IL2 treatment for cancer: from biology to gene therapy.

In this review we shall discuss the biological rationale and the clinical findings obtained using Interleukin 2 (IL2)-based immunotherapy in the management of cancer patients. Objective and long-lived clinical responses have been documented in a proportion of cases, particularly renal cell carcinoma, melanoma and acute myeloid leukaemia. Though encouraging, the clinical use of IL2 has so far been limited by toxicity, as well as by the heterogeneous and unpredictable responses and by the lack of specific anti-tumour effect. These considerations have led to the belief that more sophisticated technologies aimed at introducing the IL2 gene into the neoplastic cells may potentially overcome some of the limitations coupled to the in vivo infusion of high doses of IL2. The data accumulated in animal models and, more recently, also with human tumour cells indicate that the IL2 gene may be successfully inserted into neoplastic cells. The constitutive secretion of IL2 by the tumour cells leads to a reduced or abrogated tumorigenicity in several different tumour models. The evidence that in some experimental tumours the transduction of the IL2 gene into the neoplastic cells may elicit a specific cytotoxic response and confer anti-tumour memory, suggests that vaccination protocols based on this innovative strategy may represent a potential new tool in the management of cancer patients

Direct Gene Transfer for the Understanding and Treatment of Human Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75762/1/j.1749-6632.1994.tb21709.x.pd

Interleukin-2 gene transfer into human transitional cell carcinoma of the urinary bladder

Transitional cell carcinoma of the bladder is one of the human cancers most responsive to immunotherapy, and local interleukin-2 (IL-2) production appears to be an important requirement for immunotherapy to be effective. In this study, we engineered two human bladder cancer cell lines (RT112 and EJ) to constitutively release human IL-2 by retroviral vector-mediated gene transfer. Following infection and selection, stable and consistent production of biologically active IL-2 was demonstrated at both the mRNA and the protein level. Morphology, in vitro growth rate and proliferation, as well as other cytokine gene mRNA or membrane adhesion receptor expression, were not altered in IL-2 transduced cells as compared to their parental or control vector-infected counterparts. Moreover, IL-2 engineered cells lost their tumorigenicity into nu/nu mice and the mechanism of rejection appeared to involve multiple host effector cell populations, among which a prominent role was played by neutrophils and radiosensitive cells. These findings may offer support to the development of an IL-2-based gene therapy approach to human bladder cancer. 1999 Cancer Research Campaig

Differential baseline and response profile to IFN-γ gene transduction of IL-6/IL-6 receptor-α secretion discriminate primary tumors versus bone marrow metastases of nasopharyngeal carcinomas in culture

<p>Abstract</p> <p>Background</p> <p>Understanding of immunobiology of bone marrow metastases (designated BM-NPC) <it>versus </it>primary tumors (P-NPC) of the nasopharynx is far from complete. The aim of this study was to determine if there would be differences between cultured P-NPCs and BM-NPCs with respect to (i) constitutive IL-6 and the IL-6 receptor gp80 subunit (IL-6Rα) levels in the spent media of nontransduced cells, and (ii) IL-6 and IL-6Rα levels in the spent media of cells transduced with a retroviral vector containing the <it>IFN-γ </it>gene.</p> <p>Methods</p> <p>A panel of NPC cell lines were transduced with the <it>IFN-γ </it>gene through a retroviral vector. Four clonal sublines were isolated <it>via </it>limiting dilution methods. Cytofluorometric analysis was performed for the detection of cell surface antigens of HLA class I, HLA class II and ICAM-1. ELISA was used to assay for IFN-γ, IL-6 and IL-6Rα in the spent media of cultured cell lines.</p> <p>Results</p> <p>Our results showed that in day 3 culture supernatants, low levels of soluble IL-6 were detected in 5/5 cultured tumors derived from P-NPCs, while much higher constitutive levels of IL-6 were detected in 3/3 metastasis-derived NPC cell lines including one originated from ascites; the difference was significant (<it>p </it>= 0.025). An inverse relationship was found between IL-6Rα and IL-6 in their release levels in cultured P-NPCs and metastasis-derived NPCs. In <it>IFN-γ</it>-transduced-P-NPCs, IL-6 production increased and yet IL-6Rα decreased substantially, as compared to nontransduced counterparts. At variance with P-NPC cells, the respective ongoing IL-6 and IL-6Rα release patterns of BM-NPC cells were not impeded as much following <it>IFN-γ </it>transduction. These observations were confirmed by extended kinetic studies with representative NPC cell lines and clonal sublines. The latter observation with the clonal sublines also indicates that selection for high IL-6 or low IL-6Rα producing subpopulations did not occur as a result of <it>IFN-γ</it>-transduction process. P-NPCs, which secreted constitutively only marginal levels of IFN-γ (8.4 ~ 10.5 pg/ml), could be enhanced to produce higher levels of IFN-γ (6.8- to 10.3-fold increase) after <it>IFN-γ </it>transduction. Unlike P-NPCs, BM-NPCs spontaneously released IFN-γ at moderate levels (83.8 ~ 100.7 pg/ml), which were enhanced by 1.3- to 2.2-fold in the spent media of their <it>IFN-γ</it>-transduced counterparts.</p> <p>Conclusion</p> <p>Our results showed that cultured P-NPCs and BM-NPCs could be distinguished from one another on the basis of their differential baseline secretion pattern of IFN-γ, IL-6 and IL-6Rα, and their differential response profiles to <it>IFN-γ </it>gene transfer of the production of these three soluble molecules. These results suggest that the IL-6 and IFN-γ pathways in a background of genetic instability be involved in the acquisition of metastatic behaviour in BM-NPCs.</p

