Methodology for Anti-Gene Anti-IGF-I Therapy of Malignant Tumours

Abstract

<jats:p>The aim of this study was to establish the criteria for methodology of cellular “anti-IGF-I” therapy of malignant tumours and particularly for glioblastoma multiforme. The treatment of primary glioblastoma patients using surgery, radiotherapy, and chemotherapy was followed by subcutaneous injection of autologous cancer cells transfected by IGF-I antisense/triple helix expression vectors. The prepared cell “vaccines” should it be in the case of glioblastomas or other tumours, have shown a change of phenotype, the absence of IGF-I protein, and expression of MHC-I and B7. The peripheral blood lymphocytes, PBL cells, removed after each of two successive vaccinations, have demonstrated for all the types of tumour tested an increasing level of CD8<jats:sup>+</jats:sup>and CD8<jats:sup>+</jats:sup>28<jats:sup>+</jats:sup>molecules and a switch from CD8<jats:sup>+</jats:sup>11b<jats:sup>+</jats:sup>to CD8<jats:sup>+</jats:sup>11. All cancer patients were supervised for up to 19 months, the period corresponding to minimum survival of glioblastoma patients. The obtained results have permitted to specify the common criteria for “anti-IGF-I” strategy: characteristics sine qua non of injected “vaccines” (cloned cells IGF-I(−) and MHC-I(+)) and of PBL cells (CD8<jats:sup>+</jats:sup>increased level).</jats:p>

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“…Similar results of CD8 typing were observed in immunogene therapy of other tumors (i.e. prostate, colon and liver cancers) [7,12] (Figure 2). In the first step of clinical trial Phase I proposed in Colombia in UNAB University/ Foscal Clinic, three to four cases of every following cancer diseases will be treated: glioblastoma, cancers of prostate and colon [12,13].…”

“…These cells injected into syngeneic animals induced a T-cell mediated immune reaction both against themselves and against their non transfected tumorigenic progenitor cells. IGF-I antisense or triple helix transfectants were shown to elicit a curative antitumor immune response with tumor regression at distal sites [8] Both IGF-I anti-gene therapies: IGF-I antisense and IGF-I triple helix, were introduced in clinical trial of glioblastoma (Cleveland, USA; Bangkok, Thailand; Bromberg, Poland-collaboration with Paris, France), liverhepatocarcinoma (Shanghai, China, and Cracow, Poland), cancers of prostate, colon, liver, uterus and ovary (NATO Science Program-USA, France, Poland, Germany), and melanoma, prostate and colon (Bogota and Bucaramanga, Colombia -clinical study in progress) [5,[7][8][9][10][11]. The first clinical results were very promising and indicated an increase in immune response in vaccinated patients.…”

IGF-I biomarker testing in an ethical context

“…The modified strategy, using anti-gene (antisense/triple helix) anti IGF-I technology, has shown promising results in clinical trials; the median survival of glioblastoma patients reached 21 months and in some cases, reaching up to three to four years. This strategy was also proven to be efficient in the treatment of six different cancer diseases (as reported by the NATO Science program on cancer gene therapy: USA, France, Poland, Germany; 2002-2007) [27,39] . To target specific genetic defects, different kinds of molecules (antibodies, antisense oligodeoxynucleotides, antisense cDNAs, short peptides, and other small molecules) have been employed.…”

“…Among them, serum albumin, transferrin, AFP [2] , growth hormones such as epithelial growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta), and especially IGF I and II [20,21] reappear in neoplastic developing tissues [3,4,6,22] such as in brain, liver, prostate, ovarian, colon, and uterus cancers [23][24][25][26][27] .…”

“…Genetic engineering has allowed the isolation and manipulation of genes to take place. Its impact has been particularly important as it has led to the creation of transgenic animals used as experimental models for research and the observation of genetic diseases, and to the creation of organic substances for therapeutic purposes through the process of enabling or disabling of a gene [6,27,[94][95][96][97] . The creation in the early 1990s of a new medical domain, termed gene therapy, has become the most important revolution in the treatment of different diseases such as cancers, infections, and fetal diseases.…”