Patrizio Giacomini M.D. patrizio.giacomini@ifo.gov.it IRCCS - - PowerPoint PPT Presentation

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Patrizio Giacomini M.D. patrizio.giacomini@ifo.gov.it IRCCS - - PowerPoint PPT Presentation

Apr 11, 2024 118 likes •284 views

A Liquid Biopsy hub: integrating nano-technologies to improve cancer diagnosis and therapy Patrizio Giacomini M.D. patrizio.giacomini@ifo.gov.it IRCCS Istituto Nazionale Tumori Regina Elena Rome, Italy --- www.ifo.it Staff,

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SLIDE 1

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

patrizio.giacomini@ifo.gov.it

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SLIDE 2

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

  • f Care

tissue and liquid biopsies

Cycle 1 Cycle 2 Cycle 3 Cycle n

Her2 Br Ca longitudinal

https://www.oncotech.org/gim21

GIM21 multi-center

ctDNA signatures

  • n progression
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SLIDE 3

Liquid Biopsy

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SLIDE 4

https://www.oncotech.org/gim21

Alessandra Fabi Michelangelo Russillo Edoardo Pescarmona Simonetta Buglioni Paolo Romania Francesco Cognetti Gianluigi Ferretti

TTZ/PTZ + taxanes etc Cycle 1 T-DM1 Cycle 2 T-DM1 Cycle 3 T-DM1 Cycle n T-DM1

relapse

progression Trastuzumab

  • emtansine

(T-DM1)

Progression by ctDNA Progression by PET

VAF 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 54

Progression by ctDNA Progression by 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

Progression by ctDNA Progression by 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 Progression by ctDNA Progression by PET

Lead time: 2.9 months Blood drawings

pt#7 age52

primary resistance adaptive resistance Long response

Allegretti, M. … and Fabi, A. 2019, in preparation

response + adaptive resistance

Monitoring T-DM1 treated patients by liquid biopsy

Matteo Allegretti Elena Giordani

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SLIDE 5

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
  • SD

not available yet

  • brain metastasis

Pts w/actionable SNVs

  • n 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 Molecular Biologist medical

  • ncologist

nurse Pharmacologist – Hospital Pharmacist

IRE Molecular Tumor Board

hematologist pathologist

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SLIDE 6

Liquid Biopsy by Nanophotonics

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SLIDE 7

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 MUT WT MUT+WT no ampl PNA wt PNA G12D

TURNOFF

Francesco Michelotti

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SLIDE 8

Nano-therapy

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SLIDE 9

TOOLBOX: modular objects for step-wise nano-therapy

HER2 breast cancer

(5-10 nm)

flu-specific

T cell

4 1

Strep-Tagged huW6/800 to HER2

2

Strep Tactin multimer

3

Strep-Tagged drugs (e.g. DM1) Strep-Tagged HLA-A2 tetramer

ADC T-CAR

TOOLBOX Joachim Bertram Karl Heinz Friedrich Loredana Cecchetelli Leonardo Sibilio

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SLIDE 10

From ADCs to 𝑦DCs

ADC

Pierpaolo Ceci Elisabetta Falvo

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SLIDE 11

H-nanoferritin (HFt): cage and carrier for antiblastic payloads

  • ferritin is a natural non-toxic protein selected during evolution to

be stable in body fluids and pass body barriers

  • Made of 24 subunits (H and L chains), it is produced in recombinant

form 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 mol

depending on the drug) as compared to albumin (HSA) or ADCs.

  • HFt is actively uptaken through its natural receptor (CD71, the

transferrin receptor). This is adaptively over-expressed (10-100 fold) in cancer cells

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SLIDE 12

Recombinant HFt in vivo

  • Cisplatin
  • Doxorubicin
  • Doxorubicin analogues
  • MMAE
  • Mitoxantrone
  • Topoisomerase inhibitors
  • 2. Wide Drug

nano-caging spectrum

  • 1.

Innovative industrial process

Bacteria 5g/L Autoassembly Double drug loading surface Up to >100 drugs/molecule Shelf-life lyophilization

  • 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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SLIDE 13

drug resistance loss of target

A Liquid Biopsy ‘hub’: integrating nano-technologies to improve cancer diagnosis and therapy: conclusions

Cycle 1 Cycle 2 Cycle 3 Cycle n

combination targeting combination drugging

ctDNA ctDNA

LB-guided

CD71 HER2

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SLIDE 14

EP3186192B1 WO2017167967A1 WO2018138676A1

recent patents main industrial partners non-profit support

  • H2020 RIA and MSCA

Eureka E!5995

  • Lazioinnova

main academic partners

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SLIDE 15

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
  • ncology, 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