Cytokines are hormonal agents which often act at short distances to enhance physiologic processes in an autocrine or paracrine fashion. Many of the genes encoding these potent molecules have been cloned, allowing development of novel gene therapies for application in cancer, autoimmunity and transplantation. Cytokine gene therapies have been developed utilizing a variety of different chemokines including RANTES and MIP1alpha, proinflammatory agents such as TNFalpha, T-cell growth factors including IL-2, and a variety of different cytokines including IL-4, IL-10 and IL-12 produced early during the immune response. Our underlying hypothesis for this Program Project Grant is that tumors have developed effective means to avoid immune detection and that measures to enhance immune reactivity including systemic cytokine administration (such as IL- 2) subsequent to the delivery of agents capable of effectively immunizing the host to his own cancer are likely to realize benefit for the cancer patient. We believe that such approaches should mimic natural immune processes and that cytokine gene therapies most closely mimic the local release of cytokines occurring during a natural immune response, stimulate new thymic emigrants which have not been subjected to the apparently tolerizing effects of the tumor, and ultimately promote tumor destruction and acquisition of a state of long-lived and effective immunity. To that end we propose to continue and expand our efforts by conducting three projects supported by four cores: Project 1. IL-4 Gene Transfection to Enhance Dendritic and Endothelial Cell Activation during Tumor Immunization. Principal Investigator: Michael T. Lotze, MD.; Project 2. Cancer Gene Therapy in murine models using cellular IL-10: Development of improved cIL-10 vectors to induce tumor autoimmunity. CoPrincipal Investigators: Hideaki Tahara, MD, PhD and Paul D. Robbins, PhD.; and Project 3. IL-12: A heterodimeric cytokine for gene therapy to stimulate immunity and to enhance anti-tumor effector cell function. Principal Investigator: Walter J. Storkus, PhD. These projects are synergistic, integrated intrinsically and investigator initiated. They will be supported by four separate core facilities which are well established and operational. These include: Administrative Core, (Michael T. Lotze, MD); Immunologic Monitoring and Diagnostic Laboratory Core (IMDL), (Theresa L. Whiteside, PhD); Vector Core; Human Gene Therapy Applications Laboratory (HGTAL) Core, (John A. Barranger, MD, PhD). Collectively this application supports extension of a vigorous, mature program in cancer therapeutics, applying the tools of molecular biology to enhance biologic therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Centers and Research Programs Review Committee (CCRP)
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University of Pittsburgh
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DeMarco, Richard A; Fink, Mitchell P; Lotze, Michael T (2005) Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. Mol Immunol 42:433-44
Witham, Timothy F; Villa, Lorissa; Yang, Tianbing et al. (2003) Expression of a soluble transforming growth factor-beta (TGFbeta) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo. J Neurooncol 64:63-9
Son, Young-Ik; Dallal, Ramsey M; Lotze, Michael T (2003) Combined treatment with interleukin-18 and low-dose interleukin-2 induced regression of a murine sarcoma and memory response. J Immunother 26:234-40
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Yang, Tianbing; Witham, Timothy F; Villa, Lorissa et al. (2002) Glioma-associated hyaluronan induces apoptosis in dendritic cells via inducible nitric oxide synthase: implications for the use of dendritic cells for therapy of gliomas. Cancer Res 62:2583-91
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Son, Y I; Dallal, R M; Mailliard, R B et al. (2001) Interleukin-18 (IL-18) synergizes with IL-2 to enhance cytotoxicity, interferon-gamma production, and expansion of natural killer cells. Cancer Res 61:884-8
Okada, H; Attanucci, J; Giezeman-Smits, K M et al. (2001) Immunization with an antigen identified by cytokine tumor vaccine-assisted SEREX (CAS) suppressed growth of the rat 9L glioma in vivo. Cancer Res 61:2625-31
Hiroishi, K; Tuting, T; Lotze, M T (2000) IFN-alpha-expressing tumor cells enhance generation and promote survival of tumor-specific CTLs. J Immunol 164:567-72

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