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| Hersh,Evan Professor,M.D. Therapeutic Development |
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| Address: HEMATOLOGY/ONCOLOGY - 1969h PO BOX 245024 - AZCC Work Phone: 520-626-2250 Fax Number: 520-626-2225 Email: mailto:hersh@azcc.arizona.edu |
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Biography:
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| Summary of Research Activity: The main thrust of our laboratory is to discover, develop, and apply novel approaches to the immunotherapy and gene therapy of cancer. To accomplish these goals, we evaluate novel agents in terms of their in vitro biological activity, mechanism of action, and dose response relationships. After in vitro characterization, the agents are studied in animal models and then introduced into clinical trials. Novel agents under study include a series of cationic lipids for gene delivery, adenovirus and vaccina virus constructs to deliver tumor antigen genes such as MUC1, cytokine genes such as IL-2, and novel expression vectors with either high levels of constitutive gene expression or with heat/ultrasound regulatable gene expression. We recently have initiated a project to develop radiation-sensitive liposomes for gene delivery. The gene gun is being developed to deliver tumor antigen genes and immune-activating genes, such as GM-CSF and Interferon-gto the skin for cancer vaccine therapy. The immunotherapy and gene therapy of lung cancer is being investigated in the Lewis Lung model to test strategies that could be applied to the clinic. These include the intratumoral transfer of the HSP-65 DNA (coding and immunomodulatory heat shock protein) plus systemic low-dose IL-2 as an immunorestorative agent. Clinical trials of gene therapy and immunotherapy are ongoing. Using intratumoral transfer of the HLA-B7 gene (into HLA-B7 negative patients) and the IL-2 gene, we have shown clinical responses to melanoma, renal cell carcinoma, and soft tissue sarcoma. Currently, we are investigating combination gene therapy with the concurrent administration of the HLA-B7 and IL-2 genes and the combination of gene transfer with systemic low- dose IL-2 as an immunomodulator. Tumor vaccine work also is ongoing in collaboration with the John Wayne Cancer Institute and the NCI. We are participating in studies of cellular vaccines for Stage III and IV melanoma. Also, in patients with metastatic melanoma, we are investigating combination chemotherapy plus concurrent Interferon-a and IL-2. Finally, we are developing an Immunotherapy/Gene Therapy Core Facility for the Arizona Cancer Center. This facility will produce clinical grade reagents for immunotherapy and gene therapy clinical trials and also will conduct the monitoring of the immune responses of the patients on the protocols. Reagents to be produced include tumor cell lines and tumor cell line lysates for vaccines. Lysates are fresh tumor cells for vaccines, dendritic cells pulsed with tumor antigens, and gold particles coated with GM-CSF plasmids for gene gun delivery to the skin. The first clinical protocols using reagents from this laboratory were available in the fall of 1999.
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| Selected Publications:
• Clark PR, Hersh EM. Cationic lipid-mediated gene transfer: current concepts, current opinion. Molecular Therapeutics 1:158-176, 1999. • Stopeck AT, Hersh EM, Brailey JL, Norman J, Parker SE. Transfection of primary tumor cells and tumor cell lines with plasmid DNA/lipid complexes. Cancer Gene Therapy 5:1126-1129, 1998. • Hersh EM, Stopeck AT. Advances in the biological therapy and gene therapy of malignant disease. Clinical Cancer Research 3:2623-2629, 1997. • Unger E, Wright WH, Stopeck AT, Hersh EM. Imaging's special role as gene therapy guide. Diagnostic Imaging. 157-161, 1996. • Stopeck A, Hersh E, Akporiaye E, Harris D, Grogan T, Unger E, Warneke J, Stahl S. Phase I study of direct gene transferof an allogeneic histocompatability antigen, HLA-B7, in patients with metastatic melanoma. Journal of Clinical Oncology 15:341-349, 1997. • Hersh EM, Stopeck AT. Recent advances in the treatment of malignant melanoma with gene therapy. Molecular Medicine 3:636-651, 1997. • Hersh EM, Stopeck AT, Clark P. Intratumoral gene delivery for cancer treatment. Current Research in Molecular Therapeutics 5:335-338, 1998. • Hersh EM. Cancer gene therapy by direct transfer of plasmid DNA in cationic lipids. Gene Therapy of Cancer, Academic Press, pp. 319-331, 1998.
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| Collaborative Research: • Emmanuel Akporiaye, Ph.D., Microbiology and Immunology: immunomodulation in cancer. • Robert Dorr, Ph.D., Pharmacology: pharmacokinetics of novel agents. • Eugene Gerner, Ph.D., Radiation Oncology: development of vectors for cancer therapy. • William Grimes, Ph.D., Biochemistry: T-cells in cancer immunotherapy. • Emmanuel Katsanis, M.D., Pediatrics: dendritic cells in cancer therapy. • Douglas Lake, Ph.D., Microbiology and Immunology: immunotherapy models, monitoring of immune responses. • Katherine McGovern, Ph.D., Radiation Oncology: development of radiation activatible vectors for gene therapy. • David O'Brien, Ph.D., Chemistry: liposomal gene delivery. • Alison Stopeck, M.D., Hematology/Oncology: gene therapy and immunotherapy studies.
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