Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer.

Rosenberg, S A

doi:10.1200/jco.1992.10.2.180

Cited by 372 publications

(145 citation statements)

References 107 publications

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“…8,9,20,23,26,29,36 When different cytokine genes were compared, GM-CSF most effectively prevented subsequent tumor growth in a poorly immunogenic tumor model. 20 We confirmed these findings in a similar protection model.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous clinical trials have been initiated recently using cytokine gene-modified autologous tumor cells or tumor-infiltrating lymphocytes for the treatment of advanced cancer patients. [23][24][25][26] Data from these studies imply that high local cytokine levels in the vicinity of tumor cells are as effective as systemic cytokine administration; the concentration of the cytokine in the tumor microenvironment is the critical factor. 27 Previous clinical gene therapy protocols have relied on the delivery of cytokine DNA into tumor samples, with subsequent placement of these altered tumor cells as an antitumor vaccine.…”

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confidence: 99%

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by cDNA-transfected tumor cells induces a more potent antitumor response than exogenous GM-CSF

et al. 1999

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Clinical cancer gene therapy trials have generally focused on the transfer of cytokine cDNA to tumor cells ex vivo and with the subsequent vaccination of the patient with these genetically altered tumor cells. This approach results in high local cytokine concentrations that may account for the efficacy of this technique in animal models. We hypothesized that the expression of certain cytokines by tumor cells would be a superior immune stimulant when compared with local delivery of exogenous cytokines. Granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA in a nonviral expression vector was inserted into MDA-MB-231 (human breast cancer), M21 (human melanoma), B16 (murine melanoma), and P815 (mastocytoma) cells by particle-mediated gene transfer. The ability of transfected tumor cells to generate a tumor-specific immune response was evaluated in an in vitro mixed lymphocyte-tumor cell assay and in an in vivo murine tumor protection model. Peripheral blood lymphocytes cocultured with human GM-CSF-transfected tumor cells were 3-to 5-fold more effective at lysis of the parental tumor cells than were peripheral blood lymphocytes incubated with irradiated tumor cells and exogenous human GM-CSF. Mice immunized with murine GM-CSF-transfected irradiated B16 murine melanoma cells or P815 mastocytoma cells were protected from subsequent tumor challenge, whereas mice immunized with the nontransfected tumors and cutaneous transfection of murine GM-CSF cDNA at the vaccination site developed tumors more frequently. The results indicate that GM-CSF protein expressed in human and murine tumor cells is a superior antitumor immune stimulant compared with exogenous GM-CSF in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by cDNA-transfected tumor cells induces a more potent antitumor response than exogenous GM-CSF

et al. 1999

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“…This synergism of drug-induced TNF secretion and enhanced chemosensitivity confirms the feasibility of also cause severe side-effects. 23,24 The localized and modulated expression of the cytokine in the tumor or this approach. The activation of gene expression by chemotherapy is tumor vicinity may circumvent these problems.…”

Section: Figure 6 Schematic Representation Of the Construction Of Thementioning

confidence: 99%

Employment of the mdr1 promoter for the chemotherapy-inducible expression of therapeutic genes in cancer gene therapy

1997

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Numerous approaches in gene therapy of human cancers exploit this property, we linked the mdr1 promoter sequence are focused on the establishment of cell type specific or to the human tumor necrosis factor alpha (TNF) cDNA in a inducible expression vectors allowing the targeted and reguretroviral vector and transduced the vector into human mamlated expression of therapeutic genes. Various conditionally mary and colon carcinoma cell lines. These cells were active vectors have been created carrying promoters treated with various mdr1-associated drugs to induce TNF responding to certain factors or therapeutic modalities (eg expression in vitro. We have shown that the mdr1 promoterhormones, irradiation). The promoter of the multidrug resistdriven TNF expression is drug-inducible and that this inducance gene (mdr1) harbors such responsive elements and tion is drug concentration and time dependent. The studies two of these elements have been related to drug responsivedemonstrate the feasibility of the novel vector system for a ness. In earlier studies we and others have characterized chemotherapy-inducible expression of a chemosensitizing the mdr1 drug responsive-element in CAT reporter assays cytokine that is successful at enhancing cytotoxicity of drugs demonstrating its inducibility by MDR-associated drugs. To in cancer therapy.

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“…Animal studies revealed that it is particularly important to induce MHC-restricted CD4 + and CD8 + T cells because they retain a memory potential providing long lasting immunity. [52][53][54][55] On the other hand, non-MHC-restricted cytotoxic cells have been identified as the only source of effector cells in many RCC patients. 18,56 While their dependence on CD4 + T cell help has not been studied, they are dependent on IL-2.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer of human interferon gamma complementary DNA into a renal cell carcinoma line enhances MHC-restricted cytotoxic T lymphocyte recognition but suppresses non-MHC-restricted effector cell activity

et al. 2000

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Even though renal cell carcinomas (RCC) are thought to be immunogenic, many tumors express variations in surface molecules and intracellular proteins that hinder induction of optimal antitumor responses. Interferon gamma (IFN␥) stimulation can correct some of these deficiencies. Therefore, we introduced the complementary DNA (cDNA) encoding human IFN␥ into a well-characterized RCC line that has been selected for development of an allogeneic tumor cell vaccine for treatment of patients with metastatic disease. Studies were performed to determine how endogenous IFN␥ expression influences tumor cell immunogenicity. IFN␥ transductants showed minimal increases in surface expression of MHC class I and adhesion molecules but

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Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer.

Cited by 372 publications

References 107 publications

Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by cDNA-transfected tumor cells induces a more potent antitumor response than exogenous GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by cDNA-transfected tumor cells induces a more potent antitumor response than exogenous GM-CSF

Employment of the mdr1 promoter for the chemotherapy-inducible expression of therapeutic genes in cancer gene therapy

Gene transfer of human interferon gamma complementary DNA into a renal cell carcinoma line enhances MHC-restricted cytotoxic T lymphocyte recognition but suppresses non-MHC-restricted effector cell activity

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