol will be used to obtain information about the pharmacokinetics of GCV administration by measuring GCV levels within tissues after administering varying single intravenous doses of GCV to patients at defined times before their surgical debulking. In the third aim, a clinical trial involving an alternate ganciclovir dosing regimen is proposed. Based on the results of Specific Aims 1 and 2 and Project 2, the best new GCV dosing regimen will be tested in a phase I trial. This will likely involve increased doses of GCV delivered intravenously. In the fourth aim, the toxicity, gene transfer efficacy, and immune responses following the repeated administration of H5.001RSV.tk will be determined. Finally, a phase I Clinical trial using the most promising newly developed vector or vector approach from Project 3 will be implemented. These studies should provide a great deal of valuable information about the use of adenoviral gene therapy for localized malignancy and will hopefully lead to a phase II multi-centered trial aimed at the treatment of mesothelioma.

Tags: Drug Screening /evaluation, Ganciclovir, Gene Therapy, Human Therapy Evaluation, Mesothelioma, Pharmacogenetics Clinical Trial Phase I, Neoplasm /cancer Chemotherapy, Transfection /expression Vector Adenoviridae, Biotechnology, Clinical Research, Human Subject, Positron Emission Tomography

  • Followup Grant: 5P01CA066726-060004
  • Followup Grant: 5P01CA066726-070004
  • Followup Grant: 5P01CA066726-080004
  • Followup Grant: 5P01CA066726-090004

Abstract: The purpose of this amended Phase I study will be to evaluate the safety and toxicity of escalating doses of intravenous ganciclovir (GCV) coupled with intrapleural delivery of a “third generation” El/E4-deleted adenoviral vector expressing the Herpes Simplex Thymidine kinase (HSVtk) gene to treat patients with inoperable malignant mesothelioma. This study is a logical extension of our past and present Phase l studies evaluating the safety and toxicity of escalating doses of intrapleural recombinant adenoviral-HSV tk vector in combination with intravenous GCV to treat patients with mesothelioma.

Tags: Combination Antineoplastic Therapy, Ganciclovir, Gene Therapy, Human Therapy Evaluation, Mesothelioma Adenoviridae, Clinical Trial Phase I, Neoplasm /cancer Chemotherapy, Transfection /expression Vector Clinical Research, Human Subject

  • Followup Grant: 3M01RR000040-40S30856
  • Followup Grant: 3M01RR000040-40S40856
  • Followup Grant: 5M01RR000040-410856
  • Followup Grant: 3M01RR000040-41S10856
  • Followup Grant: 5M01RR000040-420856

Abstract:

  • Followup Grant: 5P01CA066726-120002
  • Followup Grant: 5P01CA066726-130002

Abstract: DESCRIPTION (provided by applicant): This project will address the therapy of mesothelin expressing tumors by developing and testing engineered T cells with potent antitumor cytotoxicity. Mesothelin is a tumor-associated antigen that is frequently over expressed on mesothelioma, non-small cell lung cancer, pancreatic and ovarian cancers. Our strategy is the “T-body” approach, which uses genetically reprogrammed, patient-derived lymphocytes transfected with a novel chimeric receptor that contains combinations of the signal transduction domains of 4-1BB (CD137), CD28, and CD3?; as well as anti-mesothelin scFv (anti-meso-CD28-41BB-?. The central hypothesis that we wish to test is that insufficient numbers of CTL with adequate engraftment, persistence and effector function to self antigens have been used in previous trials of adoptive therapy for cancer. Presently, we are the only laboratory in the world that is actively testing lentiviral modified T cells in the clinic, and in that trial we have demonstrated safety and prolonged lentiviral gene transfer. The following three specific aims will test the hypothesis that engineered human T cells expressing an anti-mesothelin-CD28-41BB-?; chimeric receptor will have potent antitumor activity in vitro and in vivo by: (1) developing and optimizing the anti-meso scFv vector. The avidity and the cytosolic signaling modules will be optimized to obtain highly efficient lentiviral vectors that retarget T cells to specifically kill tumor cells that express mesothelin at low effector to target ratios in vitro; (2) carrying out in vitro experiments to optimize the effector functions of anti-mesothelin scFv CD28-41BB-?; T bodies. Experiments will determine optimal conditions for redirected T cell serial killing, cytokine production and proliferation, and compare this to natural MHC restricted CTLs; and (3) performing in vivo experiments in immunodeficient NOD/SCID/?2null mice xenografted with human tumors that express mesothelin. Here we will test the hypothesis that vectors with high affinity scFv receptors and 4-1BB and CD28 signaling modules will have the most potent anti-tumor effects. Finally, the engraftment, persistence and antitumor effects of chimeric T cells given by intravenous and intraperitoneal routes will be compared using bioluminescence imaging. In summary, we have assembled an outstanding team of basic and translational scientists to develop and test a universal T cell receptor to target some of the most common and drug resistant tumors. Lay Description. A common reason for failure of immunotherapy of epithelial tumors is that the immune system does not generate sufficient numbers of T cells to eradicate the tumor cells. It is now possible to use lentiviral vector technology to engineer T cells with potent and specific antitumor effects. In this project we will test engineered T cells that target mesothelin that is overexpressed on both uncommon tumors such as mesothelioma and a variety of commonly lethal tumors including pancreatic, ovarian and non-small cell lung carcinoma.

