Open access peer-reviewed chapter

Neoplastic Brain, Glioblastoma, and Immunotherapy

Written By

Annabelle Trojan, Heliodor Kasprzak, Oscar Gutierrez, Pedro Penagos, Ignacio Briceno, Heber O. Siachoque, Donald D. Anthony, Alvaro Alvarez and Jerzy Trojan

Submitted: September 17th, 2018 Reviewed: January 25th, 2019 Published: January 29th, 2020

DOI: 10.5772/intechopen.84726

Chapter metrics overview

745 Chapter Downloads

View Full Metrics

Abstract

IGF-I, insulin-like growth factor 1, is present in normal fetal/neonatal brain development and reappears in the mature brain participating in the development of malignant tumor, glioblastoma multiforme. Targeting the IGF-I system has emerged as a useful method to reduce glial malignant development. Downregulation in the expression of IGF-I using antigene anti-IGF-I technology (antisense, AS, and triple helix, TH) applied in glioma cell culture established from glioblastoma biopsies induces the expression of B7 and MHC-I antigens in transfected cells (immunogenicity). The transfected cancer cells, “vaccines,” after subcutaneous injection, initiated an immune response mediated by T CD8+ lymphocytes, followed by tumor regression (immunotherapy). The median survival of patients treated by surgery followed by radiotherapy and immunotherapy was 21–24 months. On the other side, the experimental work has demonstrated that IGF-I AS or TH transfected tumor cells fused with activated dendritic cells, DC, showing more striking immunogenic character. Using IGF-I TH/DC “vaccination,” the efficiency in suppressing rat glioma tumors is not only relatively higher than that obtained using IGF-I TH cells but is also more rapid.

Keywords

  • brain neoplastic development
  • glioblastoma
  • IGF-I
  • antisense
  • triple helix
  • immunogene therapy
  • cell hybridomas
  • dendritic cells
  • CD8

1. Introduction

There is a convergence between onto-genesis and onco-genesisgenesis and the same specific oncoproteins like alpha-fetoprotein (AFP) or growth factors, such as IGF and TGF-beta, are present in embryo/fetal tissues and in neoplastic developing tissues and particularly in the central nervous system (CNS). As far as AFP and IGF-I are considered, there is an important remarque: the first antigen is present in both neural and glial developing and cancerous cells, whereas the second one is only present in glial developing and tumoral cells. This striking difference has oriented our studies toward the most malignant brain tumor expressing IGF-I gene: glioblastoma.

In this chapter, we have described our scientific approach coming from the analysis of neoplastic CNS development conducted to glioblastoma malignancy up to the establishment of immunogene therapy of this tumor: the first cancer immunogene therapy. The strategy of therapy consisted of blocking IGF-I synthesis in cancer cells inducing apoptotic and immunogenic phenomena. Both phenomena, related to the arrest of IGF-I expression in neoplastic glial cells, were used to prepare antitumor cell vaccines for therapy of glioblastoma. Successful clinical results were obtained in USA, EU, and China and the therapy is introduced in Colombia (Wikipedia—Gene therapy, History 1990s–2010s).

Advertisement

2. Neoplastic brain

To understand the morphology of CNS neoplastic development, the model of mouse teratocarcinoma derived from PCC3 and PCC4 embryonal carcinoma cell lines was investigated. Thanks to this unique model reproducing “caricatural” development of the normal CNS, after examining histologic and electron microscopy sections, the different stages of abnormal nervous tissue histogenesis [1, 2, 3, 4] were established as follows: 1. undifferentiated carcino-embryonic structures; 2. medulloepithelial structures (composed of a mixture of ectoblastic and neuroectoblastic components); 3. neuroblastic structures; and 4. neuroepithelial structures. The final differentiation was the encephaloid tissue. These results were confirmed by studying the localization of oncoproteins as alpha-fetoprotein (AFP), serum-albumin (SA), and IGF-I directly included in normal and neoplastic histogenesis, the last using teratocarcinoma model [3, 5, 6, 7, 8].

As to the application of these observations in the pathology of human central nervous system (CNS) tumors, the model of mouse teratocarcinomas, containing neuroglial structures [3, 6, 9, 10] (described in the first studies of Stevens and then by his followers during almost 40 years of investigations [11, 12, 13, 14, 15, 16, 17, 18, 19, 20]), should be useful as well in understanding human embryonic tumors of the CNS, which are able to differentiate into both neuronal and glial lineages [1, 10, 21, 22, 23], as in future gene therapies, including CNS malignant tumors [24, 25, 26, 27].

Advertisement

3. IGF-I

In 1992, Trojan and his coworkers demonstrated that another oncodevelopmental antigen, an insulin like-growth factor, IGF-I [28, 29, 30, 31, 32], is present in glioma cells but absent in neuroblastoma cells [33]. Using the teratocarcinoma model, Trojan and his coworkers showed that neoplastic neuroblastic cells express IGF-II [34]. These observations permitted to study separately, using IGF-I and IGF-II as the oncoprotein markers, different tumors, especially glial and neural tumors [28, 29, 30, 31, 35, 36, 37, 38, 39, 40].

Comparative studies of the presence of AFP, IGF-I, and IGF-II in neoplastic cells [3, 33, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49] have demonstrated that IGF-I constitutes an essential target for genetic testing and therapy purpose. IGF-I, similar to AFP, is involved in tissue development and differentiation, especially in the development of the nervous system [6, 50, 51] as a mediator of growth hormone and glucose metabolism and acting locally with autocrine/paracrine, with a predominant role compared to other growth factors [29, 39, 51, 52, 53, 54, 55]. IGF-I is currently considered as one of the most important growth factors related to normal and neoplastic differentiation, and its overproduction is considered to be a participating factor in cancer development [32, 54, 56, 57, 58] (Figure 3). IGF-I reconstitutes the first step of the following signal transduction pathway: IRS/PI3K-PKC/PDK1/AKT-Bcl2/GSK3/GS [59, 60]. The elements of the said IGF-I-related transduction pathway were also considered as targets for diagnostic and therapeutic purposes [51, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70].

Considering the IGF-1 gene, an overexpression of this gene in mature tissues is a sign of neoplastic processes, especially brain tumors [40]. IGF-I becomes useful in the molecular diagnosis of neonatal CNS malformations and tumors [9, 21, 38, 51, 71, 72]. Diagnosis and treatment should logically be related, at first using IGF-I gene testing for diagnosis [73, 74, 75] and then targeting IGF-I gene through special therapy, such as cancer gene therapy, especially therapy of gliomas [40, 76, 77, 78, 79].

Advertisement

4. Gene therapy

4.1 Introduction

IGF-I and -II are expressed at high levels in nervous system–derived tumors, for example, astrocytomas and meningiomas [37, 44, 80]. In contrast, the block of IGF-I synthesis in these tumors induces apoptotic and immunogenic phenomena [81].