Activation of T lymphocytes for the adoptive immunotherapy of cancer

Background: Adoptive immunotherapy of malignancy involves the passive transfer of antitumor-reactive cells into a host in order to mediate tumor regression. Based on animal models, the transfer of immune lymphoid cells can eradicate widely disseminated tumors and establish long-term systemic immunity. Critical for successful adoptive immunotherapy is the ability to isolate large numbers of immune cells. For clinical therapy, it will require the development of in vitro methods to promote the sensitization and propagation of tumor-reactive cells. However, this is formidable task since human cancers are postulated to be poorly immunogenic because of their spontaneous origins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41399/1/10434_2006_Article_BF02303568.pd

Ein Vergleich der medizinischen Ausbildungen in Deutschland und den USA: Von der Bewerbung zum Medizinstudium bis zu den Anfängen der Facharztweiterbildung

Both Germany and the United States of America have a long tradition of science and medical excellence reaching back as far as the nineteenth century. The same tribute must be paid to the medical educational system in both countries. Despite significant initial similarities and cross-inspiration, the paths from enrolling in a medical university to graduating as a medical doctor in Germany and the US seem to have become much different. To fill a void in literature, the authors' objective therefore is to delineate both structures of medical education in an up-to-date review and examine their current differences and similarities. Recent medical publications, legal guidelines of governmental or official organizations, articles in media, as well as the authors' personal experiences are used as sources of this report.Tuition loans of over $200,000 are not uncommon for students in the US after graduating from medical schools, which are often private institutions. In Germany, however, the vast majority of medical universities are tax-funded and, for this reason, free of tuition. Significant differences and surprisingly multiple similarities exist between these two systems, despite one depending on government and the other on private organizations. Germany currently employs an integrated medical curriculum that typically begins right after high school and consists of a 2-year long pre-clinical segment teaching basic sciences and a 4-year clinical segment leading medical students to the practical aspects of medicine. On the other hand, the US education is a two-stage process. After successful completion of a Bachelor's degree in college, an American student goes through a 4-year medical program encompassing 2 years of basic science and 2 years of clinical training. In this review, we will address some of these similarities and major differences.Deutschland und die Vereinigten Staaten von Amerika haben beide eine lange Tradition der Naturwissenschaft und medizinischen Exzellenz, die bis weit in das neunzehnte Jahrhundert zurückreicht. Den gleichen Tribut muss man den medizinischen Ausbildungssystemen beider Länder zollen. Trotz zu Beginn bedeutsamer Ähnlichkeiten und gewisser Querinspiration scheinen sich die Wege von der Immatrikulation an einer medizinischen Fakultät bis zum Studienabschluss als Arzt in Deutschland und den USA getrennt zu haben. Um eine Lücke in der Fachliteratur zu schließen, ist das Ziel der Autoren, die beiden Strukturen der medizinischen Ausbildung mittels einer aktuellen Übersichtsschrift darzustellen und deren Unterschiede und Gemeinsamkeiten zu untersuchen. Die neusten medizinischen Publikationen, verbindliche Richtlinien von amtlichen oder offiziellen Organisationen, Artikel in der Presse, aber auch die persönlichen Erfahrungen der Autoren dienen als Quellen für diese Arbeit.Studienkredite von über$200.000 sind nicht selten für Studenten in den USA nach deren Abschluss an einer medizinischen Hochschule, die meist in privatem Eigentum ist. In Deutschland dagegen ist die große Mehrheit der Universitäten mit medizinischen Fakultäten in öffentlicher Hand, aus Steuern finanziert und deshalb frei von Studiengebühren. Signifikante Unterschiede doch auch überraschenderweise eine Reihe von Ähnlichkeiten existieren zwischen den Systemen der zwei Länder, obwohl eines von privaten Einrichtungen und das andere von staatlichen Hochschulen abhängig ist. Deutschland verwendet aktuell ein ganzheitliches medizinisches Curriculum, das klassischerweise direkt nach dem Abitur beginnt und aus zwei Jahren vorklinischer und vier Jahren klinischer Ausbildung besteht, wobei letzteres die Studenten an die praktischen Aspekte der Medizin heranführen soll. Auf der anderen Seite herrscht in den USA ein zweistufiger Ausbildungsprozess. Nach erfolgreichem Erreichen eines Bachelorgrads im College führt der Weg eines amerikanischen Studenten durch ein vierjähriges Medizinstudium, welches aus zwei Jahren Grundlagenlehre und zwei Jahren klinischer Ausbildung besteht. In dieser Überblicksarbeit werden wir uns mit einigen dieser Gemeinsamkeiten und Hauptunterschiede befassen