a liquid biopsy ‘hub’: integrating nano-technologies to ... icpermed award patrizio giac… ·...
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A Liquid Biopsy ‘hub’:
integrating
nano-technologies
to improve cancer diagnosis and therapy
Patrizio Giacomini M.D.
IRCCS Istituto Nazionale Tumori Regina Elena
Rome, Italy --- www.ifo.it
Staff, Oncogenomics & Epigenetics
Member, Molecular Tumor Board
Escuela Nacional de Sanidad National Institute of Health Carlos III, Monforte de Lemos 5, Madrid, November 5th-6th
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Liquid Biopsy Predicting outcome by LB (lead time) Discovery adaptive resistance to clinical HER2 blockade Assign target therapy based on LB Moving liquid biopsy into nanophotonics
- Standard of Care - Real-Life trials
nano-drugging nano-delivery
nanoferritin
nano
ADC
Molecular
Tumor Board
- Beyond Standard of Care
tissue and liquid biopsies
Cycle 1Cycle 2
Cycle 3Cycle n
Her2 Br Ca longitudinal
https://www.oncotech.org/gim21
GIM21 multi-center
ctDNA signatureson progression
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Liquid Biopsy
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https://www.oncotech.org/gim21
Alessandra Fabi
MichelangeloRussillo
EdoardoPescarmona
SimonettaBuglioni
Paolo Romania
Francesco Cognetti
Gianluigi Ferretti
TTZ/PTZ + taxanes etc
Cycle 1T-DM1
Cycle 2T-DM1
Cycle 3T-DM1
Cycle n
T-DM1
relapse progression
Trastuzumab
-emtansine
(T-DM1)
Progressionby ctDNA
Progressionby PET
VA
F
Blood drawings
0,0%
1,0%
2,0%
3,0%
4,0%
5,0%
6,0%
1 2 3 4 5 6 7 8 9
Lead time:
2.1 months
pt#1 age 54Progression
by ctDNA
Progressionby CT scan
Blood drawings
0,0%
0,2%
0,4%
0,6%
0,8%
1,0%
1 2 3 4 5 6 7 8 9 101112
Lead time:2.8 months
pt#2 age 59
Blood drawings
Progressionby ctDNA
Progressionby PET
0,00%
0,04%
0,08%
0,12%
0,16%
0,20%
1 3 5 7 9 11 13
Lead time:0.9 months
pt#3 age 38
0,0%
0,2%
0,4%
0,6%
0,8%
1,0%
1 2 3 4 5 6 7
Progressionby ctDNA
Progressionby PET
Lead time:2.9 months
Blood drawings
pt#7 age52
primaryresistance
adaptiveresistance
Long response
Allegretti, M. … and Fabi, A. 2019, in preparation
response + adaptive resistance
Monitoring T-DM1 treated patients by liquid biopsy
MatteoAllegretti
Elena Giordani
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Liquid biopsy reveals new vulnerabilities not present in archival tumor tissues
ID
Tissue mutations(number)
Plasma mutations Clinical behaviour(imaging)
Plasma behaviour(ctDNA)
Actionable (OncoKB level ≤3)
Primary Metastasis T=0 Prog T=0 Prog
pt#1 - - PD
pt#2 12 1 PD
pt#3 - - PD
pt#4 - 43, 11, 7 PD
pt#5 4 64 NA SD NA
pt#6 1 1, 1, 1 PD
pt#7 - - PD
pt#9 2 - NA SD NA
pt#10 2 PD
pt#12 - - NA SD NA
pt#13 - - PD
pt#14 - 1 - SD not available yet -
pt#15 2 - - SD not available yet -
pt#16 - - - SD not available yet -
pt#17 - 0 - SD not available yet -
brain metastasis
Pts w/actionable SNVson progression
5/8 (62.5%)
NA: Not Applicable
- Tumor vulnerabilities only seen in blood
- Tumor vulnerabilities not present at the beginning of T-DM1 treatment
bioinformatician
surgeon
biostatistician
MolecularBiologist
medicaloncologist
nurse
Pharmacologist –Hospital Pharmacist
IRE Molecular Tumor Boardhematologist
pathologist
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Liquid Biopsy by Nanophotonics
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ULTRAPLACAD: ULTRAsensitive PLAsmonic CAncer Diagnosis
www.ultraplacad.eu
Giuseppe Spoto
EU H2020 Grant no: 633937
Since October 24th 2018 a compact plasmonic industrial prototype is installed at IRE.
