RIGT RIGT T R I G T R I G T T Radiation Radiation immunomodulatory immunomodulatory gene tumor therapy gene tumor therapy gene tumor therapy gene tumor therapy Bertil R.R. Persson PhD, Bertil R.R. Persson PhD, MDh.c MDh.c. Professor of Professor of medical medical radiation radiation physics physics 隆德 隆德 大学 大学 隆德 隆德 大学 大学 Lund University, Lund University, 221 85 LUND 221 85 LUND Sweden Sweden 瑞典 瑞典
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Immunization withImmunization with autologousautologous interferoninterferon--Immunization with Immunization with autologousautologous interferoninterferon--gamma secreting glioma cells in patients with gamma secreting glioma cells in patients with
A h 1A h 1 2 li i l t i l2 li i l t i lA phase 1A phase 1--2 clinical trial2 clinical trialSalfordSalford LGLG 1,2*1,2* SiesjöSiesjö PP 1,2*1,2* SkagerbergSkagerberg GG 1,2*,1,2*, RydeliusRydelius AA 2,32,3SalfordSalford LG LG ,, , , SiesjöSiesjö P P ,, , , SkagerbergSkagerberg G G , ,, , RydeliusRydelius A A ,3,3, ,
BlennowBlennow C C 1,21,2, , LiljaLilja Å Å 1,4,1,4, Persson BRR Persson BRR 2,42,4, , StrömbladStrömblad S S 1,21,2,Visse E ,Visse E 1,21,2 and and WidegrenWidegren B B 2,52,5
Purpose: 目的 mu4 di4 :p
Th i i f th BRIGTT t d tThe primary aims of the BRIGTT study were to ascertain
• Safety, 安全 an1 quan2
• Feasibility 可行性 and k 3 i 2 i 4• ke3 xing2 xing4
• Efficacy 效力xiao4 li4
of immunotherapy with autologous IFN- transfected tumor cells in patients with glioblastoma multiformetumor cells in patients with glioblastoma multiforme
S d i iSends migrating“guerilla-cells”I t thInto the sur-rounding brain
h th BBBwhere the BBBis intact
Salford
Timeline of immunization andTimeline of immunization andTimeline of immunization and Timeline of immunization and monitoring procedures.monitoring procedures.g pg p
BRIGTT St d d i 研究设计BRIGTT Study design: 研究设计yan2 jiu1 she4 ji4
A t l t ll lt d d t f t d ithAutologous tumor cells were cultured and transfected with the human IFN- gene by the use of an adenoviral vector.
After irradiation with 100 Gy the cells were administered as intradermal immunizations in the upper arm every 3rd week.
Endpoints • for safet ere: records of to icit and ad erse e ents• for safety were: records of toxicity and adverse events, • for feasibility percent treated patients out of eligible
patients and time to treatment andpatients and time to treatment and • for clinical efficacy overall survival (OS) and progress
Results8/17 (47%) of eligible patients, aged between 50 and 69 years, were immunized between 8-14 times after surgery and radiotherapy.
• No adverse events or toxicity were recorded.
• There was no deterioration in neurological status of the• There was no deterioration in neurological status of thepatients during treatment.
i i ifi• The treated patients had a significantly longer overall survival (p<0.05) than the control group of 9 patients (525 days 17 4 months vs 325 days 10 4 months)(525 days, 17.4 months vs 325 days, 10.4 months).
The treated group and control groups did not differ in terms of age, extent of tumor resection or performance. p
The prolongation of survival was also significant when compared to historical and published controls within the same age group. p g g p
KaplanKaplan--Maier graph showing overall Maier graph showing overall survival of survival of i i d (i l d d) d t l ti ti i d (i l d d) d t l ti t ThThimmunized (included) and control patients. immunized (included) and control patients. The The
survivalsurvival waswas analyzedanalyzed with the with the loglog--rankrank test.test.
MRI (T1 with gadolinium) MRI (T1 with gadolinium) images from nonimages from non--responding responding and responding patients and responding patients
postoperativelypostoperatively andandpostoperatively postoperatively and and
at the 6th immunizationat the 6th immunization. .
The postoperative image of The postoperative image of the nonthe non responding patientresponding patientthe nonthe non--responding patient responding patient shows a dense area, which shows a dense area, which constituted a haemorrhageconstituted a haemorrhageconstituted a haemorrhage constituted a haemorrhage also seen on nonalso seen on non--gadolinium gadolinium enhanced images (not enhanced images (not shown).shown).
After the ”BRIGTT” After the ”BRIGTT” studystudy has has shownshown that that thethe immunotherapyimmunotherapy isis safesafe wewe wishwish totothe the immunotherapyimmunotherapy is is safesafe wewe wishwish to to improveimprove the the efficacyefficacy by by combiningcombining it it
ithith di tidi ti ththwith with radiationradiation therapytherapy,,
WeWe wishwish to to useuse a a singlesingle lowlow dosedosef tif ti i d t bi d t b blbl tt t tt tfractionfraction in order to be in order to be ableable to to treattreatpreviouslypreviously irradiatedirradiated patients.patients.
Investigation of Rats with intracerebral implanted N29 Brain Tumors after Single implanted N29 Brain Tumors after Single fraction 5 or 15 Gy Radiotherapy combined with Immunotherapywith Immunotherapy.