Tags: Cell, Immunotherapy, Neoplasm /cancer Scid Mouse, T Cell Receptor, Adenocarcinoma, Antigen, Autoantigen, Bioluminescence, Carcinoma, Clinical Trial, Conditioning, Culture, Cytokine, Cytotoxicity, Ergonomics, Experience, Gene, Glycoprotein, Human, Immune System, Lead, Lung, Lymphocyte, Mesothelioma, Neoplasm /cancer Immunotherapy, Neoplasm /cancer Therapy, Ovary Neoplasm, Pancreas Neoplasm, Phenotype, Receptor, Small Cell Lung Cancer, Success, Therapy, Tissue /cell Culture, Tumor Antigen, Xenotransplantation Clinical Research

  • Followup Grant: 5R01CA120409-03
  • Followup Grant: 1R01CA120409-01
  • Followup Grant: 5R01CA120409-04

Abstract: OBJECTIVE: Malignant tumors of the mesothelial lining of serous cavities, mesotheliomas, are relatively uncommon tumors for which definitive diagnostic methods are not available. I am pursuing the following protocol for establishing definitive diagnostic methods for these tumors. APPROACH AND PROGRESS: Normal mesothelial cells, present in pleural and peritoneal effusions, were cultured in RPMI 1640. The cultured cells were harvested by scrapping with a rubber policeman and washed in serum-free medium RPMI 1640. The isolated mesothelial cells were suspended in complete Freund’s adjuvant and injected into rabbits. Following 3-4 booster doses of mesothelial cells suspended in saline the antiserum was collected from the rabbits and heat inactivated. The antiserum was absorbed with human red cells, liver powder and MOLT-4 cell line lymphocytes. The resulting antiserum was specific for mesothelial cells as judged by indirect immunofluorescence. The mesothelial cell-specific antiserum has been used as a diagnostic agent in differentiating mesothelioma cells from other malignant cells in serous effusions. The antiserum is being evaluated for use in immunoperoxidase staining of formalin-fixed paraffin embedded material to enchance the usefulness of the reagent. The next phase of the project calls for isolation of the mesothelial cells specific antigen and preparation of a high-titered antiserum to the antigen. An immunoassay similar to ELISA or RIA will then be established for quantitation of the antigen in effusion fluids and sera of patients. The assay is expected to measure the mesothelial cell mass and be useful in follow-up of patients with suspected or known mesotheliomas. It is possible that at a latter date the antiserum may be used in a site-directed chemotherapy regimen.

Tags: Allergy And Immunology Study Section, Neoplasms Diagnosis, Immunodiagnosis Of Neoplasms, Neoplasms Of Body Cavities, Mesothelioma Diagnostic Quality-standards, Immunological Tests And Immunoassay, Immunoassay, Neoplasms Characteristics, Host-neoplasm, Neoplasms Immunology, Tumor Antigens Human, Tissues, Fluids Etc. From Non-related Sources Outside Immediate Project, Immunological Tests And Immunoassay, Immunofluorescence, Mammals, Lagomorphs, Physical Separation, Chromatography, Affinity, Physical Separation, Electrophoresis, Gel, Tissue (cell) Culture

  • Followup Grant: 5R01CA027081-03
  • Followup Grant: 5R01CA027081-02

Abstract: Malignant mesothelioma (MM) is a neoplasm for which no effective therapy currently exists. We conducted a Phase I clinical trial to assess the safety and feasibility of intrapleural delivery of recombinant adenovirus (rAd) containing the Herpes Simplex Virus thymidine kinase gene (HSVtk) driven by the Rous Sarcoma Virus (RSV) promoter into the pleural space of patients with MM followed by systemic treatment with the antiviral drug ganciclovir (GCV) for 14 days. Prior implementation of the rAd.RSVtk -GCV protocol in animal models of MM resulted in significant reduction of tumor burden and prolongation of survival with minimal systemic toxicity. The clinical trial was a dose escalation study designed to determine the maximally-tolerated intrapleural dose of rAd.RSVtk. Twenty-six patients have completed treatment at dose levels up to l.0x10 12 plaque forming units (pfu) Ad.RSVtk with minimal complications. Toxicities seen include low-grade fever after viral instillation, anemia, transient elevation of liver function tests, and vesicular skin eruptions near the instillation site. Evaluation of selected post-gene delivery biopsy samples revealed eavidence of tk gene transfer via DNA PCR, in situ hybridization, and immunohistochemistry in a dose-dependent fashion. Neutrophil-predominant inflammatory responses were seen on IHC analysis of post-vector administration biopsy samples. Patients develop significant evidence of humoral and cellular immune responses against the adenoviral vector. In summary, Ad.RSVtk/GCV gene therapy is safe in MM paatients, there appears to be evidence of TK gene transfer in a dose-dependent fashion, and recombinant adenoviruses elicit strong immune responses when delivered into the pleural space.

Tags: Adenoviridae, Gene Therapy, Human Therapy Evaluation, Mesothelioma, Neoplasm /cancer Therapy, Transfection Vector Outcomes Research Clinical Research, Human Subject

  • Followup Grant: 3M01RR000040-38A10615
  • Followup Grant: 5M01RR000040-370615
  • Followup Grant: 3M01RR000040-37S40615
  • Followup Grant: 5M01RR000040-400615
  • Followup Grant: 3M01RR000040-40S30615
  • Followup Grant: 3M01RR000040-40S40615

Abstract: Recent work suggests that asbestos and SV40 can act as co-carcinogens in the etiology of malignant mesothelioma (MM) and that AKT, a critical mediator of cell survival signals, is frequently activated in this disease. Human MMs often exhibit mutation of the NF2 tumor suppressor gene (TSG). Furthermore, homozygous deletion of the INK4a/ARF locus, which encodes the TSG products p16(INK4a) and p14(ARF), is frequently observed, although the relative contribution of p16(INK4a) versus p14(ARF) in MM pathogenesis has not been elucidated. Our hypothesis is that alterations of these three TSGs and expression of SV40 and AKT oncoproteins represent key disturbances in mesothelial cell physiology that collectively contribute to the development of MM. Understanding the molecular pathogenesis of MM and signaling pathways perturbed in this malignancy may elucidate invaluable molecular targets for therapeutic/preventive intervention, which is the broad, long-term objective of this project. The specific aims are: 1) Using in vitro and in vivo assays, we will determine whether restoration of NF2 expression can inhibit the growth and invasiveness of NF2-deficient MM cells. We will also conduct experiments to evaluate the therapeutic potential of adenovirus-mediated expression of NF2 and selective PAK inhibitors, as well as experiments to further elucidate merlin’s function. 2) Using various murine knockout models, evaluate the relative contribution of Nf2, p19(Arf), and p16(lnk4a) inactivation to induction of MM by asbestos. Molecular genetic characterization of tumors derived from these mice will be conducted to establish the requirement for biallelic inactivation of the predisposing TSG and/or cooperation of oncogenes or other TSGs. We will compare susceptibility to asbestos-induced MM in p16(lnk4a)+/-, p14(Arf)+/- and doubly heterozygous Ink4a/Arf+/- mice in the same genetic background. In addition, determine if a SV40 Tag/tag mouse model is predisposed to MM spontaneously and/or following treatment with asbestos. 3) Further characterize the involvement of AKT in MM and determine whether pharmacologic inhibition of the AKT signaling pathway can repress MM cell growth and if combining an AKT pathway inhibitor with chemotherapeutic agents having a different mode of action results in increased efficacy. This Project will provide important insights regarding the involvement of key oncoproteins and TSG products in the pathogenesis of MM and will benefit from the availability of human and hamster MM samples through Project 1 and Cores B and C as well as from co-carcinogenesis and signaling work conducted in Project 2.

Tags: Asbestos, Cocarcinogen, Environment Related Neoplasm /cancer, Enzyme Activity, Enzyme Mechanism, Mesothelioma, Neoplasm /cancer Genetics, Neoplastic Process, Serine Threonine Protein Kinase, Simian Virus 40 Focal Adhesion Kinase, Gene Environment Interaction, Molecular Pathology, Neoplasm /cancer Pharmacology, Oncogene, Oncogenic Virus, Tumor Suppressor Gene Athymic Mouse, Genetically Modified Animal, Hamster, Laboratory Mouse, Transfection /expression Vector, Xenotransplantation

  • Followup Grant: 5P01CA114047-020003
  • Followup Grant: 5P01CA114047-030003

Abstract: Implementation of any human gene therapy protocol requires experimental evidence of efficacy as defined by metabolic, pathologic, and/or clinical correction of the disease processes. In addition to efficacy, vectors used in administering genetic information must be rigorously tested for safety. Animal models play a critical role in the development of new recombinant adenoviruses, such as those currently under development for the gene therapy of cancer. Authentic animal models provide the most appropriate experimental setting in which to assess these parameters. As formalized requirements for preclinical toxicology studies are developed, it is clear that careful assessment of toxicity must be performed in at least two species of animals, one of which is a non-human primate. Further, the availability of appropriate test animals greatly simplifies the testing of gene therapies, and allows the identification of problems which would otherwise lead to patient morbidity or even mortality in the clinical setting. The University of Pennsylvania provides an outstanding environment in which to utilize animal models for the development of successful cancer gene therapy protocols. The Animal Models Core (AMC) will take a leading role in the preclinical toxicology testing of recombinant viruses. The AMC has built on the strengths of existing programs, including the University Laboratory Animal Resources and the Wistar Institute Animal Facility, to develop expertise, facilities, and resources necessary for the development of gene therapies and athe rapid application of these technologies to the treatment of cancer. The following components of the AMC will be available for testing of experimental strategies; (1) Colonies of Fischer F344 rats will be maintained for the assessment of preclinical toxicology. These mice are susceptible to adenoviral infection, and are especially useful in testing the safety in testing the safety of treatment of mesothelioma by recombinant adenoviruses. (2) To further facilitate the preclinical assessment of toxicity associated with proposed gene therapies of cancer, a specialized primate colony, which is capable of housing up to 60 primates under biohazard containment conditions in accordance with Good Laboratory Practices. Facilities and support staff will be available to appropriate participants for preclinical toxicity studies. All studies will be done with Standard Operating Procedures (SOP), to operate under Good Laboratory Practices (GLP). (3) Specialized biohazard operating room suites have been renovated at the University of Pennsylvania and the Wistar Institute for use by investigators who require animal models in which to test gene therapy strategies for the treatment of cancer, including this proposed trial for mesothelioma.

Tags: Animal Care, Biomedical Facility, Drug Adverse Effect, Drug Screening /evaluation, Gene Therapy, Mesothelioma, Nonhuman Therapy Evaluation Primate, Laboratory Mouse, Laboratory Rabbit, Laboratory Rat

  • Followup Grant: 5P01CA066726-049003
  • Followup Grant: 3P01CA066726-04S19003

Abstract: DESCRIPTION: (Applicant’s Description) The overall goal of this project is to optimize the suicide gene therapy approach to achieve maximum clinical benefit. This will be accomplished through the development of non-invasive imaging techniques and by devising the most efficient method for delivery of ganciclovir to the tumors of human subjects transfected with Herpes simplex virus thymidine kinase (HSVtk). Pharmacokinetic models will be constructed using analytical methodology based on liquid chromatography/mass spectrometry as the foundation for non-invasive imaging strategies for use in patients being treated with suicide gene therapy. We hypothesize that there is a relationship between systemic exposure of ganciclovir and concentrations that are found in tumors. Initial experiments will be performed using animal tumor models so that this hypothesis can be tested. In addition, all optimal dosing strategy will be defined, and the relationship between plasma and tumor concentrations will be determined. The n vivo metabolism of ganciclovir will be studied in order to ensure that it is not altered in the animal tumor models when compared with control animals. Ganciclovir metabolites that are found in tumor tissue will also be characterized and quantified. The experiments with animal models will lay the groundwork for phase I pharmacokinetic studies in patients with ovarian cancer and malignant mesothelioma. Extensive modeling will be performed in order to provide parameter estimates that describe the experimental data. These should permit predictions of, for example, likely dosing regimens and probable plasma drug levels using different dosing schedules or different routes of administration. An important component of this proposal involves the development of non-invasive methodology to assess the duration and distribution of gene expression. We propose to develop imaging methodology so that we can monitor HSVtk activity and thereby provide information that can be used to further improve this strategy. These studies will be performed using a new PET imaging technique to measure the thymidine kinase enzymatic activity. This study will have important implications for suicide gene therapies in general, and will validate novel technique for assessing gene transfer.

