Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic...
Transcript of Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic...
![Page 1: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/1.jpg)
Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS, with or without cyclophosphamide, in patients with recurrent or refractrory multiple myeloma
Angela DispenzieriMV-NIS protocol PI
David DingliLead scientist
Kah Whye PengPharm/tox
Evanthia GalanisMV-CEA protocol PI
Mark FederspielManufacture
Steve RussellSponsor
Anthony WelchNCI RAID Program
Karen SchweikartNCI RAID Program
![Page 2: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/2.jpg)
Multiple myeloma
Plasma cell malignancyParaproteinaemiaBone destructionHypogammaglobulinaemia
Currently incurable11,000 deaths per year (USA)Disseminated from outsetSurvival ~ 4yrs
![Page 3: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/3.jpg)
Virotherapy
Viruses destroy tissue
Maybe this destructive power could be Harnessed for cancer therapy
![Page 4: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/4.jpg)
Measles as an oncolytic agentHFHFHFHFHFHFHFHFHFHFHFHFHFHFHFHFH
FHFHF
HFHFHF
HFHF H
FHFHFHF
N P M F H L
115894
N PVC M F H L
Bluming and Ziegler (1971) Lancet ii, 105-106
-Efficiently infects and kills human myeloma cells (via CD46)
-Selectively kills myeloma cells, spares normal cells
-Has potent antitumor activity against xenograftmodels of human multiple myeloma
-Can be engineered to express additional genes;recombinants are extremely stableSLAM only SLAM + CD46
![Page 5: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/5.jpg)
Edmonston Vaccine Lineage
Edmonston
Edmonston-EndersEdmonston “Wild Type”
EdmonstonSeed A
AIK-C
Edmonston Seed B
Zagreb
Schwarz
Moraten MV-SPUDEdmonston BRubeovax
HK/7Vero/6 HK/24
HA/28
HK/24HA/28
HA/12SK (33oC)/17*CEF (33oC)/22*
CE (am)/22DK/15WI-38/19*
CE(am)/6CEF/3
CEF/5CEF (32oC)/85
HeLaCEF(36oC)/8CEF(32oC)40
CEF(36oC)/3
Infectious clone
(Rota et al. 1994, Virus Res., 31:317)
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
(Radecke et al., 1995 EMBO J, V14, p5773)
![Page 6: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/6.jpg)
Measles virus cytopathic effect (cell fusion)
Entry
Fusion
Apoptosis
![Page 7: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/7.jpg)
Fusogenic proteins: measles F and H
CD46SLAM
H F
H binds to CD46 or SLAMF triggers fusion
SLAM is expressed only on activated immune cells.CD46 is ubiquitous CD46 is overexpressed on human myeloma cells…..
![Page 8: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/8.jpg)
•Expressed at higher density on myeloma cells•NOT myeloma specific•Therapy should specifically attack high density
High CD46 expression in multiple myeloma
CD46 FITC
CD
38 P
E
CD46 density of plasma cells vs non-plasmacells in whole bone marrow
PC NPC10
100
1000
Groups
Unsorted bone marrow aspirated from patients with multiple myeloma
Plasma cells Non-plasma cells
![Page 9: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/9.jpg)
Syncytia Index
CEA levels
Cell viabilityS
yncy
tial
inde
x
Syncytial Index
Cell Killing
![Page 10: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/10.jpg)
MV-Edm oncolytic activity in myeloma
Peng et al., Blood, 98, p. 2002-7 (2001).
![Page 11: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/11.jpg)
Measles virotherapy for myeloma:Problems with MV-Edm.
1. Inability to monitor spread
2. Anti-measles antibodies may block vascular delivery
3. Anti-measles cytotoxic T lymphocytes may prevent intratumoral spread
![Page 12: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/12.jpg)
Recombinant measles viruses
N P M F H L
CEA NIS
MV-NIS: IV multiple myeloma
MV-CEA: IP ovarian cancer
![Page 13: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/13.jpg)
MV-CEA Clinical Protocol
•Advanced ovarian cancer
•IP administration of MV-CEA in 500 ml saline
•Repeated every four weeks x 6
•Dose escalation (103 to 108)
•CEA monitoring to guide dose escalation
•No manufacturing problems
•Six patients treated (three at 103, three at 104)
•No dose-limiting toxicities
•Transient viremia in two patients
•No CEA elevations yet……
![Page 14: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/14.jpg)
![Page 15: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/15.jpg)
The thyroidal sodium iodide symporter (NIS)
Radioiodine
I-123 gamma 0.5 daysI-124 positron 4 daysI-125 gamma 60 days
I-131 beta + gamma 8 daysTc99m gamma 0.2 days
QuickTime™ and aPhoto - JPEG decompressor
are needed to see this picture.
