Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma.
Natural killer-like T lymphocytes termed cytokine-induced killer (CIK) cells have been shown to eradicate established tumours in a severe combined immune deficient (SCID) mouse/human lymphoma model. Recently, we demonstrated that CIK cells transfected with cytokine genes possess an improved proliferation rate and a significantly higher cytotoxic activity as compared to non-transfected cells. Here, in a phase I clinical protocol, autologous CIK cells were generated from peripheral blood obtained by leukapheresis in patients with metastatic renal cell carcinoma, colorectal carcinoma and lymphoma. CIK cells were transfected with a plasmid containing the interleukin-2 (IL-2) gene via electroporation. Transfected cells generated IL-2 in the range of 330-1800 pg 10(-6) cells 24 h(-1) with a mean of 836 pg 10(-6) cells 24 h(-1). Ten patients received 1-5 intravenous infusions of IL-2-transfected CIK cells; five infusions with transfected CIK cells were given. In addition, the same patients received five infusions with untransfected CIK cells for control reasons. In three patients, WHO grade 2 fever was observed. Based on polymerase chain reaction of peripheral blood transfected cells could be detected for up to 2 weeks after infusion. There was a significant increase in serum levels of interferon gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-beta) during treatment. Interestingly, there was also an increase in CD3+ lymphocytes in the blood of patients during therapy. In accordance, a partial increase in cytotoxic activity in peripheral blood lymphocytes (PBLs) was documented when patient samples before and after therapy were compared. Concerning clinical outcome, six patients remained in progressive disease, three patients showed no change by treatment, and one patient with lymphoma developed a complete response. In conclusion, we were able to demonstrate that CIK cells transfected with the IL-2 gene can be administered without major side-effects and are promising for future therapeutic trials.
Schmidt-Wolf
I G
IG
Department of Medicine, Humboldt-Universität zu Berlin, Germany.
Finke
S
S
Trojaneck
B
B
Denkena
A
A
Lefterova
P
P
Schwella
N
N
Heuft
H G
HG
Prange
G
G
Korte
M
M
Takeya
M
M
Dorbic
T
T
Neubauer
A
A
Wittig
B
B
Huhn
D
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007694:Killer Cells, Natural / Q000276:immunology*; D008223:Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D007376:Interleukin-2