∆%R
∆%R
Time (sec) Time (sec)
healthy donor
dPCR
SPRI
KRAS G12D mutation
MUTWTMUT+WT
no ampl
PNA wt
PNA G12D
TURNOFF
Francesco Michelotti
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Nano-therapy
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TOOLBOX: modular objects for step-wise nano-therapy
HER2
breast
cancer
(5-10 nm)
flu-specific
T cell
4
1
Strep-TaggedhuW6/800 to HER2
2
Strep Tactinmultimer
3Strep-Tagged
drugs (e.g. DM1)
Strep-TaggedHLA-A2 tetramer
ADC T-CAR
TOOLBOX
Joachim Bertram
Karl Heinz Friedrich
LoredanaCecchetelli
Leonardo Sibilio
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From ADCs to 𝑥DCsADC
Pierpaolo Ceci
Elisabetta Falvo
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H-nanoferritin (HFt): cage and carrier for antiblastic payloads
- ferritin is a natural non-toxic protein selected during evolution tobe stable in body fluids and pass body barriers
- Made of 24 subunits (H and L chains), it is produced in recombinantform as HFt (24 heavy chains)
- HFt (heavy chains only) is produced in high yields (5 g/L) in E. Coli,it is stable at 75 ˚C and at pH=2.0
- HFt entraps more drug molecules inside its cavity (30-200 moldepending on the drug) as compared to albumin (HSA) or ADCs.
- HFt is actively uptaken through its natural receptor (CD71, thetransferrin receptor). This is adaptively over-expressed (10-100 fold)in cancer cells
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Recombinant HFt in vivo
- Cisplatin
- Doxorubicin
- Doxorubicin analogues
- MMAE
- Mitoxantrone
- Topoisomerase inhibitors
2. Wide Drug
nano-caging
spectrum
1. Innovative industrial
processBacteria 5g/L
Autoassembly
Double drug loading surface
Up to >100 drugs/molecule
Shelf-lifelyophilization
- Pancreas adenocarcinoma
- Melanoma
- Breast Carcinoma 3N
- Sarcoma
- Colorectal Carcinoma
- Head & Neck
3. Wide spectrum of
potential tumor targets
6. derivatization
post-
synthesis & recombinant
HFt
free drug
4. Favorable PK
HT-1080
human
sarcoma
0,000
500,000
1000,000
1500,000
2000,000
2500,000
3000,000
3500,000
4000,000
4500,000
1 2 3 4 5 6 7 8
No Drug
DOXO
INNO
INNO MP
5. Therapeutic
efficacy
naked drug
HFt-caged drug
no drug
doxo
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drug resistance
loss of target
A Liquid Biopsy ‘hub’: integrating nano-technologies
to improve cancer diagnosis and therapy:conclusions
Cycle 1Cycle 2
Cycle 3Cycle n
combination
targeting
combination
druggingctDNA
ctDNA
LB-guided
CD71
HER2
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EP3186192B1
WO2017167967A1
WO2018138676A1
recent patentsmain industrial partners
non-profit support
• H2020 RIA and MSCA
Eureka E!5995
• Lazioinnova
main academic partners
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A ‘Precision Oncology open day’
- To be held in Rome Q1 2020.- Co-supported and co-sponsored by the ICPerMed recognition prize award- The purpose will be to raise awareness about the new mutational oncology model and
the precision oncology potential- Target audience: specialists and non-specialists, e.g. surgeons, medical oncologists,
radiologists, pathologists etc, science writers and journalists, patients and patient advocacy organizations, entrepreuners, the general public, policy makers and the Italian and EU Institutions
- Short introductory talks for both specialists and non-specialists about genome-driven oncology, its tools (molecular diagnosis report, the Molecular Tumor Board, off-label treatment), and relevant financial, regulatory, deontological, and ethical issues
- Duet-talks by patients and their physicians: exceptional responders, liquid biopsy therapy assignee, Lazarus responders etc seen by the Regina Elena MTB.
Final agenda to be assembled: ICPerMed, the Italian Ministry of Health, and the local Health Autorities in Rome