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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

Radiation Radiation immunomodulatoryimmunomodulatory gene

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Page 1: Radiation Radiation immunomodulatoryimmunomodulatory gene

R I G TR I G T TTR I G T R I G T TT

Radiation Radiation immunomodulatoryimmunomodulatorygene tumor therapygene tumor therapygene tumor therapy gene tumor therapy

Bertil R.R. Persson PhD, Bertil R.R. Persson PhD, MDh.cMDh.c..Professor of Professor of medicalmedical radiationradiation physicsphysics

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 SwedenSweden85 U85 U SS

瑞典瑞典

Page 2: Radiation Radiation immunomodulatoryimmunomodulatory gene

“BRIGTT”“BRIGTT” 脑免疫基因肿瘤治疗脑免疫基因肿瘤治疗BRIGTTBRIGTT 脑免疫基因肿瘤治疗脑免疫基因肿瘤治疗nao3 mian3 yi4 ji1 yin1 zhong3 liu2 zhi4 liao2 nao3 mian3 yi4 ji1 yin1 zhong3 liu2 zhi4 liao2

BrainBrain ImmunoImmuno GeneGene TumourTumour TherapyTherapyBrain Brain ImmunoImmuno Gene Gene TumourTumour TherapyTherapy

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

GlioblastomaGlioblastoma MultiformeMultiformeGlioblastoma Glioblastoma MultiformeMultiforme

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

Page 3: Radiation Radiation immunomodulatoryimmunomodulatory gene

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

2010-11-13 3 [email protected]

Page 4: Radiation Radiation immunomodulatoryimmunomodulatory gene

Grows with armsas an octopus

S d i iSends migrating“guerilla-cells”I t thInto the sur-rounding brain

h th BBBwhere the BBBis intact

Salford

Page 5: Radiation Radiation immunomodulatoryimmunomodulatory gene

Timeline of immunization andTimeline of immunization andTimeline of immunization and Timeline of immunization and monitoring procedures.monitoring procedures.g pg p

2010-11-13 5 [email protected]

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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

free survival (PFS).

2010-11-13 6 [email protected]

Page 7: Radiation Radiation immunomodulatoryimmunomodulatory gene

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

2010-11-13 7 [email protected]

Page 8: Radiation Radiation immunomodulatoryimmunomodulatory gene

ConclusionsConclusions

Immunizations with autologous, irradiated tumor cells transfected with the gene for IFN- in patients with glioblastoma multiforme is

• Safe,

• Feasible in slightly less than 50% of eligible patients

• Show signs of clinical efficacy.

The small number of patients warrants further studies in larger cohorts.

2010-11-13 8 [email protected]

Page 9: Radiation Radiation immunomodulatoryimmunomodulatory gene

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.

2010-11-13 9 [email protected]

Page 10: Radiation Radiation immunomodulatoryimmunomodulatory gene

MRI (T1 with gadolinium) MRI (T1 with gadolinium) images from nonimages from non--responding responding and responding patients and responding patients

preoperativelypreoperativelypreoperatively, preoperatively,

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).

2010-11-13 10 [email protected]

Page 11: Radiation Radiation immunomodulatoryimmunomodulatory gene

”RIGTT” ”RIGTT” RadiationRadiation ImmunoImmunoGene Tumor Gene Tumor TherapyTherapy

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.

2010-11-13 [email protected]

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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)

1)Dept. Neurosurgery, Lund University, SE-221 85 LUND, Sweden2)Dept. Radiation Physics, Lund University, SE-221 85 LUND, Sweden3)Dept Tumorimmunology Lund University BMC Box 7031 SE 220 07 Sweden;3)Dept. Tumorimmunology, Lund University, BMC Box 7031, SE 220 07, Sweden;4)Rausing Laboratory, Biomedical Centre, Lund University, 221 85 LUND, SwedenE-mail: [email protected]

2010-11-13 [email protected]

Page 13: Radiation Radiation immunomodulatoryimmunomodulatory gene

Groups of animals with various treatments in the various experiments with N29 and N32 tumorsvarious experiments with N29 and N32 tumors.

text

2010-11-13 [email protected]

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Animals were given a single radiation treatment using a 60Co radiotherapy unitg py

text

2010-11-13 [email protected]

Page 15: Radiation Radiation immunomodulatoryimmunomodulatory gene

Inoculation at day 0 and treatments were performed at day 7 after inoculationperformed at day 7 after inoculation

text

Complete remissions 75 %

Day 40-60

2010-11-13 [email protected]

Page 16: Radiation Radiation immunomodulatoryimmunomodulatory gene

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.

text

2010-11-13 [email protected]

Page 17: Radiation Radiation immunomodulatoryimmunomodulatory gene

Survival plot of intra cerebral implanted N29 tumors Controls (Lower panel). Immunization withsyngeneic N29 tumor cells (2nd panel); radiation therapy (3rd panel) and a combination of

radiation therapy and immunization (upper panel).

text

2010-11-13 [email protected]

Page 18: Radiation Radiation immunomodulatoryimmunomodulatory gene

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.

text

2010-11-13 [email protected]

Page 19: Radiation Radiation immunomodulatoryimmunomodulatory gene

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.

