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... Klinik und Poliklinik. Companion Diagnostics. Agarwal, A. et al.: The current and future state of companion diagnostics. Pharmgenomics Pers. Med. 8 (2015).
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Nuklearmedizinische Klinik und Poliklinik

The growing field of theranostics and companion imaging diagnostics Markus Schwaiger Technische Universität München Germany

11th Biennial International Symposium of IS3R , Amsterdam 2015

Nuklearmedizinische Klinik und Poliklinik

Introduction

Theranostics Theranostic agents are designed to contain both diagnostic and therapeutic functions in a single integrated system that is capable of sensing the endogenous biomarkers of a host organism and accordingly exerting therapeutic functions. Kojima, R., Aubel, D., et al.: Novel theranostic agents for next-generation personalized medicine: small molecules, nonoparticles, and engineered mammalian cells. Current Opinion in Chemical Biology. 28 (2015).

Companion Diagnostics A companion diagnostic is a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product. The test helps a health care professional to determine whether a particular therapeutic product‘s benefits to patients will outweigh any potential serious side effects or risks. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407297.htm

Nuklearmedizinische Klinik und Poliklinik

Companion Diagnostics

Agarwal, A. et al.: The current and future state of companion diagnostics. Pharmgenomics Pers. Med. 8 (2015).

Nuklearmedizinische Klinik und Poliklinik

Companion Diagnostics

Ideal integration of companion diagnostics in drug approval

Review of 676 NSCLC Studies with and without biomarker (1998-2012) Success Rate: 11% vs 62% , Phase III 29% vs 100%; Costs: 1,89 vs 1,40 billion USD Biomarkers and Receptor Targeted Therapies Reduce Clinical Trial Risk in NSCLC Falconi et al., Journal of Thoracic Surgery; 9,2,2014

Imaging Companion Diagnostics

Nuklearmedizinische Klinik und Poliklinik

Amyloid PET as Biomarker of Neurodegeneration Studie (clinical Trials.gov)

Status

Cohort

Intervention

Amyloid PET

API NCT01998841

Phase II (Recruitment)

Asymptomatic PSEN1 E280A

Crenezumab

Outcome

AD A4 Trial NCT02008357

Phase III (Recruitment)

Asymptomatic

Solanezumab

Inclusion

NCT01561430

Phase II (completed)

MCI bei AD

LY2886721

Inclusion

NCT01953601

Phase III (Recruitment)

Prodromal AD

MK-8931

Inclusion and Outcome

Nuklearmedizinische Klinik und Poliklinik

Theranostics

Kelkar, S., and Reineke, T.: Theranostics: Combining Imaging and Therapy. Bioconjugate Chemistry. 22 (2011).

Nuklearmedizinische Klinik und Poliklinik

Theranostics

Kojima, R., Aubel, D., et al.: Novel theranostic agents for next-generation personalized medicine: small molecules, nonoparticles, and engineered mammalian cells. Current Opinion in Chemical Biology. 28 (2015).

Nuklearmedizinische Klinik und Poliklinik

Theranostics Nano Partrticels

Published in: Kelkar, S., and Reineke, T.: Theranostics: Combining Imaging and Therapy. Bioconjugate Chemistry. 22 (2011).

Nuklearmedizinische Klinik und Poliklinik

Translational Research

Evaluation of Dox-TSL in cats with spontaneous fibrosarcoma

PET/MRI

Complete tumor necrosis

Viable tumor cells

From: Lindner, L., Liposome Laboratory, Department of Internal Medicine III, University Hospital of Munich LMU. Dept Veterinarian Medicine LMU, Nuclear Medicine TUM

Specific in vivo tracking of T-cell receptor-engineered human T cells by Immuno-PET Mall S, Yusufi N, Wagner R, Klar R, Bianchi H, Laitinen I, Steiger K, Aichler M, Peschel C, Schwaiger M, D`Alessandria C, Krackhardt AM 250

Cb

Cell

2

L

K

K

a.

40 30

**

20 10 10 8 6 4 2 0

**

ML2-B7

ML2-WT

spleen

lung

a.

TCR2.5D6

a.

Nontransd. PBS

89-Zirconium labeling of TCRmu-F(ab`)2

9

**

ML2-B7

a.

10

**

50

L

7

6

5

4

Non-transduced

TCRmu Antibody –

membrane

0

days post T-cell injection

– 48h p.i.

Antibody labeling

specific recognition of murinized TCR β domain

0

-1

i.v.

3

89Zr-TCRmu-F(ab`) 2

1

1.

Organ to blood ratio

Ca

mm2

TCM cells i.v. (TCR2.5D6 and controls)

TCR2.5D6

Vb

100 50

1.

89Zr-aTCRmu-F(ab`)

Va

150

**

mu

TCR construct with murinized TCR constant domains

Retroviral transduction

200

AMLML2 WT

**

mu P2A TCR α

AML-ML2 HLA-B7 GFP

n.s.

Recognition of a MPO-derived peptide presented by HLA-B7

TCR β

TCR2.5D6 non-transduced PBS

ML2-B7

Leukemia-reactive T-cell receptor (TCR2.5D6)

ML2-WT

Nuklearmedizinische Klinik und Poliklinik

Small Molecules Theranostics

European Experience of Somatostatine-Receptor Targeted Radionuclide Therapy European experiance

: van der Zwan, W., Mueller-Brand, J., et a.: Radionuclide therapy in neuroendocrine tumors. Euro. J. Endocrinol. 172 (1), 2015.