Our experimental approach of gene therapy has centered on the comparative use of IGF-I RNA antisense and IGF-I RNA–DNA triple helix [82, 83], to stop the translation and transcription of the IGF-I gene, respectively. Triple helix strategy [84, 85] and antisense strategy [86, 87, 88] have been applied successfully to a growing number of genes in cultured cells. However, the antisense approach has sometimes been not completely efficient due probably to insufficient antisense RNA levels [89].

We have applied the antisense strategy by employing a self-amplifying episomal vector that replicates to high copy numbers extrachromosomally [33]. The utility of episome-based expression vectors for the effective inhibition of cellular RNA expression has been subsequently confirmed by others [90]. C6 rat glioma cells expressed MHC-I [91, 92] and B7 [55, 93, 94] antigens when transfected with vectors producing IGF-I antisense RNA (IGF-I AS) or inducing IGF-I triple helix RNA-DNA (IGF-I TH) [95, 96]. IGF-I AS or IGF-I TH blockade of IGF-I syntheses changes the phenotype of transfected CNS-1 and PCC-4 cells. Moreover, it was demonstrated that transfected C6 cells become pro-apoptotic [96]. The AS and TH cells lost tumorigenicity and were able to induce a T-cell–mediated immune response in syngeneic animals against both themselves and the nontransfected tumorigenic parental cells [34, 40, 82, 97]. The experiment described here has permitted us to prepare human “vaccine” for a Phase 1 clinical trial.

4.2 Material and methods

Cell culture.The CNS-1 cell line was offered by the Dartmouth Medical School, Hanover, NH, USA (Dr W. Hickey) and then cultivated in the Laboratory of INSERM, Salpetriere Hospital, Paris (Dr M. Sanson). The PCC-4 cell line was provided by Institut Pasteur, Paris (Dr J.F. Nicolas). The cell lines were cultivated as described earlier [97]. Primary cell cultures of human glioma derived from tumors of glioblastoma multiforme patients were established (Clinical Laboratory of Collegium Medicum, UJ University, and School of Medicine, CWRU) according to the technique described earlier [96, 98, 99, 100] (Figure 1).

Figure 1.

In vitrostaining of IGF-1 biomarker human in human glioma cell culture. The tissue and cells are stained for IGF-1 using anti-IGF-1 antibodies applied in immunoperoxidase technique. Nine days of culture established from human glioblastoma biopsy. (left down) Note the cells (head arrows) proliferating from compact tissue of biopsy (left down corner) (200×); (right up) Note the cluster of cells showing dark cytoplasm of staining (400×).

Plasmids.The vector pMT-EP [6, 26] was described earlier [33] (Figure 2). IGF-I “antisense” and “triple helix” technology was used to construct episome-based plasmids expressing IGF-I RNA antisense, pMT-anti IGF-I [26], or IGF-I triple helix–inducing vector, pMT-AG TH [33, 82]. The vector pMT-EP containing cDNA expressing IGF-II antisense RNA as insert was used in control experiments [34]. In parallel, using the vector pMT-EP, the vectors expressing MHC-I and B7, as well as vectors “antisense” MHC-I and B7, were prepared [96].

Figure 2.

Diagrammatic representation of steps employed to construct the episomal vector pMT/EP used for preparation of IGF-I antisense and triple helix expression vectors.

Transfection.The FuGENE 6 Transfection Reagent (Boehringer Mannheim) was used. Hygromycin B (Boehringer Mannheim) at a concentration of 0.05 mg/ml was added 48 h after transfection to select for transfected cells.

Northern blot.The content of IGF-I antisense RNA was determined in 50% confluent cell cultures. Northern blot and hybridizations were done according to Maniatis [98]; the 770 bp human IGF-I cDNA and 500 bp rat IGF-I cDNA were used as probes (Figure 3).

Figure 3.

Antisense transcripts in cultured C6 glioma cells. Molecular sizes of IGF-I transcripts are shown in kilobases. Lane 1, parental nontransfected C6 glial cells exposed to serum-free medium. Lanes 2 and 3, transfected C6 glioma cells incubated in serum-free medium in the absence (lane 2) or presence (lane 3) of ZnSO4. For lanes 2 and 3, nick-translated rat IGF-I cDNA was used.

Flow cytometric analysis.Cells were incubated (30 min, 40°C) with saturated amounts of monoclonal antibodies, rat or human MHC-I (HLA ABC), MHC- II, CD80, and CD86 (Becton Dickinson Pharmingen). Cells were collected (10.000 events per sample) in FACScan BD cytometer (Figure 4).

Figure 4.

Flow cytometry analysis (FACScan Becton Dickinson). Expression of MHC-I (left) and B7 (right) in primary human glioblastoma cell line. Upper panels: non transfected cells; lower panels: transfected cells (upregulation of MHC-I and B7).

Ex vivo generation of dendritic cells.Two techniques for the generation of dendritic cells were used:

  1. CD34+ hematopoietic progenitor cells were isolated, using the MACS CD34 Cell Isolation Kit, and functional DC cells were generated by culturing CD34+ cells in the presence of GM-CSF, TNFalpha, and SCF for 10 days [101].

  2. Monocytes were isolated, using MACS CD14 MicroBeads. Monocytes were cultured in the presence of GM-CSF and IL-4 generated activated DCs [102].

Hybridomas of transfected cells with dendritic cells.The fusion of dendritic cells with tumor transfected cells was obtained as follows [103]: activated DCs (one of the two techniques mentioned above) were fusioned with tumo IGF-I antisense or triple helix transfected cells using polyethylene glycol—PEG [104]. Fusions were carried out with 40% PEG in PBS without Ca2+ and Mg2+.

In vivo experiment.For the determination of tumorigenicity, 5 x 106 rat CNS-1 cells were injected subcutaneously into Lewis rats. Experimental sets were injected with: (a) parental cells; (b) IGF-I “triple helix” transfected cells expressing MHC-I; and (c) IGF-I “triple helix” transfected cells expressing both MHC-I and B7 molecules.

4.3 Results and discussion

Northern blot analysis is shown in Figure 3. The RNA of nontransfected cells is distributed in 7.5 and 1.0 kb bands. The RNA of anti-IGF-I transfected cells shows only an abundant 1.0 kb band. The transfected cultures were positively stained either for both MHC-I and B7 antigens (in 60% of cloned lines) or for MHC-I (only in 40% of cloned lines). The data show that transfection with “antisense” and “triple helix” vectors induced a significant increase in the expression of MHC-I and B7 (Table 1). The “triple helix” rat and human cells as compared to “antisense” cells showed slightly higher expression of MHC-I or B7. As to apoptosis, it was detected in approximately 70% of the IGF-I antisense and triple helix transfected cells. As expected, the hybridomas of IGF-I triple helix or IGF-I antisense cells fused to activated dendritic cells, IGF-I TH//DC or IGF-I AS//DC, were negative for IGF-I. The most important observations concerned the increased level of MHC-I and MHC-II, and especially the presence of B7 in IGF-I TH//DC and IGF-I AS//DC hybridomas (Table 1). No tumors were observed in animals injected subcutaneously with CNS-1 cells transfected with IGF-I “triple helix” vector, expressing both MHC-I and B7.

CellsRat glioma CNS-1 cells
MHC-IMHC-IIB7
NT<0.5<0.5<0.5
IGF-I AS12.3<0.518.1
IGF-I TH14.6<0.519.6
IGF-I AS/IGF-I TH12.8<0.518.4
IGF-I AS/MHC-I AS/B7 AS1.0<0.51.0
IGF-I TH/MHC-I AS/B7 AS1.0<0.51.0
IGF-I AS//DC14.73.819.3
IGF-ITH//DC16.94.221.9

Table 1.

Expression of MHC-I, MHC-II, and B7 in the cells of rat glioma.*

The data of flow cytometry (the average of three experiments) are presented as percent change in value of fluorescence relative to fluorescence in control nontransfected cells (CC). The increase in MHC-I, -II, and B7 is significant at the P < 0.01 level (Wilcoxon’s signed rank test).


NT: parental nontransfected cells; pMT-EP: cells transfected with “empty vector”; IGF-I AS or IGF-II AS: cells transfected with IGF-I or IGF-II antisense expression vector; IGF-I TH: cells transfected with IGF-I triple helix expression vector; IGF-I AS/IGF-I TH: cotransfection with antisense and triple helix vectors; IGF-I AS/MHC-I AS/B7 AS, and IGF-I TH/MHC-I AS/B7 AS: triple cotransfection with IGF-I antisense or triple helix, MHC-I antisense and B7 antisense expression vectors; IGF-I TH//DC or IGF-I AS//DC: cells transfected with IGF-I antisense or triple helix expression vectors, and fused to dendritic cells.

The simultaneous increase in the presence and role of B7 and MHC-I antigens in the induction of T-cell immunity against tumors has been extensively investigated [33, 93, 94]. The injection of IGF-I antisense and triple helix transfected cells presenting both MHC-I and B7 molecules stopped effectively the established rat glioma tumors. This was not the case for cells expressing MHC-I only (Table 1). Injection of cell hybridomas composed of IGF-I antisense cells and activated dendritic cells (IGF-I AS//DC) into tumor-bearing animals suppressed the established glioma tumors in 4/6 cases of Lewis rats. The experience was repeated using cell hybridomas composed of IGF-I triple helix cells and activated dendritic cells (IGF-I TH//DC). In this case, the subcutaneous injection of the hybridomas into glioma-bearing animals completely suppressed tumors in a ratio 6/6.

MHC-I molecules were in general not sufficient to stimulate T-cell response. In the absence of B7 molecule, MHC-peptide complexes could selectively inactivate T cells [105]. B7 molecules bound to the counter-receptor CD28 and/or CTLA4 expressed on the T cells [9, 106, 107]; enhancement in B7 costimulation through a cAMP mechanism linked to tyrosine kinase of the CD28 receptor has been previously reported [108]. The mechanism of signaling (tyrosine kinase activates IRS-1, and then IRS-1 activates PI3K [109, 110]) could be considered in the cytokine induced B7-1 expression demonstrated in fetal human microglia in culture [111].

Using CNS-1 glioma, we have confirmed the relation between the immunogenicity and apoptosis found in IGF-I transfected cells [96]. The phenotypic modifications due to apoptosis may explain the recognition of the transfected cells by the immune system like tumor-specific immunity mediated by CD8+ T described earlier by us [40, 98]. Apoptotic cells, in the context of MHC-I, are recognized by dendritic cells activating lymphocytes T-CD8 [112, 113]. B7 molecules can be included in this mechanism, because both MHC-I and B7 molecules are necessary for T-cell activation [4, 55, 79, 93, 114, 115, 116]. Considering the role of dendritic cells, the presented results may be useful in introducing IGF-I TH//DC “vaccines” into cellular therapy of human gliomas. Moreover, the obtained results of tumor suppression are in agreement with the immunogenic character of used “vaccines”—the efficiency of “vaccines” being related to the expression level of MHC-I, -II, and B7 (Table 1) [97, 117, 118, 119].

Advertisement

5. Clinical gene therapy

5.1 Methodology

Using radiotherapy and chemotherapy, the mortality of glioblastoma remains close to 100% and the median survival, using conventional therapy, is 9–14 months. Current pharmacology increases the survival to 15 and rarely to 18 months [120]. The etiology of glioma is still being investigated using molecular biology techniques [64]. New or proposed therapies are based either on immune treatment or on immuno-gene strategies [121]. The AS and TH technologies [84, 85, 86, 87] have permitted us to establish new and successful immuno-gene therapy strategies targeting glioma’s growth factors [40, 122]. Other technologies include those of potentially useful siRNA [123, 124] and miRNA (microRNA) [125]. The role of 21–23mer double-stranded RNA (siRNA) in the silencing of genes is strongly similar to that of the TH DNA mechanism, which also involves 23mer RNA [85]. Whether or not siRNA technology or miRNA knockdown will supplant the AS oligodeoxynucleotide approaches remains in question at this time [124, 126, 127]. The AS oligodeoxynucleotides reinforced by association with polycations (polyethyleneimine), polylysine, or cationic lipids (DOTMA, DOTAP) were also used for transfection of cells with plasmids encoding antisense RNA [128].

As to growth factors, historically, first IGF-I and its receptor and then TGF-beta were targeted in experimental preclinical studies [40, 57, 122, 129, 130] and then glycogen synthase, GS [51]. The absence of IGF-I, TGF-beta, and GS synthesis in “AS” transfected cells leads to a compensated increase in IGF-I-receptor [51] (relation between the signal transduction pathway of tyrosine kinase (IGF-I-R) and the induction of B7 [131]). Other growth factors such as EGF and VEGF, and their receptors, have also been investigated by AS technology in preclinical studies. The in vitroand in vivoresults were similar to the results obtained with AS IGF-I technology [51, 130]. Thus IGF-I via IGF-I-R not only increases cell proliferation but also “supervises” mitogenic action of other growth factors (EGF, PDGF, etc.) by its autocrine-paracrine stimulation, becoming some kind of growth factor director. In clinical IGF-I antisense/triple helix immunotherapy, the cells used for “vaccination” were downregulated in IGF-I and presented both MHC-I and B7.1 molecules (Figure 4).

5.2 Results and discussion

The first clinical assay for human GBM using AS IGF-I approach was performed by Anthony et al. and by Trojan et al. [96, 100, 114]. After each of three AS IGF-I vaccinations, there was an increase in the percentage of CD8+T cells in peripheral blood lymphocytes with a characteristic phenotype—switch CD8+CD11b+/CD8+CD11b(Figure 5). In patients with GBM treated in Bromberg (NATO Science Programme—U.S.A./France/Poland), life from time of diagnosis to time of demise was 19 and 24 months.