2010-11-13 [email protected]

Page 20: Radiation Radiation immunomodulatoryimmunomodulatory gene

Subcutaneously implantedN29 Brain Tumors

2010-11-13 [email protected]

Page 21: Radiation Radiation immunomodulatoryimmunomodulatory gene

N29 tumours inoculated N29 tumours inoculated Subcutaneously on both sidesSubcutaneously on both sides

lsls

50 0

00 c

ells

50 0

00 c

ells

200

000

cel

200

000

cel

Only the righttumour was

55 22tumour was irradiated

RRS 2009 [email protected]

Page 22: Radiation Radiation immunomodulatoryimmunomodulatory gene

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)

1)Dept. Neurosurgery, Lund University, SE-221 85 LUND, Sweden2)Dept. Radiation Physics, Lund University, SE-221 85 LUND, Sweden3)Dept Tumorimmunology Lund University BMC Box 7031 SE 220 07 Sweden;3)Dept. Tumorimmunology, Lund University, BMC Box 7031, SE 220 07, Sweden;4)Rausing Laboratory, Biomedical Centre, Lund University, 221 85 LUND, SwedenE-mail: [email protected]

2010-11-13 [email protected]

Page 23: Radiation Radiation immunomodulatoryimmunomodulatory gene

10000Cotrol Group 11 Left side

ControlsControls1000

t 5410me

/ mm

3

ControlsControls

100

rat 5410 rat 5411 rat 5412 rat 5413 rat 5414 rat 5415 rat 5416rat 5417

Tum

or V

olum

0 10 20 30 40 50 60 70 80 90 10010

rat 5417 Average Exp Growth fit

r2 0.98

Time after inoculation / daysCotrol Group 11 Right side

Time after inoculation / days

1000

10000

e / m

m3

100

rat 5410 rat 5411 rat 5412 rat 5413 rat 5414 rat 5415 rat 5416rat 5417Tu

mor

Vol

ume

0 10 20 30 40 50 60 70 80 90 10010

rat 5417 Average Exp Growth fit

r2 0.92

Time after inoculation / days

RRS 2009 [email protected]

y

Page 24: Radiation Radiation immunomodulatoryimmunomodulatory gene

10000Immunotherapy Left side IFN

at days 15; 29; 43;

1000

rat 5334ume

/ mm

3 ImmunotherapyImmunotherapy100

rat 5334 rat 5341 rat 5353 rat 5372 rat 5356 rat 5364 rat 5369 rat 5337Average

Tum

or V

olu

i.p injection of

0 10 20 30 40 50 60 70 80 90 10010

g Exp growth

r2 0.999

Time after inoculation / days

p jIFN

tumor cells

10000Immunotherapy Right side IFN at days 15; 29; 43;

1000

IFN at days 15; 29; 43;

me

/ mm

3

100

rat 5334 rat 5341 rat 5353 rat 5372 rat 5356 rat 5364 rat 5369rat 5337

Tum

or V

olum

i.p injection of IFN

tumor cells

0 10 20 30 40 50 60 70 80 90 10010

rat 5337 Average Exp Growth fit

r2 0.997

Time after inoculation / days

RRS 2009 [email protected]

Page 25: Radiation Radiation immunomodulatoryimmunomodulatory gene

10000RT Untreated Left side

Radiation therapRadiation therap1000

rat 5327t 5336lu

me

/ mm

3 Radiation therapyRadiation therapy

100

rat 5336 rat 5345 rat 5348 rat 5360 rat 5357 rat 5367 rat 5370 AverageExp Growth fit

Tum

or V

ol

RTRigthside

0 10 20 30 40 50 60 70 80 90 100 11010

Exp Growth fit r2 0.90

Time after inoculation / days 10000RT Right side treatment at days 29; 30; 32; 33;

1000

rat 5327 rat 5336ol

ume

/ mm

3100

rat 5345 rat 5348 rat 5360 rat 5357 rat 5367 rat 5370 Average

Tum

or V

oRT

0 20 40 60 80 10010

Exp Growth fit r2 0.89

Time after inoculation / days

RRS 2009 [email protected]

Page 26: Radiation Radiation immunomodulatoryimmunomodulatory gene

RadiationRadiationandandImmuno therapy + RT

andandImmunotherapyImmunotherapy

1000

10000 Untreated Left side IFN

at days 27; 42; 47; 55;

/ mm

3 pypy

100

1000

rat 5328 rat 5371 rat 5331 rat 5335 rat 5339m

or V

olum

e /

i p injection of

10

100 rat 5342 rat 5364 rat 5365 Average Exp Growth fit

r2 = 0.90

Tum i.p injection of

IFN tumor cells

RTright

tumor

10000Immuno therapy + RT Right side IFN

at days 27; 42; 47; 55;

0 10 20 30 40 50 60 70 80 90 100 110

Time after inoculation / days

1000

RT 29; 30; 32; 33

t 5328me

/ mm

3

100

rat 5328 rat 5371 rat 5331 rat 5335 rat 5339 rat 5342 rat 5364rat 5365

Tum

or V

olu

i.p injection of IFN

tumor cells

0 10 20 30 40 50 60 70 80 90 100 11010

rat 5365 Average Exp Growth fit

r2 = 0.93

Time after inoculation / days

RT

RRS 2009 [email protected]

Time after inoculation / days

Page 27: Radiation Radiation immunomodulatoryimmunomodulatory gene

Exponential Tumour Growth Model

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)

RRS 2009 [email protected]

Page 28: Radiation Radiation immunomodulatoryimmunomodulatory gene

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

40

10

11

12re

ated

tum

ou

t

19

88

9

10

a-la

tera

l unt

red

tum

our

pal ef

fect

15

5

6

7

r day

; Con

tra

r day

; Tre

ate

Abs

cop

2

3

4

TG

R /

% p

e T

GR

/ %

pe

Contro

ls

RT

IFNg

FNg +

RT --

0

1

2010-11-13 [email protected]

IFNg

Type of treatment

Page 29: Radiation Radiation immunomodulatoryimmunomodulatory gene

Tumour Growth rate ”TGR” of subcutaneous tumours implanted on both Right and Left hind leg. p g g

= The right tumour was treated with radiation (RT). Average of all experiments

Resultat LEFT SE Right SE N t ctrl L t Ctrl /R t R/L

Controls 9.1 0,3 8.5 0.3 40 NS

INF 9.2 0,8 7.6 0.6 19 NS NS NS

RT 6.1 0.4 4.5 0.3 15 <0.001 <0.001 <0.01

RT +INF 6.4 0.5 5.9 0.5 7 <0.001 <0.01 NS

2010-11-13 [email protected]

Page 30: Radiation Radiation immunomodulatoryimmunomodulatory gene

Specific Therapeutic Effect “STE”Specific Therapeutic Effect “STE”

is defined as followis defined as followis defined as follow.is defined as follow.

STE C ETGR TGRSTE = ; C E

C

TGR TGRTGR

ETGRThe average of the individual Tumour growth rate constant in the

f d t d 1ETGR

TGR

group of exposed rats. day-1

The average of the individual Tumour growth rate constant in CTGR the group of control rats. day-1

RRS 2009 [email protected]

Page 31: Radiation Radiation immunomodulatoryimmunomodulatory gene

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

group, is equal to 0.

RRS 2009 [email protected]

Page 32: Radiation Radiation immunomodulatoryimmunomodulatory gene

Specific therapeutic effect of subcutaneous N29 tumorsSpecific therapeutic effect of subcutaneous N29 tumors

Type of treatment

after RT, Immunization with IFNafter RT, Immunization with IFN and their combination RT+ IFNand their combination RT+ IFN

88

Radiation + IFN

Type of treatment

19

Left None Right Irradiated

1919

IFN

15Radiation

p < 0.0001

p < 0.0001

0,0 0,1 0,2 0,3 0,4 0,5

Left Specific Abscopal Effect "SAE"Right Specific Therapeutic Effect "STE"

2010-11-13 [email protected]

Right Specific Therapeutic Effect STE

Page 33: Radiation Radiation immunomodulatoryimmunomodulatory gene

CONCLUSIONCONCLUSION::

SignificantSignificant AbscopalAbscopal effecteffect waswas confirmedconfirmedpponon subcutaneouslysubcutaneously implantedimplanted NN2929 ratrat gliomagliomatumourstumours,, fromfrom contracontra--laterallateral treatmentstreatments withwithradiationradiation therapytherapy alonealone andand inin combinationcombination withwithimmunizationimmunization byby usingusing syngeneicsyngeneic interferoninterferon--yy gg y gy ggammagamma secretingsecreting tumortumor cellscells..

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Mechanism of Abscopal effect ?Ionizing radiaation ???ROS???

p

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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.

2010-11-13 [email protected]

Page 37: Radiation Radiation immunomodulatoryimmunomodulatory gene

In view of the finding that radiation enhance the antitumor effect of antitumor effect of Immune-therapy, mm py,

h bi i The combination approach should be approach should be studied further for studied further for clinical translation.

2010-11-13 [email protected]

Page 38: Radiation Radiation immunomodulatoryimmunomodulatory gene

Conclusion:

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.

2010-11-13 [email protected]

Page 39: Radiation Radiation immunomodulatoryimmunomodulatory gene

Conclusion:

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.

2010-11-13 [email protected]

Page 40: Radiation Radiation immunomodulatoryimmunomodulatory gene

Conclusion:Conclusion:

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.

2010-11-13 [email protected]

g

Page 41: Radiation Radiation immunomodulatoryimmunomodulatory gene

In view of the finding that radiation enhance the antitumor effect of antitumor effect of Immune-therapy, mm py,

h bi i The combination approach should be approach should be studied further for studied further for clinical translation.

2010-11-13 [email protected]

Page 42: Radiation Radiation immunomodulatoryimmunomodulatory gene

Conclusion:Conclusion:

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.

2010-11-13 [email protected]

Page 43: Radiation Radiation immunomodulatoryimmunomodulatory gene

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

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