Theranostics CXCR4

Nuklearmedizinische Klinik und Poliklinik

[68Ga]Pentixafor /[177Lu]Pentixather [68Ga]Pentixafor PET in lymphoproliferative diseases

Further optimization and characterization of ligands o o o o

a-emitters, low-energy ß-emitters Fluorescent CXCR4 ligands Hybrid Probes CXCR7 ligands

CXCR4 affinity

Mantle cell lymphoma

Multiple Myeloma

Wester HJ, Schottelius M et al

(Jurkat, [125I]FC-131)

Peptide

IC50 [nM]

Ga-Pentixafor

24.8 ± 2.5

Lu-Pentixather

14.6 ± 1.0

Y-Pentixather

20.4 ± 0.3

Bi-Pentixather

4.4 ± 1.3

AlF-NOTA-Pentixather

17.9 ± 0.3

Cu-NOTA-Pentixather

14.9 ± 2.1

Experimental Therapy

Nuklearmedizinische Klinik und Poliklinik

[177Lu]Pentixather – PRRT in multiple myeloma

t=0

5w

6w

3w

9w

7w

[177Lu]Pentixather First-in-man experience of CXCR4-directed endoradiotherapy with 177Lu- and 90Y-labelled pentixather in heavily pretreated multiple myeloma K. Herrmann, M. Schottelius, C. Lapa et al. 2015, submitted

11 w

13 w

12 w

16 w

13 w + 1

[90Y]Pentixather Nuklearmedizinischen Klinik, UKW LS für Pharmazeutische Radiochemie, TUM München, II. Medizinische Klinik, Hämatologie /Onkologie, UKW III. Medizinische Klinik , Hämatologie /Onkologie ,TUM Scintomics GmbH, Fürstenfeldbruck

Theranostics

Nuklearmedizinische Klinik und Poliklinik

Multidisciplinary Management of Prostate Cancer

PSA-relaps

Imaging

Individualized Therapy

Theranostics

Nuklearmedizinische Klinik und Poliklinik

“Radioguided Surgery” using PSMA-ligands 63y/o patient, s/p RPE 11/13, Gleason 9, pT3a pN0, PSA (06/15): 0.23 ng/ml

7 mm

RGS+

RGS-

Histo+

32

2

Histo-

4

47

• salvage lymphadenectomy is gaining acceptance in rec. PCa • small metastatic lymph nodes are difficult to localize

Prostate Cancer

Nuklearmedizinische Klinik und Poliklinik

Lu-177 PSMA Theranostics

PSA-Werte

01.08.20…

01.07.20…

01.06.20…

01.05.20…

01.04.20…

LDH-Werte 01.03.20…

Eiber, Tauber, Retz et al, 2015

03.08.2015

AP-Werte

01.02.20…

M.K. 71 years, 6 cycl. Docetaxel, Abiraterone, 3 x Radium-223-Dichlorid, ECOG 0 4 cycles of Lu177 -PSMA

1000 900 800 700 600 500 400 300 200 100 0

26.05.2015

01.01.20…

24.03.2015

01.12.20…

• • •

30.01.2015

01.11.20…

10.12.2014

Nuklearmedizinische Klinik und Poliklinik

Conclusion

Companion Diagnostics • Companion diagnostics will be integral part of targeted therapy • Imaging will compete with in-vitro testing in regulatory process • Integration of in-vitro and in-vivo will be necessary to optimize therapeutic management and response evaluation • Partnerships between academia and industry will drive the market

Theranostics • Innovative and exciting technologies are currently be tested • Translation slowed by complex regulatory approval / pot. toxicity • Small molecule approaches most promising in combination with radiotherapy and navigated interventions

Nuklearmedizinische Klinik und Poliklinik

Companion Diagnostics

„Rx-CDx“ Co-Development The European Commission suggests that the following requirements are considered as a standard for successful approval of a CDx: • • • • •

High analytical validity Appropriate sensitivity and specificity Clinical validity / Clinical utility Ability to influence treatment plan Ethical and social acceptance

Akhmetov, I., Ramaswamy, R., et al.: Market Access Advancements and Challenges in „Drug-Companion Diagnostic Test“ Co-Development in Europe. J. Pers. Med. 5 (2015).

Acknowledgements Ambros Beer Florian Gärtner Michael Souvatzoglou Christoph Rischpler Stefan Förster Igor Yakushev

Stephan Nekolla Sibylle Ziegler Sebastian Fürst Sandra van Marwick Isabel Dregely Axel Martinez-Möller

Ernst J. Rummeny Matthias Eiber Stephan Förster

Sylvia Schachoff Anna Winter Gitti Dzewas Coletta Kruschke PET- and Cyclotron-Team

Hans-Jürgen Wester Johannes Notni Michael Herz Petra Watzlowik Jens Siveke Mert Erkan Tobias Maurer Jürgen Gschwend Markus Niemeyer Marion Kiechle

ERC Advanced Grant MUMI PET/MR Munich (TUM/LMU), funded by the DFG