George Sgouros, Ph.D.

Russell H. Morgan Dept of Radiology & Radiological Science

Johns Hopkins University, School of Medicine

Baltimore MD

Physics in Theranostics

Disclosures

Consultant: Bayer, Roche

Scientific Advisory Board: Orano Med

Founder: Radiopharmaceutical Imaging and

Dosimetry (RAPID), LLC

Theranostics, Defined

Choudhury, P Gupta M.

Current Radiopharm. 2017

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

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?

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

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

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

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.

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

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:

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)

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

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

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

• 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

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

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

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