Tags: Ganciclovir, Gene Therapy, Mathematical Model, Mesothelioma, Pharmacokinetics, Positron Emission Tomography, Transfection /expression Vector Chimeric Protein, Dosage, Drug Administration Route, Noninvasive Diagnosis, Ovary Neoplasm Mammalia, Bioimaging /biomedical Imaging, Biotechnology, Clinical Research, Human Subject, Tissue /cell Culture

  • Followup Grant: 5P01CA066726-060005
  • Followup Grant: 5P01CA066726-070005
  • Followup Grant: 5P01CA066726-090005

Abstract: DESCRIPTION (provided by applicant): Our long-term goal is to develop an effective immunologic therapy to improve the survival of patients with ovarian and primary peritoneal cancer. Despite the advent of newer chemotherapies, the 5-year survival for patients with advanced disease remains 25%. The development of immune and biologic therapies is necessary to complement traditional cytotoxic treatments. In this application, we propose to test the CENTRAL HYPOTHESIS that cellular immunity may be augmented by adoptive immunotherapy using autologous T cells lentivirally transduced with anti-mesothelin chimeric immunoreceptor (CIR) scFv in patients with intraperitoneal malignancies through the following three SPECIFIC AIMS: (1) To conduct a phase I clinical trial to study the safety and feasibility of anti-mesothelin CIR transduced autologous T cells in patients with chemotherapy-refractory advanced ovarian, primary peritoneal, and pancreatic cancer, as well as peritoneal mesothelioma, We plan to administer a single dose of transduced autologous T cells either intravenously or intraperitoneally to patients who have measurable disease following at least two prior courses of cytotoxic chemotherapy. We will determine the safety and feasibility of treatment by determining (a) clinical toxicity, (b) the response rate through 6 months post- treatment, (c) the engraftment and persistence of transduced T cells in the peripheral circulation, (d) the development of host immunity to transduced T cells, (e) and the safety of lentiviral engineered cell products by monitoring for the presence of VSV-G RNA, VSV-G antibody responses, and biological RCL testing. (2) To determine the induction or enhancement of anti-tumor immunity for patients undergoing treatment, and to examine T cell trafficking by performing ELISPOT assays, and post-treatment tumor biopsies for tumor- infiltrating lymphocytes and down-regulation of mesothelin expression. (3) To examine factors effecting the development of host immunity by determining the level of soluble mesothelin in patient serum by ELISA, the level of regulatory T cells by flow cytometry, and the presence and levels of serum Th1 cytokines by ELISA. Project Relevance: Ovarian cancer is the leading cause of gynecologic cancer death, and though most patients respond to initial chemotherapy, the majority eventually relapse and die of chemotherapy resistant disease. We aim to develop complimentary immunotherapies to augment traditional treatment strategies.

Tags: Cell Rna, Antibody, Autoantigen, Biopsy, Cell Membrane, Cellular Immunity, Chemotherapy, Clinical Trial, Clinical Trial Phase I, Complement, Concept, Culture, Cyclophosphamide, Cytokine, Death, Emotion, Flow Cytometry, Gene, Glycoprotein, Immunity, Immunosuppression, Immunotherapy, Lead, Lymphocyte, Major Histocompatibility Complex, Membrane, Mesothelioma, Motivation, Neoplasm /cancer, Neoplasm /cancer Immunotherapy, Neoplasm /cancer Therapy, Ovary Neoplasm, Pancreas Neoplasm, Passive Immunization, Peritoneum Neoplasm, Phenotype, Receptor, Safety Equipment, Serum, Small Cell Lung Cancer, Therapy, Tissue /cell Culture Clinical Research

  • Followup Grant: 1R21CA115049-01A1

Abstract: This project will address the therapy of mesothelin expressing tumors by developing and testing engineered T cells with potent antitumor cytotoxicity. Mesothelin is a tumor-associated antigen that is frequently over expressed on mesothelioma, non-small cell lung cancer, pancreatic and ovarian cancers. The strategy to be used is the “T-body” approach, which employs genetically reprogrammed, patient-derived lymphocytes transfected with a novel chimeric receptor that contains combinations of the signal transduction domains of 4-1BB (CD137), CD28, and CD3zeta as well as anti-mesothelin scFv (anti-meso-CD28-41BB-zeta). The central hypothesis to be tested is that previous trials of adoptive therapy for cancer have used insufficient numbers of cytotoxic T lymphocytes (CTL) that have shown inadequate engraftment, persistence and effector function to self antigens. Presently, we are the only laboratory in the world that is actively testing lentiviral modified T cells in the clinic, and in that trial we have demonstrated safety and prolonged lentiviral gene transfer. The following three specific aims will test the hypothesis that engineered human T cells expressing an anti-mesothelin-CD28-41BB-zeta chimeric receptor will have potent antitumor activity in vitro and in vivo by: (1) developing and optimizing the anti-meso scFv vector. The avidity and the cytosolic signaling modules will be optimized to obtain highly efficient lentiviral vectors that retarget T cells to specifically kill tumor cells that express mesothelin at low effector to target ratios in vitro; (2) carrying out in vitro experiments to optimize the effector functions of anti-mesothelin scFv CD28-41BB-zeta T bodies. Experiments will determine optimal conditions for redirected T cell serial killing, cytokine production and proliferation, and compare this to natural MHC restricted CTLs; and (3) performing in vivo experiments in immunodeficient NOD/SCID/beta2null mice xenografted with human tumors that express mesothelin. These experiments will test the hypothesis that vectors with high affinity scFv receptors and 4-1BB and CD28 signaling modules will have the most potent anti-tumor effects. Finally, the engraftment, persistence and antitumor effects of chimeric T cells given by intravenous and intraperitoneal routes will be compared using bioluminescence imaging. In summary, an outstanding team of basic and translational scientists has been assembled that will develop and test a universal T cell receptor to target some of the most common and drug resistant tumors. Lay Description. A common reason for failure of immunotherapy of epithelial tumors is that the immune system does not generate sufficient numbers of T cells to eradicate the tumor cells. It is now possible to use lentiviral vector technology to engineer T cells with potent and specific antitumor effects. This project will evaluate engineered T cells that target mesothelin that is overexpressed on both uncommon tumors such as mesothelioma and a variety of commonly lethal tumors including pancreatic, ovarian and non-small cell lung carcinoma.

