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