![Page 16: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/16.jpg)
Imaging virus spread (MV-NIS)
I-123 or I-124 ip
NIS gene
PET/CT
SPECT/CT
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
MV-NIS iv
NIS protein
Gamma camera
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
![Page 17: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/17.jpg)
MV-NIS (intravenous) is a potent anti-myeloma agent
d3
d9
d14
-10 0 10 20 30 40 50 60 70 80 90 100 110 1200
500
1000
1500
2000
2500
3000
UV-inactivated104 MV-NIS105 MV-NIS106 MV-NIS107 MV-NIS
Time After Therapy (days)
Tumor volum
e (mm
3)
KAS6/1 model
![Page 18: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/18.jpg)
Measles virotherapy for myeloma:Problems with MV-Edm.
1. Inability to monitor spread
2. Anti-measles antibodies may block vascular delivery
3. Anti-measles cytotoxic T lymphocytes may prevent intratumoral spread
![Page 19: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/19.jpg)
Low Anti-Measles Antibody Titers in Myeloma Patients
Normal MGUS MM MM (SCT)0
100
200
300NormalMGUSMMMM (SCT)
EU/m
l
![Page 20: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/20.jpg)
Cyclophosphamide suppresses immune response to MV
IFNAR Ko CD46 Ge mice
+/- cyclophosphamide 125 mg/kg
10
100
1000
10 4
4 8 11 15 22 29
- cyclo+ cyclo
[CEA
] ng/
ml
Time (days)
IP injection MV-CEA
Detectionlimit 0.5 ng/ml1
10
100
1000
104
105
0 2 4 6 8 10
Days post infection
Seru
m [C
EA] n
g/m
l
10e7 pfu
10e5 pfu
12
Peng et al, Nature Medicine 2002, 8, 527-531
![Page 21: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/21.jpg)
The Status of Myeloma Therapy
• Progress past decade….Transplantation, thalidomide, lenilidomide, bortezumib
• But patients dying—no cure in sight11,000 deaths per year; 15,000 new cases
• Innovative therapies are required
![Page 22: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/22.jpg)
No Survival Plateau
Single versus Double Transplant
Median EFS < 3 years
Attal NEJM 349:2495-02
EFS
, %
![Page 23: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/23.jpg)
Phase I TrialStep 1: MV-NIS aloneAgent Dose Route DayMV-NIS 106 to 109 30 min I.V. 1
TCID50
Step 2: MV-NIS + CyclophosphamideAgent Dose Route DayCyclo 10 mg/kg I.V. -2
MTD/100 to 30 min I.V. 181 x MTD/100)
MV-NIS
![Page 24: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/24.jpg)
Trial SchemaCTX
-2 1 8 Q 3 mo282015 42Day -4
Cytomel®
3
MV-NIS
Cyclophosphamide
MV-NIS 123-I gamma camera imaging
CBC, chemistry, coagulation
KEYFree light chain
Anti-MV antibody and T cell subsetsViral levels, Blood, sputum & urine
Bone marrow aspirate/biopsy
![Page 25: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/25.jpg)
1. Cytomel: tachycardia, tremor
Potential toxicity & complicationsScreen for symptomatic
2. 123-I: none
3. MV-NISa. Infusion reaction b. Measles-like illness c. Virus transmission
4. Cyclophosphamidea. Immunosuppression: worsening of 2b-c?
CAD and arrhythmia.Reduce dose to 25 mcg bid
![Page 26: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/26.jpg)
• Allergic → acetaminophen & benadryl
• Rigors→ meperidine hydrochloride
• Anaphylaxis → cessation of infusion; fluids, benadryl,
methylprednisone and epinephrine
Potential toxicities-MV-NISInfusion reactions
![Page 27: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/27.jpg)
Potential complications-MV-NISMeasles-like illnessFever, rash, coryza, transient immune
suppression ± otitis media, pneumonia, encephalitis
Possible since myeloma patients are immunocompromised, but should be self-limited because….
![Page 28: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/28.jpg)
Potential complications-MV-NISMeasles-like illness…. because measles vaccine….