Figure 5.

Antisense immunotherapy. Example of antisense anti-IGF-I treatment of glial malignant tumor—glioblastoma. The schema of therapy shows transfectedin vitrobrain tumor glial cells using a vector containing cDNA of IGF-I in antisense orientation. After transfection, the cells express IGF-I RNA antisense stopping the IGF-I synthesis characteristic for tumor cells. They become MHC-I [+] and B7 [+], and partially apoptotic. The transfected cells, together with apoptotic cells and APC cells inducedin vivo,activate T lymphocytes (CTL CD8+CD28+). Abbreviations used in signal transduction pathway: TK (tyrosine kinase of growth factors receptor); PI3K (phosphatidylinositol 3 kinase); PKC (protein kinase C); TAP 1,2 (transporter associated with antigen processing antigen); APC (antigen presenting cell).

Histopathologic examination of resected tumors showed peritumor necrosis and infiltration by lymphocytes CD8+T and CD4+T cells [100]. Moreover, we can underline, as described in our previous studies [51], that using anti-IGF-I approach without chemotherapy, median survival in GBM-treated patients has reached 19 months and has increased to more than 21 months (NATO Programme) when applied in combination with chemotherapy (temozolomide). The individualized therapy using IGF-I antigene treatment and pharmacology (temozolomide) has been applied in phase I/II trials [132].

In 2001, simultaneously with the first assay with AS IGF-I, Andrews et al. [133] treated 12 patients with recurrent glioblastoma and anaplastic astrocytoma using an antisense to IGF-I receptor, AS IGF-I-R, strategy. Histological analysis of tumors resected from patients with disease progression revealed lymphocytic infiltration and necrosis [133]. As new experimental therapies and efficient viral vectors expressing AS IGF-I-R are being developed, clinical trials using this approach will increase [66, 133, 134].

The approach of AS TGF-beta using an AS oligodeoxynucleotide, compound AP 12009, has given satisfactory results [135, 136, 137]. In another clinical AS TGF-beta study, a phase I clinical trial in grade IV astrocytoma (GBM) was performed using autologous tumor cells modified by an AS TGF-beta2 vector. There were indications of humoral and cellular immunity induced by the vaccine [138].

Advertisement

6. Conclusions

The clinical strategies of glioma treatment, using either inhibitors (i.e., imatinib and gefitinib) or antibodies (i.e., Avastin) targeting growth factors and their receptors [139, 140, 141, 142, 143], are currently focusing on antisense technology combined with pharmacological treatment.

The neuro-oncology research on glial cells focuses on the PI3K/AKT pathway becoming a potential target in antisense/triple helix strategy for the treatment of glioblastoma patients [59, 69]. The arrest of at least two links either IGF-I or TGF-beta or VEGF and GS of the pathway TK/PI3K/AKT/GSK3/GS [64] seems to be in line for a future clinical gene therapy trial strategy for treatment of GBM. The final result of this signal transduction pathway element inhibition is an immune response mediated in vivoby lymphocytes T CD8 and APC cells (Figure 5). But the near future in treating this group of disorders belongs to a combination of treatment [4, 42, 70, 79, 115, 130, 144, 145, 146, 147, 148, 149, 150]: classical surgery; radiotherapy with immunotherapy, including the use of dendritic cells pharmacologic therapy; growth factor inhibitors; and the use of the antisense/triple helix gene blockade approach targeting signal transduction pathway elements of cancer processes.

Advertisement

Conflict of interest

No conflict of interest.