Tags: Neoplasm /cancer, Receptor

  • Followup Grant: 5P01CA066726-120006
  • Followup Grant: 5P01CA066726-130006

Abstract: Malignant pleural mesothelioma (MPM) is a neoplasm for which no effective therapy currently exists. We completed a Phase I clinical trial involving intrapleural delivery of an E1/E3-deleted adenovirus (Ad) containing the HSVtk gene (H5.010RSVtk), followed by systemic treatment with ganciclovir (GCV) in 26 patients with MPM. Treatment at dose levels up to 5×1013 viral particles revealed evidence of dose-dependent, but superficial, intratumoral tk gene transfer, as well as significant immune responses to the Ad vector and the tk protein. Minimal toxicities were seen and no maximally tolerated dose (MTD) of H5.010RSVtk was established. In order to improve intratumoral gene transfer, we have initiated a new Phase I trial using a “third generation” E1/E4-deleted adenoviral vector (H5.001RSV.tk) that, in animal models, is equally effective, but less immunogenic and hepatotoxic. This new vector is also more cost-efficient to produce because of a lower incidence of homologous recombination. We have treated four patients with the E1/E4-deleted adenovirus to date, two each at 1.5×1013 and 5×1013 viral particles. Intratumoral gene transfer has been detected via immunohistochemistry in all 4 patients. Toxicities have been limited to transitory pyrexia after vector instillation and minimal elevation of transaminases. We plan to continue the dose-escalation protocol until a MTD is established. Determination of the immune response to vector and transgene is ongoing, as is evaluation of tumor response using volumetric Chest CT and 18-FDG PET imaging. In summary, Ad.HSVtk /GCV gene therapy with the E1/E4-deleted vector is safe in MPM patients to doses of 5×1013 viral particles, with evidence of tk gene transfer in a dose-dependent fashion. The clinical trial is supported by NIH PO1CA66726.

Tags: Adenoviridae, Ganciclovir, Gene Therapy, Human Therapy Evaluation, Mesothelioma, Neoplasm /cancer Therapy, Pleural Neoplasm, Respiratory Syncytial Virus, Transfection Vector Clinical Trial Phase I, Drug Adverse Effect, Gene Expression, Thymidine Kinase Clinical Research, Computed Axial Tomography, Human Subject, Positron Emission Tomography

  • Followup Grant: 5M01RR000040-400806
  • Followup Grant: 3M01RR000040-40S30806
  • Followup Grant: 3M01RR000040-40S40806
  • Followup Grant: 5M01RR000040-410806
  • Followup Grant: 3M01RR000040-41S10806
  • Followup Grant: 5M01RR000040-420806

Abstract: DESCRIPTION: (provided by applicant) Exposure to asbestos is the primary cause of malignant mesotheliomas (MMs), highly invasive tumors that arise from the mesothelial cell lining of the pleural, peritoneal, and pericardial cavities. MMs exhibit frequent mutation of the NF2 tumor suppressor gene (TSG) and homozygous deletion of the INK4a/ARF locus, which encodes the TSG products p16INKa and p14ARF. The tumorigenic potential of p16INK4a alterations has been previously demonstrated in MM cells, whereas evidence in support of a pathogenetic role for p14ARF loss in MM is less well established. Another putative TSG, GPC3, is markedly down regulated in many MMs. The hypothesis is that alterations of NF2, p14ARF and GPC3 are manifestations of key disturbances in cellular physiology that collectively contributes to the development and/or progression of MM. Characterization of the involvement of these TSGs in MM will contribute to a better understanding of molecular mechanisms underlying the pathogenesis of this malignancy, which is the broad, long-term objective of this project. The specific aims are: 1) Characterize mechanisms by which NF2 inactivation contributes to the pathogenesis of MM. Evaluate the effect of merlin expression on the invasive/metastatic potential of MM cells in vivo and on substrate adherence, membrane ruffling, motility and invasiveness in vitro. To discern oncogenic mechanisms associated with NF2 inactivation, determine how merlin function is modulated by phosphorylation as an effector of Rac/Cdc42/Pak1 signaling and whether merlin expression/phosphorylation alters downstream signaling involving JNK and AP-1. 2) Determine the involvement of GPC3 down regulation in the malignant phenotype of MM cells and delineate the potential role of GPC3 in the transduction of insulin-like growth factor 1 receptor (IGF1R)-mediated signaling. Assess the effect of GPC3 on MM cell growth/survival, adhesion, and invasiveness. Elucidate mechanisms by which GPC3 may contribute to oncogenesis through participation in IGF signaling. 3) Ascertain if ARF (+/-) and Nf2 (+/-) knockout mice are predisposed to the induction of MM by asbestos. Asbestos-treated ARF (+/-) and NJ2 (+/-) mice will be evaluated with regard to the incidence and invasive/metastatic potential of MMs observed in these two mouse models and the requirement for biallelic inactivation of the predisposing TSG and/or cooperation of oncogenes or other TSGs. Overall, these studies are expected to provide insights regarding mechanisms by which specific TSGs contribute to the pathogenesis of MM and delineate potential avenues for therapeutic intervention.

Tags: Mesothelioma, Molecular Genetics, Molecular Oncology, Neoplasm /cancer Genetics, Tumor Suppressor Gene Asbestos, Biological Signal Transduction, Chemical Carcinogenesis, Gene Expression, Growth Factor Receptor, Insulinlike Growth Factor, Neoplasm /cancer Invasiveness, Phosphorylation Clinical Research, Human Tissue, Laboratory Mouse, Tissue /cell Culture, Transgenic Animal

  • Followup Grant: 5R01CA045745-14
  • Followup Grant: 5R01CA045745-15
  • Followup Grant: 5R01CA045745-16
  • Followup Grant: 5R01CA045745-17

