Irradiated tumor cells adenovirally engineered to secrete granulocyte/macrophage-colony-stimulating factor establish antitumor immunity and eliminate pre-existing tumors in syngeneic mice

1998 ◽  
Vol 47 (2) ◽  
pp. 72-80 ◽  
Author(s):  
Eishi Nagai ◽  
Takahiro Ogawa ◽  
Tammy Kielian ◽  
Akashi Ikubo ◽  
Tsuneo Suzuki
Keyword(s):  
Tumor Cells ◽  
Antitumor Immunity ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Vaccination With Irradiated, Autologous Melanoma Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor by Adenoviral-Mediated Gene Transfer Augments Antitumor Immunity in Patients With Metastatic Melanoma

2003 ◽  
Vol 21 (17) ◽  
pp. 3343-3350 ◽  
Author(s):  
Robert Soiffer ◽  
F. Stephen Hodi ◽  
Frank Haluska ◽  
Ken Jung ◽  
Silke Gillessen ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Metastatic Melanoma ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Melanoma Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.Patients and Methods: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 × 106, 4 × 106, or 1 × 107tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.Conclusion: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non–Small-Cell Lung Carcinoma

2003 ◽  
Vol 21 (4) ◽  
pp. 624-630 ◽  
Author(s):  
Ravi Salgia ◽  
Thomas Lynch ◽  
Arthur Skarin ◽  
Joan Lucca ◽  
Cathleen Lynch ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Antitumor Immunity ◽  
Small Cell ◽  
Delayed Type Hypersensitivity ◽  
Colony Stimulating Factor ◽  
Small Cell Lung ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non–small-cell lung cancer (NSCLC), we conducted a phase I clinical trial.Patients and Methods: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 × 106, 4 × 106, or 1 × 107cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals.Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/106cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed.Conclusion: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Antitumor Immunity Induced by Irradiated Tumor Cells Producing Macrophage Colony-Stimulating Factor

2001 ◽  
Vol 73 (3) ◽  
pp. 378-382 ◽  
Author(s):  
Shinya Suzu ◽  
Fumihiko Kimura ◽  
Miyuki Tanaka-Douzono ◽  
Muneo Yamada ◽  
Yukitsugu Nakamura ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Antitumor Immunity ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells

2004 ◽  
Vol 24 (8) ◽  
pp. 3238-3250 ◽  
Author(s):  
Jennifer Wessells ◽  
Shoshana Yakar ◽  
Peter F. Johnson
Keyword(s):  
Growth Factor ◽  
Tumor Cells ◽  
Insulin Like Growth Factor ◽  
Colony Stimulating Factor ◽  
Factor I ◽  
Survival Factor ◽  
Igf I ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

ABSTRACT One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBPβ to prevent cell death. In contrast to wild-type cells, C/EBPβ−/− macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPβ-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPβ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPβ. Serological neutralization of IGF-I in C/EBPβ+/+ tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I−/− mice were GF dependent, similar to C/EBPβ-deficient cells. Forced expression of either C/EBPβ or IGF-I in C/EBPβ−/− bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPβ is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.

scholarly journals Obtainingvaccinia virus with increased production of extracellular enveloped virions and directing GM-CSF synthesis as a promising basis for development of antitumor drug

2020 ◽  
Vol 22 (2) ◽  
pp. 371-378
Author(s):  
T. V. Bauer ◽  
T. V. Tregubchak ◽  
S. N. Shchelkunov ◽  
R. A. Maksyutov ◽  
E. V. Gavrilova
Keyword(s):  
Genetic Engineering ◽  
Tumor Cells ◽  
Oncolytic Viruses ◽  
Whole Body ◽  
Colony Stimulating Factor ◽  
Nucleotide Substitutions ◽  
Gene Encoding ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The problems of oncological disease treatment are considered relevant and timely issues of the current research programs. Since monotherapy is increasingly clear to be less effective than combination therapy, the novel studies seek for advancement of current treatments and development of new ones employing oncolytic immunotherapy being among the most rapidly evolving approaches. Modern genetic engineering techniques enable new applications of oncolytic viruses in the frames of combined cancer therapy. These applications are feasible, due to the abilities of oncolytic viruses to destruct tumor cells, like as by changing susceptibility of cancer cells to anti-tumor drug, and upon the whole body, thus overcoming the mechanisms conferring immunoresistance of tumor cells. In the present work, we have developed a recombinant vaccinia virus which is a promising platform for designing the antitumor drugs. The following modifications of viral genome were made by means of genetic engineering: gene encoding granulocyte-macrophage colony-stimulating factor was inserted into the region of viral thymidine kinase gene; viral A34R gene encoding a membrane glycoprotein, was replaced by A34R gene with two nucleotide substitutions resulting into D110N and K151E mutations which cause increased proportion of extracellular enveloped virions during the virus reproduction. Some properties of the recombinant virus were studied in vitro. The virus was shown to produce granulocyte-macrophage colony stimulating factor, and high numbers of extracellular enveloped virions. The genome modifications had no effect upon viral replication.

scholarly journals Macrophages can recognize and kill tumor cells bearing the membrane isoform of macrophage colony-stimulating factor

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5232-5241 ◽  
Author(s):  
MR Jadus ◽  
MC Irwin ◽  
MR Irwin ◽  
RD Horansky ◽  
S Sekhon ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Bone Marrow Cells ◽  
Hybridoma Cells ◽  
Dependent Manner ◽  
Cell Cytotoxicity ◽  
Colony Stimulating Factor ◽  
Cytotoxicity Studies ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

NBXFO hybridoma cells produced both the membrane and secreted isoforms of macrophage colony-stimulating factor (M-CSF). Murine bone marrow cells stimulated by the secreted form of M-CSF (sM-CSF) became Mac1+, Mac2+, Mac3+, and F4/80+ macrophages that inhibited the growth of NBXFO cells, but not L1210 or P815 tumor cells. In cytotoxicity studies, M- CSF activated macrophages and freshly isolated macrophages killed NBXFO cells in the presence of polymyxin B, eliminating the possibility that contaminating lipopolysaccharide (LPS) was responsible for the delivery of the cytotoxic signal. Retroviral-mediated transfection of T9 glioma cells with the gene for the membrane isoform of M-CSF (mM-CSF), but not for the secreted isoform of M-CSF, transferred the ability of macrophages to kill these transfected T9 cells in a mM-CSF dose- dependent manner. Macrophage-mediated killing of the mM-CSF transfected clone was blocked by using a 100-fold excess of recombinant M-CSF. Catalase, superoxide dismutase, and the nitric oxide inhibitor, N-omega- nitro-arginine methyl ester (NAME), did not effect macrophage cytotoxicity against the mM-CSF transfectant T9 clones. T9 parental cells when cultured in the presence of an equal number of the mM-CSF transfectant cells were not killed, indicating specific target cell cytotoxicity by the macrophages. Electron microscopy showed that macrophages were capable of phagocytosizing mM-CSF bearing T9 tumor cells and NBXFO hybridoma cells; this suggested a possible mechanism of this cytotoxicity. This study indicates that mM-CSF provides the necessary binding and triggering molecules through which macrophages can initiate direct tumor cell cytotoxicity.

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