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 Eight patients were withdrawn early because of rapid disease progression.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.

scholarly journals Identification and characterization of a low-affinity granulocyte- macrophage colony-stimulating factor receptor on primary and cultured human melanoma cells

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 609-615 ◽  
Author(s):  
GC Baldwin ◽  
DW Golde ◽  
GF Widhopf ◽  
J Economou ◽  
JC Gasson
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Melanoma Cell Lines

Abstract Hematopoietic growth factor receptors are present on cells of normal nonhematopoietic tissues such as endothelium and placenta. We previously demonstrated functional human granulocyte-macrophage colony- stimulating factor (GM-CSF) receptors on small cell carcinoma of the lung cell lines, and others have reported that certain solid tumor cell lines respond to GM-CSF in clonogenic assays. In the current study, we examine human melanoma cell lines and fresh specimens of melanoma to determine whether they have functional GM-CSF receptors. Scatchard analyses of 125I-GM-CSF equilibrium binding to melanoma cell lines showed a mean of 542 +/- 67 sites per cell with a kd of 0.72 +/- 0.14 nmol/L. Cross-linking studies in the melanoma cell line, M14, showed a major GM-CSF receptor species of 84,000 daltons. Under the conditions tested, the M14 cells did not have a proliferative response to GM-CSF in vitro, nor was any induction of primary response genes detected by Northern analysis in response to GM-CSF. Studies to determine internal translocation of the receptor-ligand complex indicated less than 10% of the 125I-GM-CSF internalized was specifically bound to receptors. Primary melanoma cells from five surgical specimens had GM-CSF receptors; Scatchard analysis was performed on one sample, showing 555 sites/cell with a kd of 0.23 nmol/L. These results indicate that human tumor cells may express a low-affinity GM-CSF receptor protein that localizes to the cell surface and binds ligand, but lacks functional components or accessory factors needed to transduce a signal.

Effects of Constitutive Production of Colony-Stimulating Factors by Human Lung Cancer Cells on Invasive Capacity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4211-4211
Author(s):  
Yoshiki Uemura ◽  
Makoto Kobayashi ◽  
Hideshi Nakata ◽  
Tetsuya Kubota ◽  
Hirokuni Taguchi
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Colony Stimulating Factor ◽  
Gelatinase Activity ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract In advanced clinical stage, many cases of lung cancer produce colony-stimulating factors (CSFs), including granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and macrophage-colony stimulating factor (M-CSF). The biological properties of the overproduction of CSFs by tumor cells are not well understood. We previously found that CSFs produced by two lung cancer cell lines, OKa-C-1 and MI-4, which constitutively produce abundant amounts of G-CSF, GM-CSF, and M-CSF, stimulate the tumor’s own growth through an autoctine mechanism. In this study, we examined whether CSFs produced by tumor cells contribute to the invasion of the tumor itself. Invasive behaviors of the cancer cells were stimulated by exogenous CSFs but were suppressed by neutralizing antibodies against the CSFs. Matrix-degrading proteinases also are essential for successful tumor cell metastasis. Gelatin zymographs of conditioned media revealed two major bands of gelatinase activity at 68 and 92 kDa. The enzyme activities at 68 and 92 kDa were significantly enhanced in the presence of each CSF in the cell lines but were suppressed by the antibodies against the CSFs. The two gelatinase bands were characterized as matrix metalloproteinase (MMP)-2 and MMP-9, respectively. Our findings suggest that CSFs produced by tumor cells might be closely associated with the tumor invasion through gelatinase activation in CSF-producing lung cancer cells. In addition, an increase of invasion capacity and gelatinase activity by the CSFs might be mediated through the p44/42 mitogen-activated protein kinase (MAPK) signaling pathway. Figure Figure

scholarly journals Cytokine Working Group Study of Lymphodepleting Chemotherapy, Interleukin-2, and Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Metastatic Melanoma: Clinical Outcomes and Peripheral-Blood Cell Recovery

2010 ◽  
Vol 28 (7) ◽  
pp. 1196-1202 ◽  
Author(s):  
Krishna S. Gunturu ◽  
Kenneth R. Meehan ◽  
Todd A. Mackenzie ◽  
Todd S. Crocenzi ◽  
David McDermott ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Interleukin 2 ◽  
High Dose ◽  
Memory Cells ◽  
Colony Stimulating Factor ◽  
Regulatory Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. Patients and Methods This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m2, day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 μg/m2/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Results The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8+ cells was observed in one of four HLA-A2-positive patients. Conclusion Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

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