Abstract: DESCRIPTION: (Applicant’s Description) New treatments for ovarian cancer are clearly needed. One novel approach under active preclinical and clinical evaluation is gene therapy. Strategies being investigated include use of replication incompetent retroviruses or adenoviruses (AD) to deliver suicide genes such as herpes simplex virus (HSV) thymidine kinase (tk) to activate ganciclovir (GCV) into a cytotoxic drug. One major limitation discovered in an ongoing phase I trial for malignant mesothelioma at the University of Pennsylvania is poor depth of penetration of ADHSV tk into the tumor after intracavitary delivery. A promising approach to overcome this problem is to use replication-competent adenoviruses. When such viruses infect cells and replicate, it causes cell lysis. In addition, active virus is released to infect other tumor cells. By coupling this mechanism of enhanced killing and infection with the ability to activate GCV, we hypothesize that anti-tumor efficacy will be enhanced. However, the delivery of such replication competent viruses causes some safety concerns. To address this issue, a virus conditionally replicative in tumor cells will be constructed. Success would result in a clinical gene therapy trial. Based on the recent discovery at FCCC of a promotor which shows specificity of function in human ovarian cancer, the goal of this proposal is to construct such vectors and preclinically evaluate their efficacy and safety by accomplishing the following specific aims: Specific Aim 1. Develop and evaluate a replication-competent adenoviral vector expressing HSVtk. This will be accomplished by developing and testing a replicating adenoviral vector containing the HSVtk suicide gene. In a first series of experiments (proof of principal), we will study a fully replicative virus containing the HSVtk gene inserted into the E3 region in ovarian tumor models. This will begin to allow us to understand the dynamics of viral replication vs delivery of GCV. Specific Aim 2. Develop and evaluate a replication-competent adenoviral vector expressing HSVtk that will only replicate in ovarian cancer cells. This will be accomplished by developing Ad mutants that replicate selectively in ovarian tumors using the “U3” promoter developed by Dr. Hamilton and his group. These vectors will be made by disrupting the normal Ad E1a promoter region and inserting the ovarian cancer-selective promoter into this region. Since replication is dependent on early production of E1 proteins, viral replication will be limited to those cells in which the tumor specific promoter is active.

Tags: Adenoviridae, Gene Therapy, Neoplasm /cancer Therapy, Ovary Neoplasm, Transfection Vector Ganciclovir, Genetic Promoter Element, Method Development, Virus Replication Human Tissue, Laboratory Mouse, Laboratory Rat

  • Followup Grant: 3P50CA083638-01S10007
  • Followup Grant: 5P50CA083638-020007
  • Followup Grant: 5P50CA083638-030007
  • Followup Grant: 5P50CA083638-040007

Abstract: DESCRIPTION (provided by applicant): One of the major hurdles in cancer chemotherapy is the inability of the agent to selectively target tumor cells. The over expression of the FR-alpha on the surface of a number of tumors including ovarian, endometrial, kidney, lung, mesothelioma, breast and brain and FR-beta on the surface of myeloid leukemia has prompted the development of folic acid and the pteroyl moiety as selective targeting agents to FR-alpha expressing tumors. Thus, conjugates of folic acid and pteroates have been used to selectively deliver toxins, liposomes, imaging and cytotoxic agents to FR-alpha expressing tumors with a high degree of success. The process of utilizing a cytotoxic conjugate with the folic acid or pteroyl moiety as an antitumor agent requires the additional step of cleavage of the conjugate. This cleavage needs to occur selectively inside the tumor cell to release the cytotoxic agent. Premature release of the cytotoxic agent abrogates selectivity and leads to toxicity. The design of a cytotoxic agent that itself selectively targets the FR-alpha and is not appreciably taken up by the RFC would afford highly selective agents against FR-alpha expressing tumors without serious toxicity. We have recently discovered two compounds, AAG366 and AAG344 that are unique and are inhibitors of glycinamide ribonucleotide formyltransferase (GARFTase), are poorly taken up by the RFC and potently inhibits the growth of FR-alpha expressing KB tumor cells with IC50 values of 2.5 and 2.9 nM respectively. AAG366 and AAG344 are remarkable 100-345-fold more inhibitory to tumor cells expressing the FR-a compared to cells that do not express the FR-alpha. The Specific Aims of this proposal are: 1) to synthesize analogs of AAG366 and AAG344 to provide a structure-activity relationship (SAR) study to optimize the antitumor activity and the inhibitory activity against GARFTase as well as the high affinity binding and uptake by FR-alpha; 2) to test the analogs for cytotoxicity in isogenic (CHO, KB, SKOV3, OVAR3, CCRF-CEM) cell line models with established differences in FR-alpha, RFC and folylpolyglutamate synthetase, to identify the molecular targets by nucleoside and aminoimidazole carboxamide protection from cytotoxicity by in situ metabolic labeling with radiolabeled (glycine, formate) biosynthetic precursors to determine affinities for FR binding, and to determine the inhibition of target enzyme GARFTase and other folate metabolizing enzymes by studies with isolated enzymes; 3) to evaluate the in vivo antitumor activity of AAG366, AAG344 and selected analogs against FR-alpha expressing tumors. This study will provide a comprehensive SAR and should afford optimized analogs with increased antitumor activity against FR-alpha expressing tumors in vitro and in vivo. This study will also further define the mechanism(s) of action of these novel analogs and could provide agents to be used as monotherapy or in combination for clinical use with a different spectrum of antitumor activity and reduced toxicity than those currently in use.

Tags: Antineoplastic, Folate, Neoplasm /cancer, Receptor Analog

  • Followup Grant: 5R01CA125153-02
  • Followup Grant: 5R01CA125153-03
  • Followup Grant: 5R01CA125153-04

Abstract: DESCRIPTION: (Applicant’s Description) The goals of the Translational Research Core are to: (1) provide high quality, well-characterized vectors for animal and in vitro experiments for Projects 2 and 3; (2) provide clinical grade vectors (produced under GMP conditions) for Project 1, and (3) conduct toxicology studies under GLP conditions for promising vectors developed. To support the translational process of moving the proposed projects into phase I human clinical trials, a Translational Core has been implemented. This will consist of multiple units that already function with similar goals in the Institute for Human Gene Therapy at the University of Pennsylvania: The Vector Development Core which will assist in the molecular cloning, and selection of multiple vectors and initial scale-up of vectors as outlined in Project 2; a vector production group that will take limited numbers of these vectors and produce the under Good Manufacturing Practices (GMP) as required by the FDA for final pre-clinical safety studies as well as for human clinical trials; and a toxicology group that will conduct the safety assessment studies needed to assess potential toxicological problems that may occur in humans. These three units will perform the final development stage work under the expected regulations expected by the FDA, as well as provide the documentation for IND application in the form of summaries for the IND and detailed Final Reports for toxicology studies and Drug Master Files for selected vectors.

Tags: Biomedical Facility, Gene Therapy, Mesothelioma, Transfection /expression Vector Biotechnology

  • Followup Grant: 5P01CA066726-069005
  • Followup Grant: 5P01CA066726-089005
  • Followup Grant: 5P01CA066726-099005

Abstract: DESCRIPTION: (Applicant’s Description) The Pathology Core is designed to facilitate research in the area of gene therapy by providing pathologic interpretation and support for tissue research in the form of prepared frozen and paraffin embedded sections. Standard immunohistochemical methods for transgene detection are available to all program project participants for preclinical studies and clinical trials.