…..strains are extremely safe after billions of doses administered
…..is recommended for HIV-infected children Immunosuppressed patients following HSCTDykewicz CA. Summary of the Guidelines for Preventing Opportunistic Infections among HSCT Recipients. Clin Infect Dis. 2001;33(2):139-44
We routinely give MMR post HSCT to MM patients
![Page 29: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/29.jpg)
Potential complications-MV-NISMeasles-like illness
Contingency plan
Measles immunoglobulinRibavirin
Clin Infect Dis 1994; 19(3):454-62Antivir Chem Chemother 2004; 15(3):111-9
![Page 30: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/30.jpg)
Potential complications-MV-NIS Safety of Starting Dose?
106 TCID50HIV+ & HIV- infants
Am J Dis Child 1992; 146(5):550-5; Pediatr Infect Dis J 1991; 10(4):303-11; Vaccine 1995; 13(3):276-80.
Edmonston IV to monkeysNEJM 1960; 263(4):153-9.
Upcoming primate studiesEfficacy: Lowest effective in mice: TCID50 105 (~5 x 106/kg); Trial starting dose:
106 ~ 1.4 x 104/kg in 70 kg human
![Page 31: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/31.jpg)
Potential toxicities-MV-NIS Transmission to contacts?
RNA virus – mutation possible, but…
Vaccine strains of measles never reported to revert and/or to be transmitted
Vast majority of U.S. citizens vaccinated for measles
![Page 32: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/32.jpg)
Possible pharmacology/toxicology models
1. CD46 transgenic IFNaRko mice (+/- SCID)
2. CD46 transgenic pigs
3. Cotton rats
4. New world (eg squirrel) monkeysOld world (eg rhesus) monkeys
3. +/- cyclophosphamide
Issues: CD46 expression SLAM expression intracellular restriction
![Page 33: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/33.jpg)
MV-NIS biodistribution in CD46tg, IFNARko mice (preliminary)
Group1 105 TCID50 MV-NIS Studies performed day 90 afterGroup 2 107 TCID50 MV-NIS MV-NIS administration wereGroup 3 UV-inactivated MV-NIS negative for all organs, all groups.Group 4 125 mg/kg cyclophoshpamide plus
107 TCID50 MV-NIS
Thyr
oid
Bra
inLu
ngH
eart
Live
rKi
dney
Sm
all i
ntes
tine
Pan
crea
sSp
leen
Test
esM
uscl
e Bl
ood
Bron
chia
l lav
age
Thyr
oid
Bra
inLu
ngH
eart
Live
rKi
dney
Sm
all i
ntes
tine
Pan
crea
sSp
leen
Ova
ries
Mus
cle
Bloo
dBr
onch
ial l
avag
e
![Page 34: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/34.jpg)
Potential complications-MV-NISMeasles-like illness, virus persistence or transmission?
Group MV-NIS (TCID50)
CTX (mg/kg)
I 0 0
II 0 31
III 108 0
IV 108 31
Primate Toxicology(12 Squirrel Monkeys)
Primate studies with scheduled sacrifice
Two monkeys from each group: day 29Remaining animals: day 91
![Page 35: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/35.jpg)
Squirrel Monkey SchemaMV-NIS
-2 1 8 50292215 36 9143Day
CTX Sacrifice Sacrifice
CTX
MV-NIS
CBC, chemistry, coagulation
Cytokine measurementAnti-MV antibody measurementViral levels, sputum & urine (PCR)Viral levels, blood (PCR)
KEY
Sacrifice-necroscopy
![Page 36: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/36.jpg)
Monkey Necrospy Samples (41)
Kidneys, bladder, adrenalsBone, femoral head with articular surfaceBM: sternum and ribEyes, brain, pituitary, spinal cord, sciatic nerveStomach, esophagus, duodenum, jejunum, ileum, cecum, colonGonads, prostate, epididymidesLiver, spleen, gall bladder, pancreas
Gross lesionsHeart, AortaLip, salivary gland, tongue, tonsils Lungs, tracheaLN: bronchial, mandibular, mesentericMammary glandSkeletal muscleSkin: ventral abdomen, injection siteThymus, thyroid, parathyroid
![Page 37: Phase I trial of systemic administration of Edmonston ... · Phase I trial of systemic administration of Edmonston strain of measles virus, genetically engineered to express NIS,](https://reader031.fdocuments.in/reader031/viewer/2022041022/5ed2d88f51a89a533c3d3b55/html5/thumbnails/37.jpg)
Safety EfficacySummary
Myeloma is an incurable disease with pressing need for innovative therapeutic strategiesMV-NIS targets myeloma cells preferentially using CD46Preclinical data and careful trial design lead us to believe that we can safely administer this therapeutic agent