Therapeutic vaccination against metastatic carcinoma by expression-modulated and immunomodified autologous tumor cells: a first clinical phase I/II trial.
Therapeutic vaccination of tumor patients with cytokine gene-transfected tumor cells leads to tumor regression in animal models but has so far not resulted in significant clinical benefit. We and others demonstrated that tumor cells transfected to mediate overexpression of a cytokine gene activate immunologic effector cells for an improved proliferation rate and significantly higher antitumoral cytotoxic activity. Here, we performed a pilot study of therapeutic vaccination in patients with metastatic disease. Autologous tumor cells were simultaneously transfected with novel minimalistic, immunogenically defined, gene expression constructs (MIDGE) for overexpression of the two cytokines interleukin 7 (IL-7) and GM-CSF and newly designed double stem-loop immunomodulating oligodeoxyribonucleotides (d-SLIM) as a Th1-promoting and NK cell-stimulating adjuvant. Transfection was performed ex vivo by ballistomagnetic gene transfer. Patients received four subcutaneous injections of at least 1 x 10(6) of their expression-modulated and immunomodified autologous tumor cells. Ten patients have been enrolled in the study protocol. In all patients no adverse effects could be detected. IL-7 and interferon gamma levels were elevated in the serum of the patients after treatment. Interestingly, cytotoxicity of patient-derived PBLs increased significantly during treatment. All 10 patients had progressive disease when entering our protocol. One complete, one partial, and one mixed response with progression of abdominal metastases and regression of lung metastases were observed. Two patients showed a stable disease after treatment and five patients remained in progressive disease. Our observations confirm the capability of autologous expression-modified and immunomodulated tumor cell vaccines to stimulate a strong immune response in patients with metastatic cancer even in the presence of a large tumor burden.
Wittig
B
B
Centrum Somatische Gentherapie, Fachbereich Humanmedizin, Freie Universität Berlin, 14195 Berlin, Germany.
Märten
A
A
Dorbic
T
T
Weineck
S
S
Min
H
H
Niemitz
S
S
Trojaneck
B
B
Flieger
D
D
Kruopis
S
S
Albers
A
A
Löffel
J
J
Neubauer
A
A
Albers
P
P
Müller
S
S
Sauerbruch
T
T
Bieber
T
T
Huhn
D
D
Schmidt-Wolf
I G
IG
D000368:Aged; D017252:CD3 Complex / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D019496:Cancer Vaccines; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D003110:Colonic Neoplasms / Q000628:therapy*; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007371:Interferon-gamma / Q000096:biosynthesis; D015851:Interleukin-7 / Q000096:biosynthesis / Q000235:genetics*; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009841:Oligonucleotides / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
D017252:CD3 Complex; D019002:CD56 Antigen; D016827:CD8 Antigens; D019496:Cancer Vaccines; D016207:Cytokines; D015851:Interleukin-7; D009841:Oligonucleotides; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA