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Adenovirus mediated IFN-γ expression in cutaneous lymphomas: monitoring of local
and systemic events
R. Dummer, P. Squiban, P. Bleuzen, B. Acres, S. Eichmüller, M. Urosevic
Skin cancer unit
German Cancer Research Center
Heidelberg, Germany
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Immune intervention in MF using a third generation adenoviral vector system
Epidermis derived viability factors
Epidermis
TH 2TH 1
IL-5-
+
IL-10
-Immunosuppression
PBMC
Macro-phage
NK
T-LY
CD8
eosinophilia IgE IgA
++
+X
IK
Adeno IFN-g
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�INT INTERFERON-GAMMA
The vector:Adeno-IFN-γTG1042 (Transgene)
The recipients:H-CAR expression in CTCL
Local Local IFNIFN--γγ productionproduction
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Phase I: TNM stage Ib or higherFailure of local tumor control by at least 2 first line treatmentsDose-Escalating
3 Dose levels: 3X10E9, 3X10E10, 3X10E11 tp3 Patients / dose level
3X10E11 tp 12 additional patients March 2002- Sept. 2004
TG1042.01 : Cutaneous LymphomasTG1042.01 : Cutaneous Lymphomas
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Inclusion criteria:Histologic proof of CTCL or CBCLPerformance status 0,1 or 2 on the ECOG scaleTNM stage Ib or higherat least 2 first-line treatmentsNo systemic chemo- or immunotherapy within preceding 3 weeksMinimum life expectancy > 3 monthsAdequate hematologic, hepatic and renal function
Exclusion criteria:• HIV+ or other active systemic infections• Serious concomitant systemic medical disorders• Concomitant corticosteroid therapy• Major surgery in previous 3 weeks• Pregnancy• Other therapies for lymphoma
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Treatment plan
Baseline
d1 d8 d15
Tumor assessment
d29 (d1) d8 d15 d29
Tumor assessment
1. treatment cycle 2. treatment cycle, etc.
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Side effects
Mainly locally: erythema, oedema, painFlu-like symptoms: chills and fever, head-ache, dizzinessFatigueFlushingNo relevant changes in routine laboratory valuesNo SAEs nor Grade 3/4 toxicities
before
Adeno-IFN-γ
after 1st injection
after 2nd injection
P-M 009
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Outcome/Response
Patient Age Sex DG Stage Dose (tp)No. of
injectionsResponse
I.L.Response non I.L.
Response overall
Response duration
#001 84 M MF Ib 3·10E+9 9 PR SD PR 6 mo
#002 66 F MF IIa 3·10E+9 12 CR CR CR 1 mo
#003 25 M MF Ib 3·10E+9 12 SD SD SD n.e
#004 44 F MF IIb 3·10E+10 3 SD PD PD n.e
#005 46 M SS III 3·10E+10 9 SD SD SD n.e
#006 39 F LyP n.a. 3·10E+10 5 CR CR CR 3 mo
#007 67 M SS III 3·10E+11 3 SD SD SD n.e
#008 34 M MZL n.a. 3·10E+11 9 PR n.e. n.e. 5 mo
#009 34 M FCCL n.a. 3·10E+11 3 CR SD PR 1 mo
#010 59 M FCCL n..a. 3·10E+11 3 CR n.a. CR 14 mo
#011 87 F MF IIb 3·10E+11 14 n.e n.e. n.e. n.e
#012 58 M FCCL n.a. 3·10E+11 2 n.e
#013 46 M CD30+ LTCL IIb 3·10E+11 3 CR n.a. CR 3 mo
#014 55 M CD30- LTCL IIb 3·10E+11 3 SD PD PD n.e
#015 55 M LyP n.a. 3·10E+11 12 PR SD PR 5 mo
#016 66 F CD30+ LTCL IIa 3·10E+11 12 CR n.a. CR 9 mo +
#017 31 M GSS IIb 3·10E+11 15 PR n.a. SD ongoing
#018 93 F MF IIb 3·10E+11 12 SD SD SD n. e.
#019 49 M CD30+ LTCL IIb 3·10E+11 6 SD SD SD 6 mo +
#020 54 M CD30+ LTCL IIb 3·10E+11 3 CR n.a. CR 6 mo +
treatment interrupted due to SAE
OR: 11/20 3/12 8/17
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PUVA resistant CD30+ CTCL
3 months later
9 months later
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Mycosis fungoidesbefore after 9 injections
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Primer design for vector encoded vs. endogenous IFN-γ
ITR CMV
TG1042-derived IFN-γprimers
endogenous IFN-γprimers
intron 1 IFN-γ cDNA
Leader sequence IFN-γ cDNA
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TG1042-derived IFN-γ and endogenous IFN-γ
1
10
100
1000
10000
100000
1000000
10000000
#001
_0
#001
_3
#002
_0
#002
_3
#002
_6
#003
_0
#003
_3
#004
_0
#004
_3
#005
_0
#005
_3
#005
_6
#006
_0
#006
_3
#007
_0
#007
_3
#008
_0
#008
_3
#008
_6
#008
_9
#009
_0
#009
_3
TG1042_IFN‐γ/GAPDHIFN‐γ/GAPDH
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1
10
100
1000
10000
100000
1000000
#010
_0
#010
_3
#011
_0
#011
_3
#011
_12
#013
_0
#013
_3
#014
_0
#014
_3
TG1042_IFN‐γ/GAPDHIFN‐γ/GAPDH
TG1042-derived IFN-γ and endogenous IFN-γ
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H&E H&E
Mycosis fungoides
before after
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TIATIA
Mycosis fungoides
before after
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H&EH&E
CBCL
before after 3 Injections