Tags: Biomedical Facility, Histopathology, Immunocytochemistry, Mesothelioma

  • Followup Grant: 5P01CA066726-069004
  • Followup Grant: 5P01CA066726-079004
  • Followup Grant: 5P01CA066726-089004
  • Followup Grant: 5P01CA066726-099004

Abstract: DESCRIPTION: (Applicant’s Description) The goals of the Biostatistics and Data Management Core are to provide statistics and data management services to support research conducted by the project investigators. Core members include biostatisticians and data management and computing professionals from the Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics at Penn. Dr. Kathleen Joy Propert, Assistant Professor of Biostatistics, will serve as the Core Director overseeing all activities and personnel. The specific aims of the Biostatistics and Data Management Core are: (1) Biostatistics: (a) Advise investigators on study design issues for clinical protocols, animal studies, and other research. (b) Conduct interim analyses and assist with writing of interim reports as required for data and safety monitoring of clinical protocols. (c) Conduct statistical analyses of data from clinical and laboratory projects to address specific research hypotheses as defined in the project-specific proposals. (d) Assist with preparation for and writing of final reports, abstracts, manuscripts, and future research proposals. (e) Conduct exploratory analyses that may lead to generation of new hypotheses. (2) Data Management: (a) Implement a framework to facilitate data management and statistical analysis for all projects by establishing interaction among biostatisticians, data management specialists, computing and database personnel, and project investigators. (b) Design and implement procedures for enrolling patients to clinical projects and tracking the flow of data through various study phases. (c) Develop and implement procedures for case report forms design and coding, data entry and validation, quality assurance, and reporting. (d) Design, test, implement, and maintain database structures and application programs to support Aims 2b and 2c.

Tags: Biomedical Facility, Data Management, Mesothelioma, Statistics /biometry Experimental Design, Gene Therapy

  • Followup Grant: 5P01CA066726-069006
  • Followup Grant: 5P01CA066726-079006
  • Followup Grant: 5P01CA066726-089006
  • Followup Grant: 5P01CA066726-099006

Abstract: The Cellular morphology Core laboratory is constructed to meet the increasing demands of cell biology and transgene detection in the area of gene therapy research. Routine morphology support in the form of frozen, paraffin, and glycolmethacrylate sectioning for light level microscopy (LM) as well as standard transmission electron microscopy (EM) will be provided as a comprehensive service investigators participating in P01 projects. In addition, the core will emphasize state of the art methodologies for detecting transgene expression including in situ hybridization, immunocytochemistry, and histochemical detection of beta-galactosidase and alkaline phosphatase reporter genes. The cellular morphology core will provide techniques of in situ hybridization and immunocytochemical detection of transgenes as comprehensive services to preclinical studies of the Animal models Core and the clinical studies of th Human Applications laboratory. The cellular morphology core will interact with participating P01 projects by two mechanisms; i) comprehensive service, and ii) facilities and technical support. Comprehensive services will be predominantly applied to clinical and preclinical projects. This will assure the minimal amount of technical variability and high quality assurance. Alternatively, the CMC will provide comprehensive services of in situ hybridization, immunocytochemistry, and histochemistry through the initial developmental stages of studies pertaining to P01 projects. Once methods for developmental studies have been defined within the core, the technologies will be transferred to individual investigators. During this phase of developmental projects, users will have full support for routine sectioning and full access to equipment and commonly used reagents for specialized techniques. Due to the specialized nature of electron microscopy, all EM services will be provided as a comprehensive service. Dr. Engelhardt currently directs the operations of the morphology Core at the institute for Human Gene Therapy. He has published studies involving CFTR localization by in situ hybridization and immunocytochemistry in human bronchus as well as several manuscripts which used gene transfer technology to be t ter understand the biology of host vector interactions as it pertains to recombinant adenovirus in human proximal respiratory epithelium in xenografts, mouse liver, and cotton rat lung.

Tags: Biomedical Facility, Cell Biology, Cytology, Gene Therapy, Mesothelioma, Neoplasm /cancer Therapy Confocal Scanning Microscopy, Electron Microscopy, Immunocytochemistry, In Situ Hybridization, Light Microscopy

  • Followup Grant: 5P01CA066726-049002
  • Followup Grant: 3P01CA066726-04S19002

Abstract: The overall necessity of this facility is to provide a laboratory solely dedicated to the development of clinical applications of gene therapy. The facility will be regulated by the FDA and required to practice both Good Laboratory Practices (GLP) as well as Good Manufacturing Practices (GMP). It will also be certified to operate as a BL2 containment facility in the handling of potential biohazardous material. Specific aims are described below: A) To provide a state-of-art laboratory with BL2 containment as well as GLP and GMP guidelines, B) To provide facilities and expertise in the development of gene transfer substrates that are being reviewed and certified by the FDA. C) To provide facilities and expertise in the harvest, isolation and cultivation of human cells that will be genetically modified and used as either preclinical data in the documentation of the feasibility and safety of gene transfer or used in an actual clinical protocol. D) To provide facilities and expertise in the implementation of preclinical studies under conditions that are acceptable to the FDA. E) To establish protocols and standard operating procedures (SOPs) for the applications of human gene therapies of general use to the institution, F) To establish a series of standard quality controls based on SOPs that are acceptable to the FDA that can be utilized in the certification of protocols. Mariann Grossman, the Director of the Human Applications laboratory (HAL) at the University of Pennsylvania, was responsible for certifying both gene therapy reagents, a recombinant retrovirus and a recombinant adenovirus, that are currently being used in the two gene therapy trials now underway at the medical center. The Human Applications Laboratory is also being set up to serve as a regional resource facility whereby gene therapy reagents are used at multiple institutions. In this application, partial support is requested to produce and validate clinical grade stocks of recombinant adenoviruses that express HSVTK. It is anticipated that four new viruses will be developed over the 5 year grant.