References

  1. 1. Gaillard J, Caillaud JM, Maunoury R, et al. Expression of neuro-ectoblast in murine teratocarcinomas: Electron-microscopic and immunocytochemical studies, applications in embryology and in tumor pathology of central nervous system. (in French. Bulletin Institut Pasteur. 1984;82:335-385
  2. 2. Trojan J, Gaillard J, Vedrenne C, et al. Localization of H blood group antigen in ectoblastic derivatives of murine teratocarcinoma. Tumour Biology. 1987;8:9-18
  3. 3. Trojan J, Naval X, Johnson T, et al. Expression of serum albumin and of alphafetoprotein in murine normal and neoplastic primitive embryonic structures of teratocarcinoma. Molecular Reproduction and Development. 1995;42(4):369-378
  4. 4. Castillo T, Trojan A, Noguera MC, et al. Epistemiologic experience in elaboration of molecular biology technology for immunogene therapy (in Spanish). Revista Cientifica. 2016;2(25). DOI: 10.14483/udistrital.jour.RC.2016.25.a6
  5. 5. Trojan A, Aristizabal B, Jay LM, et al. Testing of IGF-I biomarker in an ethical context. Advances of Modern Oncology Research. 2016;2(4). DOI: 10.18282/amor:v2:i4.58
  6. 6. Trojan J, Uriel J, Deugnier MA, Gaillard J. Immunocytochemical quantitative study of alphafetoprotein in normal and neoplastic neural development. Developmental Neuroscience. 1984;6:251-259
  7. 7. François JC, Duc HT, Upegui-Gonzalez LC, et al.Alterations in tumorigenicity of embryonal carcinoma cells by IGF-I triple-helix induced changes in immunogenicity and apoptosis. Life Science. 2001;68(3):307-319
  8. 8. Trojan J, Kasprzak H, Anthony D. How to stop glial neoplastic brain development: Antisense strategy. In: Bezerra MF, Alves CR, editors. Glioblastoma: Risk Factors, Diagnosis and Treatment Options. NY: Nova Science Publishers, Inc; 2012. pp. 1-14. ch. 6
  9. 9. Harding BN, Golden JA. Developmental Neuropathology. Basel, Suiss: International Society of Neuropathology; 2004
  10. 10. Dambska M, Wisniewski K. Normal and Pathologic Development of the Human Brain and Spinal Cord. London: Ed. John Libbey & Comp; 1999
  11. 11. Stevens LC. Studies on transplantable testicular teratoma of strain 129 mice. Journal of National Cancer Institut. 1958;20:1257-1276
  12. 12. Willis RA. Nervous tissue in teratomas. In: Minckler J, editor. Pathology of the Nervous System. Vol. 2. Hamburg: McGraw-Hill. pp. 1971, 1937-1943
  13. 13. Damjanow I, Solter D, Serman D. Teratocarcinoma with the capacity for differentiation restricted to neuro-ectodermal tissue. Virchows Archives B: Zell Pathology. 1973;13:179-185
  14. 14. Gaillard JA. Differentiation and organization in teratomas. In: Sherbert GV, editor. Neoplasia and Cell Differentiation. Basel: Karger. p. 1974
  15. 15. Stevens LC, Varnum DS. The development of teratomas from part thenogenetically activated ovarian mouse eggs. Developmental Biology. 1974;37:369-380
  16. 16. Gaillard JA. Experimental teratocarcinoma. Localisation of embryonal bodies inoculated into syngeneic mouse abdominal cavity (in French). Bulletin Cancer. 1976;63:341-352
  17. 17. De Armond SJ, Vandenberg SR, Herman MH. Neural differentiation in the OTT 60-50 mouse teratoma: Effects of intracerebral environment on the neural differentiation of embryoid bodies. Virchows Archives B: Zell Pathology. 1981;393:39-52
  18. 18. Nogales FF Jr, Aguilar D. Neural tissues in human teratomas. In: Damjanov I, Knowles BB, Solter D, editors. The Human Teratomas. Clifton: Humana Press; 1983
  19. 19. Trojan J, Gaillard JA, Uriel J. Localisation of alphafetoprotein in neuroepithelial derivatives of mouse teratocarcinoma (in French). Annales of Pathology. 1983;3:137-145
  20. 20. Haugen OA, Taylor CR. Immunohistochemical studies of ovarian and testicular teratomas with antiserum to glial fibrillary acid protein. Acta Pathologica Microbiologica Scandinavia (Sect A). 1984;92:9-14
  21. 21. Love S, Arie Perry A, Ironside J, Budka H. Greenfield’s Neuropathology. 9th ed. NY: CRC Press; 2015
  22. 22. Kleihues P, Luis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. Journal of Neuropathology & Experimental Neurology. 2002;3(61):215-225. DOI: 10.1093/jnen/61.3.215
  23. 23. Benedetti E, Galzio R, D’Angelo B, et al. PPARs in human neuroepithelial tumors: PPAR ligands as anticancer therapies for the most common human neuroepithelial tumors. PPAR Research. 2010:401-427. DOI: 10.1155/2010/427401
  24. 24. Walther W, Stein US. Gene Therapy of Cancer. Methods and Protocols. NY: Human Press; 2009
  25. 25. Templeton NS. Gene and Cell Therapies. FL: CRC Press; 2009
  26. 26. You Y. Targets in Gene Therapy. Vienna, Riyeka: InTech; 2011
  27. 27. Lichtor T. Evolution of the Molecular Biology of Brain Tumors and The Therapeutic Implications. Vienna, Riyeka: InTech; 2013
  28. 28. Daughaday WH, Hall K, Raben MS, et al. Somatomedin: Proposed designation for sulphation factor. Nature. 1972;235:107
  29. 29. Froesch ER, Schmid C, Schwander J, Zapf J. Actions of insulin-like growth factors. Annual Review of Physiology. 1985;47:443-467
  30. 30. Han VKM, Hill DJ. In: Shofield PN, editor. The Insulin-Like Growth Factors: Structure and Biological Functions. Oxford, England: Oxford University Press; 1992. pp. 178-121
  31. 31. Baserga R, Sell C, Porcu P, Rubini M. The role of the IGF-I receptor in the growth and transformation of mammalian cells. Cell Proliferation. 1994;27:63-71
  32. 32. Baserga R. Oncogenes and the strategy of growth factors. Cell. 1994;79:927-930
  33. 33. Trojan J, Blossey BK, Johnson T, et al. Loss of tumorogenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor I. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(11):4874-4878
  34. 34. Trojan J, Johnson TR, Rudin SD, et al. Gene therapy of murine teratocarcinoma: Separate functions for insulin-like growth factors I and II in immunogenicity and differentiation. Proceedings of the National Academy of Sciences of the United States of America. 1994:6088-6092
  35. 35. Sturm MA, Conover CA, Pham H, Rosenfeld RG. Insulin like growth factor receptors and binding proteins in rat neuroblastoma. Endocrinology. 1989;124:388-396
  36. 36. Werther GA, Abate M, Hogg A, et al. Localisation of insulin like growth factor mRNA in rat brain by in situ hybridization—Relation to IGF-I receptor. Molecular Endocrinology. 1990;4:773-778
  37. 37. Antoniades HN, Galanopoulis T, Nevile-Golden J, Maxwell M. Expression of insulin like growth factor I and II and their receptor mRNAs in primary human astrocytomas and meningiomas: In vivo studies using in situ hybridization and immunocytochemistry. International Journal of Cancer. 1992;50:215-222
  38. 38. Zumkeller W, Westphal M. The IGF/IGFBP system in CNS malignancy. Molecular Pathology. 2001;54:227-229
  39. 39. Baserga R. The insulin-like growth factor-I receptor as a target for cancer therapy. Expert Opinion on Therapeutic Targets. 2005;9:753-768
