physics in theranosticsamos3.aapm.org/abstracts/pdf/155-53812-1531640-157608.pdfgeorge sgouros,...
TRANSCRIPT
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George Sgouros, Ph.D.
Russell H. Morgan Dept of Radiology & Radiological Science
Johns Hopkins University, School of Medicine
Baltimore MD
Physics in Theranostics
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Disclosures
Consultant: Bayer, Roche
Scientific Advisory Board: Orano Med
Founder: Radiopharmaceutical Imaging and
Dosimetry (RAPID), LLC
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Theranostics, Defined
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Choudhury, P Gupta M.
Current Radiopharm. 2017
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Radionuclide
pair
Half-lives
64Cu/67Cu 12.7 h / 2.6 d
86Y/90Y 14.7 h / 2.7 d89Zr/90Y 3.3 d / 2.7 d
86Y/90Y 14.7 h / 2.7 d123I/131I 13.2 h / 8.0 d
124I/131I 4.2 d / 8.0 d
124I/186Re 4.2 d / 3.7 d
124I/188Re 4.2 d / 17 h
68Ga/67Ga 1.13 h / 3.3 d
68Ga/177Lu 1.13 h / 6.6 d
18F/177Lu 1.83 h / 6.6 d
18F/223Ra 1.83 h / 11.4 d
111In/225Ac 2.8 d /10 d
89Zr/225Ac 3.3 d /10 d
89Zr/227Th 3.3 d /18.7 d
Theranostic Radionuclide Pairs
Sgouros, et al. Nature Reviews DD, In Press
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Radiopharmaceutical TherapyMolecular Radiotherapy (MRT),
Targeted Radionuclide Therapy
Radioimmunotherapy (RIT)
Agent distributes throughout body
Reacts with/binds to target cells
Cleared from non-target cells
Prolonged exposure to target cells
gives larger radiation dose to target cells
than to normal cells
Where (else) does the drug
concentrate, and for how long?
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Radiopharmaceutical therapy
• RPT provides targeted delivery of radiation
• Not susceptible to resistance mechanism seen in
chemotherapy
• Kills target cells vs inhibiting growth/survival
pathways; precludes adaptation
• Can measure delivery of the therapeutic agent to
tumor targets and to normal organs
• Guide escalation protocols and plan treatment
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Theranostics - Assess eligibility
• Is the target expressed?- screening for clinical trial/therapy eligibility
• analogous to genetic testing/ biomarker paradigm
- Typically use PET radionuclides
- Ga-68, Zr-89, F-18, I-124
- Image at a single time-point; optimal imaging time?
- Radionuclide half-life constrains imaging time-point
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Is the target expressed?
Ho, et al. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer. NEJM 2013
Undifferentiated
thyroid cancer
Following MEK
inhibitor
I-124 PET imaging
MEK inhibitor restores
NaI symporter in
thyroid cancer cells
that would ordinarily
no be effectively
treated by radioiodine
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What does “dose” mean?
• In chemotherapy/medicine, in general “dose” refers to the quantity of an agent that is administered to the patient.
• In RPT, the relevant quantity is “absorbed dose” –the amount of energy absorbed per unit mass.
• This is not equal to the amount of radioactivity administered.
• Absorbed dose is most closely related to biologic effect.
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Absorbed Dose → Biological Effects
• Diagnostic Imaging: risk of cancer
- Stochastic (prob of effect occurring w/ dose)
- Atomic bomb survivor epidemiological data
- BEIR organ dose estimates → probability of cancer
- Need whole organ doses to estimate risk of diag. imaging
• Therapy: efficacy and toxicity
- Deterministic (effect w/ dose)
- Radiotherapy, pre-clinical, phase 1 studies
- Dose distribution, radiobiology → efficacy, toxicity
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number of dis.
Absorbed Dose calculaton
x
energy released per dis.
x
fraction that is
absorbed
mass of target tissue
Energy absorbed per unit mass:
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Time-integrated activity
Time (d)
ÃLI
0 1 2 3 −
=0
0
t
LILI
effefAA~
eff
LILI
fAA
= 0
~
0
~
A
Af LI
eff
LILI ==
t
LILI
effefAtA−
= 0)(
ALI (t)
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Theranostics - Dosimetry surrogate
• Use “surrogate” to get dosimetry for therapeutic- In-111 for Ac-225
- Y-86 for Y-90
- I-124 for I-131
• Image surrogate (𝑺), extrapolate to therapeutic (𝑻)
𝐴𝑻(𝒕) = 𝐴𝑺(𝒕) ∙ 𝒆𝝀𝑺−𝝀𝑻 𝒕 𝝀 =
𝒍𝒏(𝟐)
𝑻• Assumes surrogate PK = therapeutic PK
- Chemistry, stability, molecule type
- MW of labeling chemistry relative to targeting molecule
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Theranostic pair for dosimetry
0 5 10 15 20 25
0.0
0.2
0.4
0.6
time (d)
Fra
cti
on
In
j. A
ct.
tumor
tumor 124
tumor 131
marrow
marrow 124
marrow 131
liver
liver 131
liver 124
I-124-Ab for I-131 Ab therapy
4.2 vs 8.02 d half-lives
0 5 10
0.00
0.05
0.10
0.15
0.20
time (d)
Fra
cti
on
In
j. A
ct.
tumor
tumor 124
tumor 131
marrow
marrow 124
marrow 131
liver
liver 124
liver 131
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Theranostic pair for dosimetry
Ga-68-peptide for Lu-177-peptide
1.13h vs 6.6d
0 24 48
0.0
0.2
0.4
0.6
time (h)
Fra
cti
on
In
j. A
ct. tumor
tumor Ga
tumor Lu
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• Current constraints will be outdated in 5-10 y
• CZT detectors
• Reconstruction algorithms
• Better energy resolution
• Higher sensitiviety
• Greater accuracy
• Image very low activities of alpha-emitters
• Very high activities folowing therapy
• Image the therapeutic rather than the surrogate
Imaging Technology
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1980
1985
1990
1995
2000
2005
2010
2015
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0a lp h a -e m it te r R P T
Y e a r
No
. o
f p
ub
lic
ati
on
s
A c -2 2 5 o r B i-2 1 3
A t-2 1 1
P b -2 1 2 o r B i-2 1 2
R a -2 2 3
T h -2 2 7
Sgouros, et al. Nature Reviews DD, In Press
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Conclusions
• Theranostics involves radionuclide pairs- Intimately tied to radiopharmaceutical therapy (RPT)
- “See then treat”
• May be used for dosimetry
• Matching half-life w/ kinetics of RPT is critical
• Imaging will be very different soon- New therapeutic agents
- Expanded scope of radionuclides
• αRPT is ascendant- High LET particles
- Impervious to conventional resistance mechanisms
- Delivered directly to cancer cells
- Radionuc supply
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Acknowledgments
NIH
DOD
DOE
Rob Hobbs
Anders Josefsson
Ioanna Liatsou
Jing Yu
Yingli Fu
Remco Bastiaannet
Alireza Karimian
Jessie Nedrow
Senthamil Srinivasan
Donika Plyku
Hong Song
Andy Prideaux
Mohana Lingappa
Sunju Park
Kitiwat Khamwan
Eric Frey
Richard Wahl
Ivan Guan
Kevin Yeh
Sagar Ranka
Nathan Ji
Ryan Lu
Martin Pomper
Benjamin Tsui
James Fox
Yuchuan Wang
Hong Fan
Ron Mease
David Huso
Kathy Gabrielson
Zaver Bhujwalla
Barjor Gimi
VP Chacko