Technique, research and benefits

Interface between technology, clinical, human and social science and public health:

Case study interventional radiology

Nicolas Grenier, Bordeaux University Hospital

Interventional Radiology

Why is IR a growing field ?

Minimally invasive, preserving body integrity, less side-effects

A real economic impact : - short recovery

- ambulatory patient care

- maintaining the patient in his social environment

Based on technical innovations : - high investment of companies in this field

Allows combination of strategies : - identification of specific targets (molecular imaging)

- development of focal therapies

- combined with new medical targeted therapies and nanotechnologies

. local drug delivery

. focal onset of biological effects (gene expression…)

…

2

Interventional Radiology

Why is IR so slowered ?

Problems to finance innovation +++

Lack of organization from scientific societies for evaluation of clinical and economical impacts

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Focal therapy of prostate cancer

Context : Prostate cancer (PC) is the most common cancer in men

The second most common cause of cancer death in men after lung cancer

Controversial strategy of repeated biopsies : - Low diagnostic accuracy

- the majority of men (i.e. 80%) diagnosed when the disease is at the localised stage

- 50% of asymptomatic men do not require active treatment

Radical whole-gland surgery or radiotherapy can result in substantial side-effects that are a consequence of damage to surrounding structures: - urinary incontinence (5–20%),

- erectile dysfunction (30–70%),

- bowel toxicity (5–10%)

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Focal therapy of prostate cancer

Problems:

Identification of the PC : - Now possible combining morphological, functional and metabolic data

with MRI : multiparametric MRI

. T2w

. Diffusion-weighted

. Perfusion-weighted

. Spectroscopy

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T2 Diffusion Perfusion Spectroscopy

Focal therapy of prostate cancer

Problems:

Accuracy of mpMRI has to be precisely defined

MR features are not specific

Detection rates are influenced by tumour Gleason score, histological volume, histological architecture and location

Separation of significant and non significant tumors

Identification of lesions to be treated conservatively

Solutions ?

Molecular imaging for identification of cancer ?

Molecular imaging-guided targeted therapies ?

Modulation of the microenvironment ?

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Prostate biopsies

Systematic biopsies are positive in only 27-40% of all patients with suspected cancer 1

• For patients with PSA between 4 and 10ng/ml 2 : the first set of biopsies is positive in 22%,

the second in 11%,

the third in 5%

the fourth in 4%

How to improve the sensitivity of repeat biopsies for PCa detection : Targeted biopsies after MRI to identify and localize

suspicious areas (≥ 3mm)

Cognitive, MRI-US fusion, CE-US, MRg-biopsies

1-Patel AR, et al, Urology 2004

2- Djavan B et al. J Urol 2000

Molecular imaging

PET-choline or PET-PSMA

Inadequate for diagnosis (recurrence, staging)

Targeted microbubles for US

Collaboration with Bracco.Inc (Milan, Italy)

Optical imaging

Collaboration with : - CEA-LETI, Grenoble

- CREATIS, Lyon

- Vermont, Tours

- Supersonic Imagine, Aix-en-Provence

VEGFR2 Targeted Microbubbles

The dimeric peptide was conjugated to a pegylated phospholipid3 and the resulting

lipopeptide was incorporated into the microbubble shell of BR55

phospholipid membrane phospholipid membrane

C 4 F 10 /N 2 C 4 F 10 /N 2

Heterodimer

peptide

PEG

phospholipid

BR55 microbubble

3Pillai R, Fan H, Marinelli E et al. .Phospholipid Linked Peptide for Ultrasound Imaging of Angiogenesis Amino acids. The forum for amino acids, peptide and protein research, vol. 37, supplement 1, July 2009, 11 th International congress on Amino Acids Peptides and Proteins, Vienna , Austria, Aug 3 rd -7 , 2009.

0

1

10

100

1000

0 100 200 300 400 500 600

Time (s)

rms

²

Prostate tumour

Healthy prostate

x40

Ultrasound imaging of a prostate cancer lesion in a rat Dunning model with BR55

VEGFR2 Targeted Microbubbles

Prostate cancer

VEGFR2 Targeted Microbubbles

Development of hybrid imaging

Development of a bi-functional endorectal probe, US-

optical, for PC (project Prostafluo, ANR 2007)

Why optical imaging ?

Possibility of development of molecular tracers

Why combined with US ?

To be able to target transrectal biopsies and focal therapies

Development of hybrid imaging

J.Boutet et al., J. Biomed. Opt., 2009

FIANIUM

CEA-LETI, VERMON

Sonde bimodale 6 fibres d’excitation

4 fibres de détection

Localisation de la tumeur sur l’image bimodale

Co-registration

Mouse

Medium simulating optical and ultrasound

properties of prostate

Bimodal Ultrasound /Optical probe

Mouse

Medium simulating optical and ultrasound

properties of prostate

Xenograft

tumor

In vivo study :

- 3 nude mice bearing subcutaneous tumors

100 200 300 400 500 600 700 800 900

50

100

150

200

250

300

350

400

450

LIPIDOTS® : Lipidic nanoparticles - Nanoemulsion -

Cœur lipidique Fluorophore lipophile

surfactant Chaines PEG

50 nm

Advantages: •Furtive •Brillance (5x ICG) •Enhanced internalisation •Stability > 5 weeks

Optical targeting : nanotechnologies

80 nm

BiTum - ANR Nanotechnologies 2012

A 2

4 H

96

H

24

0 H

0 0,2 0,4 0,6 0,8 1 1,2

scFvD2B

dye

Fluorescence (nM)

n=3

n=3

In vivo targeting of the prostate tumor by scFvD2B

Souris1

2014-90

96 H

anti-PSMA (scFvD2B) On living cells

Focal therapy of prostate cancer

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Techniques :

Laser ablation

Cryoablation

HIFU

Phototherapy

Irreversible electroporation

- Ablation in the target volume

- Reversible effect at the margins : possibility of modulation of the

microenvironment (treatment of margins)

Focal therapy : MRgFUS

Only possible with image guidance

ExAblate, InSightec

Irreversible electroporation

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IR and immunotherapy

Modulation of immune response by ablation

Combination of ablation (Cryo) with new immunotherapies : - anti CTLA4, anti-PD1 ou anti-PDL1

Enhancement of antitumor immunity and rejection of tumor metastases

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Conclusions

IR is part of various combinations of innovative diagnostic and therapeutic approaches

It requires support from research

It requires support from companies and start-ups

It requires multidisciplinary collaboration

……………………….For the greatest benefit of patients

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Acknowlegements

BR55-105 : - Bracco imaging, Milan

Prostafluo : - CEA-LETI, Grenoble : JM Dinten, J Boutet,

- CREATIS, Lyon : D Vray

Bitum : - CEA-LETI, Grenoble : JM Dinten, J Boutet,

- CNRS-UMR 5536, RMSB Bordeaux : F Couillaud, C Mazzocco

- Department of Pathology and Diagnostics, Veronna: G Fracasso

Immunomodulation : - F Cornelis, JF Moreau, P Blanco

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