  40. 40. Trojan J, Johnson T, Rudin S, et al. Treatment and prevention of rat glioblastoma by immugenic C6 cells expressing antisense insulin-like growth factor I RNA. Science. 1994;259:94-97
  41. 41. Casper JT, Borella L, Sen L. Reactivity of human brain antiserum with neuroblastoma cells and nonreactivity with thymocytes and lymphoblasts. Cancer Research. 1977;37:1750-1758
  42. 42. Trojan J, Pan YX, Wei MX, et al. Methodology for anti-gene anti-IGF-I therapy of malignant tumours. Chemotherapy Research and Practice. 2012. DOI: 10.1155/2012/721873
  43. 43. Sandberg AC, Engberg C, Lake M, et al. The expression of insulin-like growth factor I and insulin-like growth factor II genes in the human fetal and adult brain and in glioma. Neuroscience Letters. 1988;93(1):114-119. DOI: 10.1016/0304-3940(88)90022-5
  44. 44. Kiess W, Lee L, Graham DE, et al. Rat C6 glial cells synthesize insulin-like growth factor I (IGF-I) and express IGF-I receptors and IGF-II/mannose 6-phosphate receptors. Endocrinology. 1989;124(4):1727-1736. DOI: 10.1210/endo-124-4-1727
  45. 45. Trojan J, Uriel J. Localisation of alphafeprotein (AFP) in murine teratocarcinoma. Biomedicine. 1981;34(3):140-146
  46. 46. Guha A, Mukherjee J. Advances in the biology of astrocytomas. Current Opinion in Neurology. 2004;17(6):655-662. DOI: 10.1097/00019052-200412000-00004
  47. 47. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: A population-based study. Cancer Research. 2004;64(19):6892-6899. DOI: 10.1158/0008-5472.CAN-04-1337
  48. 48. Wrensch M, Rice T, Miike R, et al. Diagnostic, treatment, and demographic factors influencing survival in a population-based study of adult glioma patients in the San Francisco Bay Area. Neuro Oncology. 2006;8(1):12-26. DOI: 10.1215/S1522851705000268
  49. 49. Hajeri-Germond M, Naval J, Trojan J. The uptake of alpha-foetoprotein by C-1300 mouse neuroblastoma cells. British Journal of Cancer. 1985;51:791-797. DOI: 10.1038/bjc.1985.123
  50. 50. Ostos H, Astaiza G, Garcia F, et al. Decreased incidence of defects of neural tube closure at the University Hospital of Neiva: Possible effect promotion of folic acid (in Spanish). Biomédica. 2000;20(1):18-24. DOI: 10.7705/biomedica.v20i1.1043
  51. 51. Trojan J, Cloix JF, Ardourel MY, et al. Insulin-like growth factor type I biology and targeting in malignant gliomas. Neuroscience. 2007;145(3):795-811. DOI: 10.1016/j.neuroscience.2007.01.021
  52. 52. Le Roith D, Bondy C, Yakar S, et al. The somatomedin hypothesis. Endocrinology Review. 2011;22(1):53-74. DOI: 10.1210/edrv.22.1.0419
  53. 53. Le Roith D. The insulin-like growth factor system. Experimental Diabesity Research. 2003;4(4):205-212. DOI: 10.1155/EDR.2003.205
  54. 54. Adhami VM, Afaq F, Mukhtar H. Insulin-like growth factor-I axis as a pathway for cancer chemoprevention. Clinical Cancer Research. 2006;12(19):5611-5614. DOI: 10.1158/1078-0432.CCR-06-1564
  55. 55. Chen H, Mester T, Raychaudhuri N, et al. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. Journal of Clinical Endocrinology and Metabolism. 2014;99(9):E1635-E1640. DOI: 10.1210/jc.2014-1580
  56. 56. Kooijman R. Regulation of apoptosis by insulin-like growth factor (IGF)-I. Cytokine Growth Factor Review. 2006;17(4):305-323. DOI: 10.1016/j.cytogfr.2006.02.002
  57. 57. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nature Review Cancer. 2004;4:505-518. DOI: 10.1038/nrc1387
  58. 58. Kurmasheva RT, Houghton PJ. IGF-I mediated survival pathways in normal and malignant cells. Biochimica et Biophysica Acta. 2006;1766(1):1-22. DOI: 10.1016/j.bbcan.2006.05.003
  59. 59. Beckner ME, Gobbel GT, Abounader R, et al. Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis. Laboratory Investigation. 2005;85(12):1457-1470. DOI: 10.1038/labinvest.3700355
  60. 60. Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Annales Oncology. 2005;16(4):525-537. DOI: 10.1093/annonc/mdi113
  61. 61. Schlingensiepen KH, Jaschinski F, Lang SA, et al. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Science. 2011;102(6):1193-1200. DOI: 10.1111/j.1349-7006.2011.01917.x
  62. 62. Trojan J, Anthony DD. Antisense strategies in therapy of gliomas. Current Signal Transduction Therapy. 2011;6(3):411-423. DOI: 10.2174/157436211797483895
  63. 63. Patel S, Doble B, Woodgett JR. Glycogen synthase kinase-3 in insulin and Wnt signalling: A double-edged sword? Biochemical Society Transactions. 2004;32(5):803-808. DOI: 10.1042/BST0320803
  64. 64. Jiang R, Mircean C, Shmulevich I, et al. Pathway alterations during glioma progression revealed by reverse phase protein lysate arrays. Proteomics. 2006;6(10):2964-2971. DOI: 10.1002/pmic.200500555
  65. 65. Hutterer M, Gunsilius E, Stockhammer G. Molecular therapies for malignant glioma. Wiener Medizinische Wochenschrift. 2006;156(11):351-363. DOI: 10.1007/s10354-006-0308-3
  66. 66. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Molecular Cancer Therapy. 2007;6(1):1-12. DOI: 10.1158/1535-7163.MCT-06-0080
  67. 67. Ardourel M, Blin M, Moret JL, et al. A new putative target for antisense gene therapy of glioma: Glycogen synthetase. Cancer Biology and Therapy. 2007;6(5):719-723. DOI: 10.4161/cbt.6.5.4232
  68. 68. Zhou X, Ren Y, Moore L, et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Laboratory Investigation. 2010;90:144-155. DOI: 10.1038/labinvest.2009.126
  69. 69. Premkumar DR, Arnold B, Jane EP, Pollack IF. Synergistic interaction between 17-AAG and phosphatidylinositol 3-kinase inhibition in human malignant glioma cells. Molecular Carcinogenesis. 2006;45(1):47-59. DOI: 10.1002/mc.20152
  70. 70. Sanson M, Laigle-Donadey F, Benouaich-Amiel A. Molecular changes in brain tumours: Prognostic and therapeutic impact. Current Opinion in Oncology. 2006;18(6):623-630. DOI: 10.1097/01.cco.0000245322.11787.72
  71. 71. Esiri M, Perl D. Oppenheimer’s Diagnostic Neuropathology. 3rd ed. FL: CRC Press; 2006
  72. 72. Glick RP, Lichtor T, Unterman TG. Insulin-like growth factors in central nervous system tumors. Journal of Neuro-Oncology. 1997;35(3):315-325
  73. 73. Johnson TR, Trojan J, Rudin SD, et al. Effects of actinomycin D and cycloheximide on transcript levels of IGF-I, actin, and albumin in hepatocyte primary cultures treated with growth hormone and insulin. Molecular Reproduction and Development. 1991;30(2):95-99. DOI: 10.1002/mrd.1080300204
  74. 74. Obrepalska-Steplowska A, Kedzia A, Trojan J, Goździcka-Józefiak A. Analysis of coding and promoter sequences of the IGF-I gene in children with growth disorders presenting with normal level of growth hormone. Journal of Pediatric Endocrinology and Metabolism. 2003;16(9):1267-1275
  75. 75. Zumkeller W. IGFs and IGF-binding proteins as diagnostic markers and biological modulators in brain tumors. Expert Review of Molecular Diagnostics. 2002;2(5):473-477. DOI: 10.1586/14737159.2.5.473