Tags: Biomedical Facility, Gene Therapy, Mesothelioma Human Subject

  • Followup Grant: 5P01CA066726-049001
  • Followup Grant: 3P01CA066726-04S19001

Clinical Trials

Condition: Cancer
Intervention: Biological: recombinant adenovirus-hIFN-beta
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Condition: Malignant Mesothelioma; Metastatic Cancer; Peritoneal Cavity Cancer
Intervention: Drug: EF5; Other: fluorescent antibody technique; Other: immunohistochemistry staining method
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Condition: Pleural Mesothelioma; Metastatic Pleural Effusions
Intervention: Gene Transfer: BG00001 (adenoviral-mediated interferon-beta)
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Condition: Malignant Mesothelioma
Intervention: Drug: carboplatin; Drug: gemcitabine hydrochloride; Drug: pemetrexed disodium
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Condition: Malignant Mesothelioma
Intervention: Drug: pazopanib hydrochloride; Other: laboratory biomarker analysis
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Condition: Malignant Mesothelioma
Intervention: Biological: bevacizumab; Drug: cisplatin; Drug: gemcitabine hydrochloride
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Condition: Mesothelioma
Intervention: Drug: Pemetrexed; Drug: Gemcitabine
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Condition: Malignant Mesothelioma
Intervention: Drug: gefitinib
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Condition: Malignant Mesothelioma
Intervention: Drug: vatalanib
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Condition: Malignant Epithelial Mesothelioma; Adenocarcinoma of the Pancreas; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma of the Ovaries
Intervention: Biological: CRS-207, Live-attenuated Listeria monocytogenes expressing human Mesothelin
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Condition: Malignant Pleural Mesothelioma; MPM; Solid Tumors
Intervention: Drug: pemetrexed, cisplatin and CBP501; Drug: pemetrexed and cisplatin
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Condition: Malignant Mesothelioma
Intervention: Drug: epirubicin hydrochloride; Drug: gemcitabine hydrochloride
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Condition: Malignant Mesothelioma
Intervention: Drug: cediranib maleate; Other: laboratory biomarker analysis
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Condition: Malignant Mesothelioma
Intervention: Drug: belinostat; Genetic: reverse transcriptase-polymerase chain reaction; Other: laboratory biomarker analysis
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Condition: Mesothelioma; Lung Cancer
Intervention: Drug: Comparator: Suberoylanilide Hydroxamic Acid (Vorinostat, MK0683); Drug: Comparator: Placebo
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Condition: Malignant Mesothelioma
Intervention: Biological: recombinant interferon alfa; Drug: cisplatin; Procedure: surgical procedure; Radiation: radiation therapy
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Condition: Pancreatic Cancer; Mesothelioma; Ovarian Cancer; Non-Small Cell Lung Cancer
Intervention: Drug: MORAb-009
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Condition: Breast Cancer; Colorectal Cancer; Lung Cancer; Malignant Mesothelioma; Prostate Cancer; Psychosocial Effects of Cancer and Its Treatment; Thymoma and Thymic Carcinoma
Intervention: Other: educational intervention; Procedure: psychosocial assessment and care; Procedure: quality-of-life assessment
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Condition: Cancer
Intervention: Other: biologic sample preservation procedure
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Condition: Metastatic Non-squamous Non Small Cell Lung Cancer
Intervention: Drug: CBP501 + Cisplatin + Pemetrexed; Drug: Cisplatin + Pemetrexed
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Hospitals and Cancer Centers

Physicians

David Bartlett, M.D.
Hillman Cancer Center
5115 Centre Avenue
Pittsburgh, PA 15232
(412) 692-2852

Douglas L. Fraker, M.D.
Penn Medicine
3400 Spruce Street
4 Silverstein Pavilion
Philadelphia, PA 19104
Administrative Telephone: (215) 662-7866
Patient Appointments: (215) 615-5858

John P. Hoffman, M.D.
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia, PA 19111-2497 (215) 728-2570

Dr. Larry Kaiser
University of Pennsylvania
4th Floor
Philadelphia, PA 19104
(215) 662.7538
Kaiser@mail.med.upenn.edu

J.F. Pingpank Jr., M.D.
Hillman Cancer Center
5115 Centre Avenue
Pittsburgh, PA 15232
(412) 692-2852

Matthew Schuchert, M.D.
Shadyside Medical Building
5200 Centre Avenue, Suite 715
Pittsburgh, PA 15232
(412) 623-2025

Gregg v. V-J Auto Parts Co.
No. 38 EAP 2005, SUPREME COURT OF PENNSYLVANIA, May 30, 2007, Resubmitted, December 28, 2007, Decided

Gibson v. Workers’ Comp. Appeal Bd. (Armco Stainless & Alloy Prods.)
No. 39 WAP 2003 , SUPREME COURT OF PENNSYLVANIA, March 1, 2004, Argued , November 22, 2004, Decided

Zieber v. Bogert
30 EAP 2000, SUPREME COURT OF PENNSYLVANIA, January 29, 2001, Argued , June 19, 2001, Decided

Baker v. AC&S, Inc.
No. 43 E.D. Appeal Dkt. 1999, SUPREME COURT OF PENNSYLVANIA, February 1, 2000, Argued , June 26, 2000, Decided

Murphy v. Diogenes A. Saavedra, M.D., P.C.
No. 20 W.D. Appeal Docket 1997, No. 21 W.D. Appeal Docket 1997, SUPREME COURT OF PENNSYLVANIA, September 17, 1997, Argued , February 16, 2000, Decided

Gregg v. V-J Auto Parts Co.
No. 3528 EDA 2003, SUPERIOR COURT OF PENNSYLVANIA, August 19, 2008, Argued, June 11, 2009, Filed

Daley v. A.W. Chesterton, Inc.
No. 2763 EDA 2006, SUPERIOR COURT OF PENNSYLVANIA, April 15, 2009, Filed

Vanaman v. DAP, Inc.
No. 2849 EDA 2006, SUPERIOR COURT OF PENNSYLVANIA, February 11, 2009, Filed

Burger v. Owens Ill., Inc.
No. 2836 EDA 2006, SUPERIOR COURT OF PENNSYLVANIA, February 11, 2009, Filed

Johnson v. Am. Std.
No. 2954 EDA 2006, No. 2955 EDA 2006, No. 2956 EDA 2006, SUPERIOR COURT OF PENNSYLVANIA, February 6, 2009, Filed

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