Treatment of Established Renal Cancer by Tumor Cells Engineered to Secrete Interleukin-4

Golumbek, Paul T.; Lazenby, Audrey J.; Levitsky, Hyam I.; Jaffee, Liz; Karasuyama, Hajime; Baker, Mitzi; Pardoll, Drew M.

doi:10.1126/science.1948050

Cited by 695 publications

(291 citation statements)

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“…Some success has been achieved with this approach. 3,4,18 Relevant to this report, Dranoff et al 19 included GM-CSF in a panel of 10 molecules to compare their ability to enhance the immunogenicity of tumor cells. In the B16 melanoma model, nontransduced cells possessed little ability to stimulate systemic antitumor immunity.…”

Section: Discussionmentioning

confidence: 96%

“…Reasoning that higher and perhaps more effective cytokine levels could be sustained at the immunization site by local production rather than by local or systemic injection, tumor cells or fibroblasts genetically engineered to produce the molecule(s) of interest were included in vaccine preparations. The demonstration by Golumbek et al 3 that immunization with tumor cells engineered to secrete Interleukin(IL)-4 could induce regression of an established syngeneic renal cell cancer in mice launched many clinical trials, the available results of which were recently reviewed. 4 Some tumor regressions have been noted primarily in patients with melanoma.…”

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confidence: 99%

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Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

et al. 1999

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Seven immunocompetent, revaccinated patients with surgically incurable cutaneous melanoma underwent treatment of dermal and/or subcutaneous metastases with twice-weekly intratumoral injections of escalating doses (10 4 Ϫ2 ϫ 10 7 plaque-forming units (PFU)/lesion; 10 4 Ϫ8 ϫ 10 7 PFU/session) of a vaccinia/GM-CSF recombinant virus for 6 weeks. Patients with stable or responding disease were maintained on treatment until tumor resolution or progression. Systemic toxicity was infrequent, dose-related, and limited to mild flu-like symptoms that resolved within 24 hours. Local inflammation, at times with pustule formation, was consistently seen with doses of Ն10 7 PFU/lesion. Chronically treated lesions showed a dense infiltration, with CD4 ϩ and CD8 ϩ lymphocytes, histiocytes, and eosinophils. All seven patients developed an antivaccinia humoral immune response 14 -21 days following revaccination. Despite the presence of these antivaccinia antibodies, the reporter gene was expressed, as judged by the development of anti-␤-galactosidase antibodies in all patients. Passenger cytokine gene function was evidenced by the presence of virally encoded GM-CSF mRNA at injection sites both early (weeks 1 and 5) and late (week 31) in the course of treatment. Eosinophilia at treatment sites indicated that physiologically significant levels of functional cytokine were generated. However, there were no changes in the total number of peripheral white blood cells or in the numbers or percentages of polymorphonuclear leukocytes, monocytes, or eosinophils. GM-CSF was not detected in the sera. The two patients with the largest tumor burdens failed to respond even at treatment sites. Three patients had mixed responses, with regression of treated and untreated dermal metastases and progression of disease elsewhere. One patient had a partial response, with regression of injected and uninjected regional dermal metastases. Residual melanoma was excised, rendering the patient disease free. One patient with only dermal metastases confined to the scalp achieved a complete remission. Sequential administration of escalating doses of a GM-CSF recombinant vaccinia virus is safe, effective at maintaining passenger gene function, and can induce tumor regression.