  76. 76. Hu B, Niu X, Cheng L, et al. Discovering cancer biomarkers from clinical samples by protein microarrays. Proteomics Clinical Application. 2015;9(1-2):98-110. DOI: 10.1002/prca.201400094
  77. 77. Ertl DA, Gleiss A, Sagmeister S, Haeusler G. Determining the normal range for IGF-I, IGFBP-3, and ALS: New reference data based on current internal standards. Wien Medicina Wochenschr. 2014;164(17-18):343-352. DOI: 10.1007/sl 0354-014-0299-4
  78. 78. Gu F, Schumacher FR, Canzian F, et al. Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer. Cancer Epidemiology Biomarkers Prevention. 2010;19(11):2877-2887. DOI: 10.1158/1055-9965.EPI-10-0507
  79. 79. Trojan A, Jay LM, Kasprzak H, et al. Immunotherapy of malignant tumors using antisense anti-IGF-I approach: Case of glioblastoma. Journal of Cancer Therapy. 2014;5:685-705
  80. 80. Rodriguez-Tarduchy G, Collins MKL, Garcia I, Lopez-Rivas A. Insulin-like growth factor-I inhibits apoptosis in IL-3-dependent hemopoietic cells. European Journal of Immunology. 1992;149:535-540
  81. 81. Upegui-Gonzalez LC, Duc HT, Buisson Y, et al. Use of the IGF-I antisense strategy in the treatment of the hepatocarcinoma. Advances in Experimental Medicine and Biology. 1998;451:35-42
  82. 82. Shevelev A, Burfeind P, Schulze E, et al. Potential triple helix mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model. Cancer Gene Therapy. 1997;4:105-112
  83. 83. Upegui-Gonzalez LC, Ly A, Sierzega M, et al. IGF-I triple helix strategy in hepatoma treatment. Hepato/Gastroenterology. 2001;48:660-666
  84. 84. Derwan P. Reagents for the site-specific cleavage of mega-base DNA. Nature. 1992;359:87-88
  85. 85. Helene C. Control of oncogene expression by antisense nucleic acids. European Journal of Cancer. 1994;30:1721-1726
  86. 86. Rubinstein JL, Nicolas JF, Jacob F. L’ARN non sens (nsARN): Un outil pour inactiver spécifiquement l’expression d’un gène donné in vivo. Comptes Rendus Académie des Sciences Paris. 1984;299:271-274
  87. 87. Weintraub H, Izant G, Harland RM. Anti-sense RNA as a molecular tool for genetic analysis. Trends in Genetics. 1985;1:23-25
  88. 88. Green PJ, Pines O, Inouye M. The role of antisense RNA in gene regulation. Annual Review of Biochemistry. 1986;55:569-597
  89. 89. Kim SK, Wold BJ. Stable reduction of thymidine kinase activity in cells expressing high levels of anti-sense RNA. Cell. 1985;42:129-138
  90. 90. Whitesell L, Rosolen S, Neckers LM. Episome-generated N- myc antisense RNA restricts the differentiation potential of primi-tive neuroectodermal cell lines. Molecular Cell Biology. 1991;11:1360-1371
  91. 91. Blanchet O, Bourge JF, Zinszner H, et al. Altered binding of regulatory factors to HLA class I enhancer sequence in human tumor cell lines lacking class I antigen expression. Proceedings of National Academy of Sciences of the United States of America. 1992;89:3488-3492
  92. 92. Plautz GE, Yang ZY, Wu BY, et al. Immunotherapy of malignancy by in vivo gene transfer into tumors. Proceedings of National Academy of Sciences of the United States of America. 1993;90:4645-4649
  93. 93. Townsend SE, Allison JA. Tumor rejection after direct costimulation of CD8+ T cell transfected melanoma cells. Science. 1993;259:368-370
  94. 94. Guo Y, Wu M, Chen H, et al. Effective tumor vaccine generated by fusion of hepatoma cells with lymphocytes B cells. Science. 1994;263:518-520
  95. 95. Trojan J, Duc H, Upegui-Gonzalez L, et al. Presence of MHC-I and B-7 molecules in rat and human glioma cells expressing antisense IGF-I mRNA. Neuroscience Letters. 1996;212:9-12
  96. 96. Ly A, Duc HT, Kalamarides M, et al. Human glioma cells transformed by IGF-I triple-helix technology show immune and apoptotic characteristics determining cell selection for gene therapy of glioblastoma. Journal of Clinical Pathology. 2001;54:230-239
  97. 97. Trojan LA, Ly A, Kopinski P, et al. Antisense and triple helix anti IGF-I tumour vaccines: Gene therapy of gliomas. International Journal of Cancer Prevention. 2007;2(4):227-243
  98. 98. Lafarge-Frayssinet C, Sarasin A, Duc HT, et al. Gene therapy for hepatocarcinoma: Antisense IGF-I transfer into a rat hepatoma cell line inhibits tumorigenesis into syngeneic animal. Cancer Gene Therapy. 1997;4:276-285
  99. 99. Rininsland F, Johnson T, Chernicky C, et al. Suppression of insulin-like growth factor type-I receptor by a triple-helix strategy inhibits IGF-I transcription and tumorigenic potential of rat C6 glioblastoma cells. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:5854-5859
  100. 100. Wongkajornslip A, Ouyprasertkul M, Sangruchi T, et al. The analysis of peri-tumor necrosis following the subcutaneous implantation of autologous tumor cells transfected with an episome transcribing an antisense insulin-like growth factor I RNA in a glioblastoma multiforme subject. Journal of Medical Association of Thailand. 2001;4:740-747
  101. 101. Siena S, Di Nicola M, Bregni M, et al. Massive ex vivo generation of functional dendritic cells from mobilized CD34+ blood progenitors for anticancer therapy. Experimental Hematology. 1995;23:1465-1473
  102. 102. Pickl WF, Majdic O, Kohl P, et al. Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes. Journal of Immunology. 1996;157(9):3850-3859
  103. 103. Guo Y, Wu M, Chen H, et al. Effective tumor vaccine generated fusion of hepatoma cells with lymphocytes B cells. Science. 1994;263:518-520
  104. 104. Robin A. Immunochemistry in Practice. NY: Blackwell; 1988
  105. 105. Steiman RM, Turkey S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. Journal of Experimental Medicine. 2000;191:411-416
  106. 106. Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/13. Proceedings of the National Academy of Sciences of the United States of America. 1990;87:5031-5035
  107. 107. Freeman GB, Gray GS, Gimmi CD, et al. Structure, expression and T cell costimulatory activity of murine homologue of the human B lymphocyte activation antigen B7. Journal of Experimental Medicine. 1991;174:625-631
  108. 108. Schwartz RH. Costimulation of T lymphocytes: The role of CD28, CTLA-4 and B7/BBI in interleukin-2 production and immunotherapy. Cell. 1992;71:1065-1068
  109. 109. D’Ambrosio C, Ferber A, Resnicoff M, Baserga R. A soluble insulin-like growth factor receptor that induces apoptosis of tumor cells in vivo and inhibits tumorigenesis. Cancer Research. 1996;56:4013-4020
  110. 110. Dudek H, Datta SR, Franke TS, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science. 1997;275:661-665
  111. 111. Satoh J, Lee YB, Kim SU. T-cell costimulatory molecules B7-1 (CD80) and B7-2 (CD86) are expressed in human microglia but not in astrocytes in culture. Brain Research. 1995;704:95-96
  112. 112. Sotomayor E, Fu Y, Lopez-Cepero M, et al. Role of tumor derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. Journal of Immunology. 1991;147:2816-2823