Bertil R.R. Persson 1,4), ,
In Collabration with Catrin Bauréus K ch 2 4) Gustav Grafström 2 4) Catrin Bauréus Koch 2,4), Gustav Grafström 2,4), Crister Ceberg 2,4),Per Munck af Rosenschöld 2,4), Bengt Widegren 3,4) and Leif G. Salford 1,4)
Number of Survivals versus total number of rats in each group with intra cerebral implanted N29tumors treated with IFN-g cell immunization (IMU IFNg), single fraction radiation therapy (RT) and their
combination at 7 days after inoculation. Immunization was repeated for at least two more times at days 21 and 35.
In the lower panel is given the primary survival rate in %. The percentageof the challenged animals that didn’t develop any tumor. given in the
middle panel multiplied with the fraction of primary survival gives themiddle panel, multiplied with the fraction of primary survival gives thepercentage of cured animal. that is displayed in the upper panel.
ConclusionThe most effective therapeutic regime for N29 t s i f ti f di ti th f 5 G tumors is one fraction of radiation therapy of 5 Gy combined with immunization.The immunization repeated for at least two more The immunization repeated for at least two more times at days 21 and 35.
This regime resulted in a significant prolonged survival and 75% complete remissions (p<0.05).
Corresponding combination with 15 Gy RT resulted in 50% complete remissions Neither immune therapy 50% complete remissions. Neither immune therapy nor radiation therapy alone with 5 or 15 Gy resulted in any significant therapeutic effect.
Investigation of Rats with subcutaneously implanted N29 Brain Tumors after 4 implanted N29 Brain Tumors after 4 fractions 5 Gy Radiotherapy combined with ImmunotherapyImmunotherapy.
Bertil R.R. Persson 1,4), ,
In Collaboration with Catrin Bauréus K ch 2 4) Gustav Grafström 2 4) Catrin Bauréus Koch 2,4), Gustav Grafström 2,4), Crister Ceberg 2,4),Henrietta Nittby 1,4), Bengt Widegren 3,4) and Leif G. Salford 1,4)
Tumour growth rate “TGR” is estimatedf th t l t bfrom the tumour volume measurements byfitting the data of each individual tumourto a model of exponential growthto a model of exponential growth
0 exptTV TV TGR t 0 exptTV TV TGR t
where
“TVt” is Tumour volume at time tt is time after first treatment.
“TV0” is Tumour volume at time t = 0,“TGR” is tumour growth rate constant (% per day)
Tumour growth rate of subcutaneous N29 Tumour growth rate of subcutaneous N29 tumourstumours: : Controls and after treatment withControls and after treatment withControls and after treatment with Controls and after treatment with
RT, IFNRT, IFN immunization or their combinationimmunization or their combination ur
Th STE i l t 0Th STE i l t 0 h thh thThe STE is equal to 0The STE is equal to 0 when the average when the average of tumour growth rate constant of the of tumour growth rate constant of the exposed group, is equal to the average of exposed group, is equal to the average of the tumour growth rate constant of thethe tumour growth rate constant of thethe tumour growth rate constant of the the tumour growth rate constant of the controlcontrol..
The STE is equal to 1 when the average h f h dtumour growth rate constant of the exposed
Mechanism of Abscopal effect ?Ionizing radiaation ???ROS???
p
Conclusion:Conclusion:
Based on the findings that immunization combined with 5immunization combined with 5 Gy radiation therapy increased the y pysurvival time 87% (p=0.003) with 75% l t i i75% complete remissions, new regimes of glioma treatmentregimes of glioma treatment might be developed.
For example single fractionFor example, single fraction radiation therapy sessions with a target absorbed dose in the order of 5 10 Gy combined with clinically5 - 10 Gy combined with clinically proven immunotherapy.
Due to the moderate absorbed doseDue to the moderate absorbed dose, relapse patients previously treated to f ll d i h b fi f i lfull dose might benefit from a single fraction radiation therapy of 6 Gy py ycombined with immunotherapy.
Another benefit of the moderate absorbed dose is that if the responseabsorbed dose is that, if the response in not complete after the first
ddi i l bi dtreatment, additional combined treatments with single fraction gradiation therapy and i th i ld bimmunotherapy sessions could be given with a few weeks interval.
Other alternati es than the presentlOther alternatives than the presently used immunization by vaccination with the patient´s own tumor cells might be used, such as dendritic cell vaccines or ,other clinically proven methods of immunizationimmunization.
RIGTT History ?RIGTT History ?RIGTT History ?RIGTT History ?
E i L d 2001 INF ll• Experiment at Lund 2001: INF- cells• Lumniczky Safrani 2002: GM-CSF cellsy• Prins and Graf 2002: Autol. Tum cells• Sandra De Maria 2005: CTLA-4 blockadeSandra De Maria 2005 CTLA 4 blockade• Newcomb 2006: GM-CSF• Sharp NCI 2007: AntiFAS mAb• Sharp NCI 2007: AntiFAS mAb• Teitz-Tennenbaum 2008: Dendritic cells
N b 2010 i CD137 Th• Newcomb 2010: Anti-CD137 Therapy