Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma.
Therapeutic vaccination with dendritic cells (DC) can lead to tumor regression in animal models and has shown promising results in the first clinical trials of metastatic renal cell carcinoma and malignant melanoma. In vitro data and results of a clinical phase I/II trial using DC tumor fusions in patients with progressive metastatic renal cell carcinoma are presented here. In addition to toxicity and feasibility, complex immune monitoring was a point of interest. DC precursor cells were obtained from the peripheral blood mononuclear cells (PBMCs) of healthy donors and were fused with either allogeneic (8 patients) or autologous (4 patients) renal tumor cells. In total, 12 patients with progressive metastatic renal cell carcinoma were treated with an average of 2.8 x 10(7) tumor cells fused with 1.8 x 10(7) DC each administered on days 0, 28, and 56 intradermally. Fusion efficacy for the tumor cells used was 14.3% +/- 7.8%. Cell viability was 59.8% +/- 6.8% after fusion and irradiation. We observed no adverse effects and no difference in clinical outcome between the allogeneic and the autologous treatment. Eight patients remained in a progressive disease state and four patients in a stable disease state. T-cell immunity was carefully monitored before, during, and after treatment. Delayed-type hypersensitivity (DTH) reaction using tumor cells was positive after treatment in 7 of 12 patients, 2 of whom were found to have stable disease. An increase in the reactivity against recall antigens was seen in most patients. Interestingly, cytotoxicity of peripheral blood lymphocytes (PBLs) against renal cell carcinoma cells increased during treatment as well as the percentage of interferon-gamma-secreting cells. This effect was significantly enhanced within the group that had stable disease. The lack of adverse effects together with positive immunologic signs justifies further investigation of this novel therapeutic approach. Further studies are necessary to test for clinical effectiveness in patients with tumors, especially those with less advanced disease.
Märten
Angela
A
Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Renoth
Sabine
S
Heinicke
Thomas
T
Albers
Peter
P
Pauli
Andreas
A
Mey
Ulrich
U
Caspari
Reiner
R
Flieger
Dimitri
D
Hanfland
Peter
P
Von Ruecker
Alexander
A
Eis-Hübinger
Anna M
AM
Müller
Stefan
S
Schwaner
Ingo
I
Lohmann
Uwe
U
Heylmann
Guido
G
Sauerbruch
Tilman
T
Schmidt-Wolf
Ingo G H
IG
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002459:Cell Fusion; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009362:Neoplasm Metastasis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D019496:Cancer Vaccines; D016207:Cytokines; D007519:Isoantigens