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R I G T T RADIO IMMUNO-GENE TUMOUR THERAPY

R I G T T RADIO IMMUNO-GENE TUMOUR THERAPY. 隆德 大学 Lund University, 221 85 LUND Sweden 瑞典. Bertil R.R. Persson Professor of medical radiation physics. Survival of Rats with N29 Brain Tumors after Single fraction 5 or 15 Gy Radiotherapy combined with Immunotherapy.

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R I G T T RADIO IMMUNO-GENE TUMOUR THERAPY

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  1. R I G T TRADIO IMMUNO-GENE TUMOUR THERAPY 隆德 大学 Lund University, 221 85 LUND Sweden 瑞典 Bertil R.R. Persson Professor of medical radiation physics

  2. Survival of Rats with N29 Brain Tumors after Single fraction 5 or 15 Gy Radiotherapy combined with Immunotherapy. Bertil R.R. Persson1,4), Catrin Bauréus Koch2,4), Gustav Grafström2,4), Crister Ceberg 2,4), Per Munck af Rosenschöld 2,4), Bengt Widegren3,4) and Leif G. Salford1,4) 1)Dept. Neurosurgery, Lund University, SE-221 85 LUND, Sweden 2)Dept. Radiation Physics, Lund University, SE-221 85 LUND, Sweden 3)Dept. Tumorimmunology, Lund University, BMC Box 7031, SE 220 07, Sweden; 4)Rausing Laboratory, Biomedical Centre, Lund University, 221 85 LUND, Sweden E-mail: bertil_r.persson@med.lu.se Bertil_R.Persson@med.lu.se

  3. Aim of Research: Investigation of the effect of Radio Immuno-Gene Tumour Therapy on N29 tumours implanted either subcutaneously on the flank or in the brain of Fischer 344 rats Tumour treated with 60Co radiation therapy combined with immunization by syngeneic IFN- secreting N29 tumour cells. Catrin Bauréus Koch, Gustav Grafström, Crister Ceberg, Per Engström, Bengt Widegren, Leif G. Salford and Bertil R.R. Persson, Research team:

  4. Subcutaneous Tumours. • The rat glioma N29 was induced in The • Rausing Laboratory (BMC Lund Sweden) by subcutaneous administration in the hind legs. • 200 000 cells were inoculated into • the right leg as primary tumour • 50 000 cells were inoculated into the • left leg, as secondary tumour (metastasis) • Tumour volume is estimated as an ellipsoid by length, width and thickness measured with a calliper. When the tumours reached a volume • of 9 cm3, the animal was sacrificed of ethical reasons. Bertil_R.Persson@med.lu.se

  5. N29 tumours inoculated Subcutaneously on both sides Only the right tumour was irradiated Bertil_R.Persson@med.lu.se

  6. Tumour Volume of untreated Controlsin 4 different experimental series Bertil_R.Persson@med.lu.se

  7. Immunized with IFNg secreting cells Experiment 020404 IFNg Experiment 010529 IFNg Bertil_R.Persson@med.lu.se

  8. Radiation theraphy (RT) Only the right tumour was Irradiated with 60Co  radiation Bertil_R.Persson@med.lu.se

  9. Radiation therapy of the right tumour with 4 fractions of 5 Gy (total 20 Gy) Experiment 020404 RT Experiment 010529 RT Bertil_R.Persson@med.lu.se

  10. Combined treatment with radiation therapy of the right tumour with 4 fractions of 5 Gy (total 20 Gy) and immunization with IFNg secreting Bertil_R.Persson@med.lu.se

  11. An exponential tumour growth model is applied to quantitatively evaluate and compare the effect of tumour treatment in the various experimental groups on the tumour growth Bertil_R.Persson@med.lu.se

  12. Exponential Tumour Growth Model Tumour growth rate “TGR” is estimated from the tumour volume measurements by fitting the data of each individual tumour to a model of exponential growth where “TVt” is Tumour volume at time t t is time after first treatment. “TV0” is Tumour volume at time t = 0, “TGR” is tumour growth rate constant (% per day) Bertil_R.Persson@med.lu.se

  13. Tumour growth rate of subcutaneous N29 tumours: Controls and after treatment with RT, IFN immunization or their combination RT+ IFN Bertil_R.Persson@med.lu.se

  14. Tumour Growth rate ”TGR” of subcutaneous N29 tumours implanted on both Right and Left hind leg. Only the right tumour was irradiated (RT). Average of experiments 010529 and 020404 Bertil_R.Persson@med.lu.se

  15. The therapeutic effect “TE = -lnS”is defined as the ratio between the tumour volume of the treated tumour and the control whereTVE Tumour volume of the Exposed group TVC Tumour volume of the Control group S Tumour “Surviving fraction” TGRE Tumour growth rate constant of the exposed group day-1 TGRC Tumour growth rate constant of the control day-1 S Surviving fraction of the tumour at t days after treatment was started Bertil_R.Persson@med.lu.se

  16. The tumour growth rate TGR of the controls evaluated at various time intervals after inoculation Bertil_R.Persson@med.lu.se

  17. The therapeutic effect “TE”: TE = (TGRc-TGRE) •t Depends on time and the characteristics of each experiment By dividing with TGRC•t we get a parameter invariant with time and experimental conditions Bertil_R.Persson@med.lu.se

  18. Specific Therapeutic Effect “STE”is defined as follow. The average of the individual Tumour growth rate constant in the group of exposed rats. day-1 The average of the individual Tumour growth rate constant in the group of control rats. day-1 Bertil_R.Persson@med.lu.se

  19. The STE is equal to 0 when the average of tumour growth rate constant of the exposed group, is equal to the average of the tumour growth rate constant of the control. The STE is equal to 1 when the average tumour growth rate constant of the exposed group, is equal to 0. Bertil_R.Persson@med.lu.se

  20. Specific therapeutic effect of subcutaneous N29 tumorsafter RT, Immunization with IFN and their combination RT+ IFN . Bertil_R.Persson@med.lu.se

  21. Specific Therapeutic Effect “STE” of subcutaneous N29 tumours implanted on both Right and Left hind leg. Bertil_R.Persson@med.lu.se

  22. Synergetic effects of combined treatment It is if great interest to know if there is a therapeutic gain by combining radiation therapy and immunization with syngeneic IFN secreting tumour cells Bertil_R.Persson@med.lu.se

  23. Therapeutic Enhancement Ratio. “TER” of the combined treatments is the ratio of the specific therapeutic effect “STE” of the experimental combination of Electrical pulses and radiation and the hypothetical combination of the two agents used independently where the hypothetical specific therapeutic effect by independent (additive) action of ionizing radiation and Electrical pulses is given by Bertil_R.Persson@med.lu.se

  24. Therapeutic Enhancement Ratio “TER” is a measure of any synergistic or diminishing effect obtained in the combination of the two agents. TER > 1 may due to synergistic interaction of sub lethal lesions induced by both agents to produce more lethal events. Bertil_R.Persson@med.lu.se

  25. Therapeutic Enhancement Ratio “TER” of subcutaneous tumours implanted on both Right and Left hind leg. The right tumour was treated with radiation (RT). Bertil_R.Persson@med.lu.se

  26. Intracerebral implanted N29 tumours By stereotactic technique 5000 N29 cells in 5 l nutrient solution were injected with a Hamilton syringe into the head of the right caudate nucleus of Fischer 344 rats. To avoid extra-cranial tumour growth, the injection site was cleaned with 70% ethanol after injection and the borehole was sealed with wax. Bertil_R.Persson@med.lu.se

  27. The rat glioma models N29 Stereotactic implantation in in the brain (caudate n.) 6-7 weeks later, a tumour (diam. 4-6 mm) giving symptoms, has developed In vitro culture of rat glioma cells Bertil_R.Persson@med.lu.se Salford 99

  28. Immunization against experimentally induced brain tumour N29 brain tumour cells N29 brain tumour cells Transfected with IFN- gene IMMUNIZATION Stereotactic injection of 5000 cells Day 7 Radiation therapy Day 0 Day 7, 21, 35 By ip incection of 10 million cells Day 100 2 out of 8 dead! 6 out of 7 dead Day 100 Immuneresp Bertil_R.Persson@med.lu.se

  29. Survival diagram for the different treatments Bertil_R.Persson@med.lu.se

  30. Number of rats dead and alive in the various groups of treatment at 130 days after inoculation . Bertil_R.Persson@med.lu.se

  31. Mean survival time at 130 days after inoculation in the various groups of treatment. Bertil_R.Persson@med.lu.se

  32. Change in Mean survival time Bertil_R.Persson@med.lu.se

  33. Number of Survivals and mean survival time of intra cerebral tumours treated with IFN cell immunization, radiation therapy and their combination. Bertil_R.Persson@med.lu.se

  34. THE END Bertil_R.Persson@med.lu.se

  35. Bertil_R.Persson@med.lu.se

  36. Bertil_R.Persson@med.lu.se

  37. Intracerebral implanted N32 tumours Bertil_R.Persson@med.lu.se

  38. Survival diagram for the different treatments Bertil_R.Persson@med.lu.se

  39. Table I. Tumour Growth rate ”TGR” of subcutaneous tumours implanted on both Right and Left hind leg. The right tumour was treated with radiation (RT). Average of all experiments Bertil_R.Persson@med.lu.se

  40. Log TV of Controls Bertil_R.Persson@med.lu.se

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