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

et al. 1999

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“…In the present studies, a replication-defective recombionstrated both protective and therapeutic efficiency of nant adenovirus vector, Ad.RSV␤gal was used for transgene-modified cellular vaccines in tumors such as meladuction of the reporter gene lacZ into normal or malignoma, 4 mastocytoma, 5 renal cell carcinoma 6 and sarnant hematopoietic cells including CML and B-CLL. This coma.…”

Section: Introductionmentioning

confidence: 99%

Efficient adenovirus-mediated gene transduction of normal and leukemic hematopoietic cells

et al. 1997

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We evaluated the efficiency of adenovirus-mediated gene targeted cells. A novel protocol for the efficient transduction transfer into normal and malignant human hematopoietic of adenovirus into B-CLL cells was presented. We showed cells. An E-1 and E-3 deleted, replication-defective recomthat anti-CD40 mAb or CD40 ligand acts in synergy with binant Ad.RSV␤gal vector was used and the transduction rhIL-4 to enable the transduction of approximately 50-75% efficiency was studied at a multiplicity of infection of 13 of B-CLL cells (B-CLL, n = 6). Expression of ␤-galactop.f.u. per cell. Approximately 40-50% of normal monocytes sidase in transduced CML cells and B-CLL cells was were transduced, whereas purified normal resting T cells detected for at least 15 days after transduction. The and B cells were resistant to infection. We showed that 50-present studies underline the utility of adenovirus vectors 80% of primary chronic myeloid leukemia cells (CML, n = for the construction of cytokine gene-modified tumor vac-12) were efficiently transduced. In contrast to CML, succines for the treatment of hematopoietic malignancies such cessful transduction of resting primary chronic B lymphoas CML and B-CLL. cytic leukemia cells required appropriate preactivation of for 3 days with rhGM-CSF (100 U/ml) before infection. Activation of cells with GM-CSF did not influence the (CD14 + , 90-98%) were readily transduced and stained transduction rate (data not shown). strongly positive for ␤-galactosidase (five separate experiments). Unlike the experience with retrovirus, we rhIL-4 together with hCD40 ligand are efficient and showed that efficient transduction of normal peripheral necessary for the transduction of primary B-CLL cells blood monocytes can be achieved with adenovirus withMononuclear cells from chronic B lymphocytic leukemia out preactivation of target cells. In contrast, purified (B-CLL, n = 6) patients were studied for adenoviral vector resting T lymphocytes (CD3 + , Ͼ96%) and B lymphocytes transduction. B-CLL cells were Ig-light chain restricted (CD19 + , Ͼ95%) were, however, not permissive to transand displayed CD5 (100%) and CD19 (80-95%) on the duction (three separate experiments).cell surface. Similarly to normal resting B lymphocytes (Figure 1), Efficient transduction of primary CML cells without resting primary B-CLL cells were resistant to adenovirus preactivation of target cells infection. A number of activation protocols [15][16][17][18] were Unselected mononuclear cells from chronic myeloid leutested to improve the transduction efficacy of B-CLL kemia patients (CML, n = 12) were included in the cells. We found that neither phorbol ester induction nor present studies. Although all the CML cells were Ph + , but the combination of SAC + thioredoxin + IL-2, forskolin represented heterogeneous cell populations. CML cells nor TNF␣ were efficient in improving the transduction expressed CD13 (40-80%), CD33 (40-81%) and other cell rate. In marked contrast, approximately 70-75% B-CLL surface markers (Table 1). No sign...

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“…72,73 Mammalian Tag7/PGRP-S has been cloned from mouse, 69 human, 70 rat, 74 and cow. 75 There are small extracellular proteins (19)(20)(21)(22)(23)(24), which structurally share homology with T phage lyzozyme but do not possess any amidaze activity. Apart from their ability to recognize oligosaccharides and particularly peptidoglycan 70,75 cytotoxicity towards mammalian cells, 69,75,76 bactericidal and bacteriostatic activities 75 were detected.…”

Section: Innate Immunity Pattern Recognition Molecules In Gene Therapmentioning

confidence: 99%

Gene transfer approaches in cancer immunotherapy

Larin

Georgiev

2004

Gene Ther

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Treatment of Established Renal Cancer by Tumor Cells Engineered to Secrete Interleukin-4

Cited by 695 publications

References 28 publications

Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma

Efficient adenovirus-mediated gene transduction of normal and leukemic hematopoietic cells

Gene transfer approaches in cancer immunotherapy

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