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

Schmidt‐Wolf, Ingo G.H.; Finke, Sebastian; Trojaneck, Beate; Denkena, A.; Lefterova, Petja; Schwella, N.; Heuft, H G; Prange, G.; Korte, MA de; Takeya, Motohiro; Dorbic, Tomislav; Neubauer, Andreas; Wittig, Burghardt; Huhn, D.

doi:10.1038/sj.bjc.6690800

Cited by 204 publications

(134 citation statements)

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“…IL2 is mainly produced by T cells during their activation and enhances their own expansion. 20,21 Production of IL2 is diminished in many patients with cancer due to T cell anergy [45][46][47] and several phase I studies [23][24][25][26]48 have shown that administration of Ad5-IL2 gene-modified tumor cells can induce specific antitumor responses mediated by T cells. Although successful in these studies in solid tumors, Ad5-IL2 is limited in gene therapy of hematopoietic malignancies by its low efficacy of infection and by a high toxicity.…”

Section: Discussionmentioning

confidence: 99%

Efficient infection of primitive hematopoietic stem cells by modified adenovirus

et al. 2001

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Almost all studies of adenoviral vector-mediated gene transfer have made use of the adenovirus type 5 (Ad5). Unfortunately, Ad5 has been ineffective at infecting hematopoietic progenitor cells (HPC). Chimeric Ad5/F35 vectors that have been engineered to substitute the shorter-shafted fiber protein from Ad35 can efficiently infect committed hematopoietic cells and we now show highly effective gene transfer to primitive progenitor subsets. An Ad5GFP and Ad5/F35GFP vector was added to CD34 + and CD34 − lineage − (lin − ) HPC. Only 5-20% of CD34 + and CD34 − lin − cells expressed GFP after Ad5 exposure. In contrast, with the Ad5/F35 vector, 30-70% of the CD34 + , 50-70% of the CD34 − lin − and up to 60% of the CD38 − HPC expressed GFP and there was little evident cellular toxicity. Because of these improved results, we

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Section: Discussionmentioning

confidence: 99%

Efficient infection of primitive hematopoietic stem cells by modified adenovirus

et al. 2001

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“…NK -like T cells are established effector cells with clinical relevance. 21 Many tumors do not elicit an antigen-specific T-cell response, which may be due to the absence of functional DCs or failure of induction of effector cells in patients with tumor. 2 Recently, DCs have been used in several studies to increase the cytotoxic activity of immunologic effector cells in vitro or in vivo.…”

Section: Discussionmentioning

confidence: 99%

Transfection of dendritic cells (DCs) with the CIITA gene: increase in immunostimulatory activity of DCs

et al. 2001

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Dendritic cells ( DCs ) are the major antigen -presenting cells. They are able to present tumor antigens to immunologic effector cells. MHC class II molecules on DC surfaces play an important role in priming effector cells against tumor cells and their antigens. The transactivator CIITA ( MHC class II transactivator ) is a non ± DNA -binding transactivator, which regulates the expression of MHC class II, HLA -DM, and invariant chain and behaves as a master controller of constitutive and inducible MHC class II gene activation. Here, we transfected DCs with the CIITA gene using a novel transfection technique. The vector system consisted of a plasmid bound to an adenovirus via poly -L -lysine, which is covalently bound to a UV -irradiated adenovirus. After transfection, expression of MHC class II on DCs increased from 27% to 75% on day 2 after transfection. Transfected DCs were co -cultured with immunologic effector cells. Cytotoxicity of effector cells against tumor cells increased after co -culture with transfected DCs to 63% compared to 15% with effector cells co -cultured with irrelevantly transfected DCs ( P = .037 ) . This effect was dependent on the timing and period of coculture. In conclusion, transfection of DCs led to an increase in antitumoral immunostimulatory capacity of DCs. We can further conclude that DCs could be efficiently transfected with the CIITA gene. Transfection of DCs led to an increase in antitumoral immunostimulatory capacity of DCs and may have a major impact on immunotherapeutic protocols for patients with cancer.

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“…A number of studies [20,21] have illuminated that CIK possessed much stronger cytotoxicity than LAK to several kinds of cancer such as leukemia, renal cell carcinoma, melanoma [22] , and proved that dendritic cells increased in serum of host after transfusion of CIK to HCC patients. Here we demonstrated CIK cells from HCC patients could equally kill drug-resistant HCC cell line as those from normal.…”

Section: Discussionmentioning

confidence: 99%

“…A triplicate of same samples was placed to control variation. Cells were incubated at 37 ℃ with 50 mL/L CO 2 for 48 h prior to the addition of 10 L of MTT [18,20] (5 g/L, Sigma). After another 4 h of incubation, the plate was centrifuged at 3 000 r/min for 5 min, medium was discarded, 150 L of DMSO was added to each well.…”

Section: Drug-resistance Testmentioning

confidence: 99%

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

Youshun¹

2005

WJG

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AIM:To investigate the cytotoxicity of the cytokine-induced killer (CIK) cells from the post-operation patients with primary hepatocellular carcinoma (HCC) to multidrugresistant (MDR) cell of HCC both in vitro and in vivo. METHODS:A drug-resistant cell line was established by culturing human HCC cell line Bel-7402 in complete RPMI 1640 medium with increasing concentrations of adriamycin from 10 to 2 000 nmol/L. CIK cells were obtained by inducing the peripheral blood mononuclear cells with rhIFN-, monoclonal anti-CD3 antibody, rhIL-1 as well as rhIL-2, which were added into the culture. To detect the cytotoxicity of the CIK cells from HCC patients, the Bel-7402/R was taken as target (T) cells and CIK cells as effect (E) cells. Cytotoxic test was performed and measured by MTT. As to in vivo test, CIK cells were transfused into patients with HCC. The tumor specimens of the patients were obtained and immunohistochemistry was carried out to detect CD3, CD45, CD45RO as well as CD68. RESULTS:A MDR 1 HCC cell line Bel-7402/R was established. Its MDR1 mRNA overexpressed which was shown by RT-PCR; the P-glycoprotein expression increased from 1.32% of parent cells to 54%. CIK cells expanded vigorously by more than 70-fold and the CD3+CD56+ increased by more than 600-fold after 3-wk incubation on average. The cytotoxicity of CIK from HCC patients to Bel-7402/R was about 50% and to L-02 below 10% (t = 8.87, P<0.01), the same as that of CIK from normal individuals. Each of the 17 patients receiv ed 1 -5×10 10 of CIK cell transfusion. No side effects were observed. After CIK treatment, the tumor tissue nodules formed and a large amount of lymphocytes infiltrated in the liver cancer tissue and CD3, CD45, CD45RO, and CD68 increased greatly which was shown by immunohistochemistry. CONCLUSION:A stable MDR1 HCC cell line has been established which could recover from liquid nitrogen and CIK from HCC patients has strong cytotoxicity to MDR HCC cell. CIK adoptive immunotherapy is safe and has no side effects. Receivers improved their immunity to tumor evidently. CIK treatment may be a better choice for HCC patients after operation to prevent the recurrence, especially when tumors have developed drug resistance.

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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

Cited by 204 publications

References 22 publications

Efficient infection of primitive hematopoietic stem cells by modified adenovirus

Efficient infection of primitive hematopoietic stem cells by modified adenovirus

Transfection of dendritic cells (DCs) with the CIITA gene: increase in immunostimulatory activity of DCs

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

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