  113. 113. Matthew L, Saiter B, Bhardwag N. Dendritic cells acquire antigen from apoptotic cells and induce class I restricted CTL. Nature. 1998;392:86-89
  114. 114. Anthony D, Pan Y, Wu S, et al. Ex vivo and in vivo IGF-I antisense RNA strategies for treatment of cancer in humans. Advances in Experimental Medicine and Biology. 1998;451:27-34
  115. 115. Pan Y, Trojan J, Guo Y, Anthony D. Rescue of MHC-1 antigen processing machinery by down-regulation in expression of IGF-I in human glioblastoma cells. PLoS One. 2013;8(3):e58428. DOI: 10.1371/0058428
  116. 116. Zhu C, Trabado S, Fan Y, et al. Characterization of effector components from the humoral and cellular immune response stimulated by melanoma cells exhibiting modified IGF-1 expression. Biomedicine & Pharmacotherapy. 2015;70:53-57. DOI: 10.1016/j.biopha.2015.01.002
  117. 117. Trojan J. From unsolved mysteries of neoplastic brain development to market of gene therapyof brain tumors—glioblastoma. In: BIT’s 5th Annual World Congress of NeuroTalk 2014, Session: Frontier of Neurosystem Matters; Nanjing, China; 19 May. 2014
  118. 118. Trojan J. Cellular therapy of malignant tumours: Anti-gene anti IGF-I approach. In: BIT’S 7th Annual World Congress – WCC 2014; Session: Cancer Immunology and Cancer Metabolism; Nanjing, 22 May. 2014
  119. 119. Trojan J. Cell immunogene therapy of cancers using anti-gene anti IGF-I vaccines. In: 3rd International Conference Vaccines R&D, Session Therapeutic Vaccination; Washington, USA. November 2017
  120. 120. Stupp R, Hegi ME, van den Bent MJ, et al. Changing paradigms—An update on the multidisciplinary management of malignant glioma. The Oncologist. 2006;11:165-180
  121. 121. Kjaergaard J, Wang L, Kuriyama H, et al. Active immunotherapy for advanced intracranial murine tumors by using dendritic cell-tumor cell fusion vaccines. Journal of Neurosurgery. 2005;103:156-164
  122. 122. Fakhrai H, Dorigo O, Shawler DL, et al. Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(7):2909-2914
  123. 123. Boado RJ. RNA interference and nonviral targeted gene therapy of experimental brain cancer. NeuroRx. 2005;2(1):139-150
  124. 124. Pai SI, Lin YY, Macaes B, et al. Prospects of RNA interference therapy for cancer. Gene Therapy. 2006;13(6):464-477
  125. 125. Berezikov E, Thuemmler F, van Laake LW, et al. Diversity of microRNAs in human and chimpanzee brain. Nature Genetics. 2006;38(12):1375-1377
  126. 126. Corsten MF, Miranda R, Kasmieh R, et al. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Research. 2007;67(19):8994-9000
  127. 127. Dias N, Stein CA. Basic concepts and antisense oligonucleotides mechanisms. Molecular Cancer Therapeutics. 2002;1:347-355
  128. 128. Galderisi U, Cascino A, Goirdano A. Antisense oligonucleotides as therapeutic agents. Journal of Cell Physics. 1999;181:251-257
  129. 129. Resnicoff M, Li W, Basak S, et al. Inhibition of rat C6 glioblastoma tumor growth by expression of insulin-like growth factor I receptor antisense mRNA. Cancer Immunology and Immunotherapy. 1996;42(1):64-68
  130. 130. Trojan J. Anti-gene anti IGF-I technology applied for cancer immunotherapy. World Journal of Research Review. 2016;1(3):67-75
  131. 131. Schwartz RH. Costimulation of T lymphocytes: The role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992;71:1065-1068
  132. 132. Kasprzak HA, Trojan J, Bierwagen M, et al. Usefulness of the antisense and triplex anti-IGF-1 techniques for postoperative cellular gene therapy of malignant gliomas expressing IGF-1. Neurology Neurochirurgy. 2006;40(6):509-515
  133. 133. Andrews DW, Resnicoff M, Flanders A, et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. Journal of Clinical Oncology. 2001;19:2189-2200
  134. 134. Samani AA, Fallavollita L, Jaalouk DE, et al. Inhibition of carcinoma cell growth and metastasis by a vesicular stomatitis virus G-pseudotyped retrovector expressing type 1 insulin-like growth factor receptor antisense. Human Gene Therapy. 2001;12:1969-1977
  135. 135. Schlingensiepen R, Goldbrunner M, Szyrach MNI, et al. Intracerebral and intrathecal infusion of the TGF-beta2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: Toxicology and safety. Oligonucleotides. 2005;15(2):94-104
  136. 136. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, et al. Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine & Growth Factor Reviews. 2006;17:129-139
  137. 137. Hau P, Jachimczak P, Schlingensiepen R, et al. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: From preclinical to phase I/II studies. Oligonucleotides. 2007;17(2):201-212
  138. 138. Fakhrai H, Mantil JC, Liu L, et al. Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Therapy. 2006;13(12):1052-1060
  139. 139. Goudar RK, Shi Q , Hjelmeland MD, et al. Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Molecular Cancer Therapy. 2005;4:101-112
  140. 140. Lamszus K, Brockman MA, Eckerich C, et al. Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin. Clinical Cancer Research. 2005;11:4934-4940
  141. 141. Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clinical Cancer Research. 2006;12:860-868
  142. 142. Halatsch ME, Schmidt U, Behnke-Mursch L, et al. Epidermal growth factor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Cancer Treatment Review. 2006;32:74-89
  143. 143. Wen PY, Yung WK, Lamborn KR, et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: Norty American Brain Tumour Consortium Study 99-08. Clinical Cancer Research. 2006;12:4899-4907
  144. 144. Schlingensiepen KH, Fischer-Blass B, Schmaus S, Ludwig S. Antisense therapeutics for tumor treatment: The TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Results in Cancer Research. 2008;177:137-150
  145. 145. Trojan LA, Ly A, Upegui-Gonzalez LC, et al. Antisense anti IGF-I therapy of primary hepatic cancer. Journal of African Cancer. 2009;1:1-10
  146. 146. Biroccio A, Leonett C, Zupi G. The future of antisense therapy: Combination with anticancer treatment. Oncogene. 2003;22:6579-6588
  147. 147. Meng Y, Carpentier AF, Chen L, et al. Successful combination of local CpG-ODN and radiotherapy in malignant glioma. International Journal of Cancerology. 2005;116:992-997
  148. 148. Gonzalez J, Gilbert MR. Treatment of astrocytomas. Current Opinion in Neurology. 2005;18:632-638
  149. 149. Jane EP, Premkumar DR, Pollack IF. Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. Journal of Pharmacology and Experimental Therapy. 2006;319:1070-1080
  150. 150. Vega EA, Graner MW, Sampson JH. Combating immunosuppression in glioma. Future Oncology. 2008;4(3):433-442

Written By

Annabelle Trojan, Heliodor Kasprzak, Oscar Gutierrez, Pedro Penagos, Ignacio Briceno, Heber O. Siachoque, Donald D. Anthony, Alvaro Alvarez and Jerzy Trojan

Submitted: September 17th, 2018 Reviewed: January 25th, 2019 Published: January 29th, 2020