L'immunoterapia del cancro: una realtà già presente e una sfida per il futuro - Michele Maio - europe direct
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
L’immunoterapia del cancro: una realtà già
presente e una sfida per il futuro
Michele Maio
Center for Immuno-Oncology
SIENA, ITALYEvolving Therapeutic Options for
Cancer Treatment
Surgery Chemotherapy
RadiotherapyEvolving Therapeutic Options for
Cancer Treatment
Surgery Chemotherapy
Radiotherapy ImmunotherapyCancer immunotherapy, a very long standing concept
The concept that a vaccine could be useful in the treatment of cancer is a long-held
hope coming from the observation that patients with cancer who developed bacterial
infections experienced remission of their malignancies.
The earliest mention of cancer-fighting infections dates to a
citation from Ebers papyrus (1550 B.C.) attributed to the Egyptian
physician Imhotep (2600 B.C.), who recommended to treat
tumors (swellings) with a poultice followed by an incision which
would result in infection of the tumor and therefore its regression.
In 1896, the surgeon William Coley locally injected streptococcal
broth cultures to induce erysipelas in an Italian patient (Mr. Zola)
with an inoperable neck sarcoma, obtaining a tumour regression.
Although therapy was toxic, the patient's tumour ultimately
regressed, and he lived disease-free for 8 years before
succumbing to his cancer.
Venuti A. J Exp Clin Cancer Res. 2009.The cancer immunoediting concept
R D Schreiber et al. Science 2011T-cell Checkpoint and Co-stimulatory Pathways
APC/ T cell
Tumor
CD40 CD40L Activation
CD137L CD137 Activation These pathways can be
activated via I-O agents to
OX40L OX40 Activation counteract tumor-mediated
inhibition
B7-2 (CD86) CD28 Activation
B7-1 (CD80) CTLA-4 Inhibition
These pathways can be
PD-L1 PD-1 Inhibition
blocked via I-O agents to
PD-L2 B7-1 (CD80) Inhibition counteract tumor-
mediated inhibition
LAG-3 Inhibition
MHC
TCR
Adapted from Pardoll DM 2012.
APC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4; LAG-3=lymphocyte activation gene-3; MHC=major
histocompatibility complex;
PD-1=programmed death-1; PD-L1=PD ligand-1; PD-L2=PD ligand-2; TCR=T-cell receptor.
Pardoll DM. Nat Rev Cancer. 2012;12:252-264.
8Pioneering cancer immunotherapy researchers awarded Nobel Prize in
medicine 2018Immune Checkpoint Inhibitors Provide Durable Long-
term Survival for Patients with Advanced Melanoma
100
IPI (Pooled analysis)1
90
NIVO Monotherapy (Phase 1 CA209-003)2
80
Overall Survival (%)
NIVO Monotherapy (Phase 3 Checkmate 066)3
70
60 N=210
50
40 N=107
30
N=1,861
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Years
1. Schadendorf et al. J Clin Oncol 2015;33:1889-1894; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress.
14Diversità dei meccanismi d’azione dell’immunoterapia rispetto
alle terapie antitumorali ad azione diretta
Chemioterapico Distruzione delle
“tumor-target” therapies cellule tumorali
Attivazione
Immunoterapia Attivazione Espansione e Distruzione delle
cellule
(vaccini, anti-CTLA4…) linfociti T e B migrazione al cellule tumorali
dendritiche
sito tumoraleKinetics of appearance
of immune-related adverse event
Weber J S et al. JCO 2012;30:2691-2697
©2012 by American Society of Clinical OncologyThe evolving Cancer Immunotherapy Landscape
>800 clinical combinations with PD-L1/PD-1 inhibitors
SCLC
Marketed
Pembro+crizotinib Atezo+cobimetinib Melanoma
Phase 3 Pembro+epacadostat Atezo+CPI-444
Nivo+erlotinib Durva+tremelimumab Atezo+GDC-0919 Nivo+lirilumab
Phase 2 Pembro+erlotinib
NSCLC Nivo+epacadostat
Pembro+gefitinib
+/-chemo Nivo+urelumab Pembro+LV305
Nivo+galunisertib Atezo+IFNα-2b
Phase 1 or 1/2 Pembro+GSK-3174998 Nivo+varlilumab Pembro+lenvatinib
Ave+PF-04518600 Nivo+lirilumab Atezo+varlilumab Pembro+pexidartinib
Pembro+lenvatinib Nivo+ Pembro+ipilimumab
Ave+utomilumab Nivo+urelumab ulocuplumab Ave+PF-04518600 Pembro+SD-101
Pembro+necitumumab Pembro+AM0010
Durva+AZD6738 Nivo+varlilumab Ave+utomilumab
Pembro+PEGPH20 Pembro+CAVATAK Pembro+X4P-001
Durva+epacadostat PDR001+LAG525 Durva+dabrafenib+trametinib
Atezo+CPI-444 Pembro+pexidartinib Nivo+ PDR001+LAG525
Atezo+cobimetinib
Durva+gefinitib PDR001+canakinumab
Pembro+ramucirumab Rova-T Durva+epacadostat Pembro+CMP-001 Nivo+BMS-986016 RCC
Durva+ibrutinib PDR001+CJM112
Pembro+CAVATAK Nivo+BMS-986016 Pembro+darbafenib+trametinib
Atezo+epacadostat PDR001+EGF816 Nivo+lirilumab
Durva+mocetinostat Pembro+GSK-3174998
Pembro+ipilimumab Nivo+cabiralizumab Nivo+NKTR-214
Atezo+erlotinib Durva+ramucirumab PDR001+trametinib Pembro+ipilimumab
Pembro+entinostat Pembro+entinostat
Nivo+epacadostat
Atezo+GDC-0919 Nivo+CV-301 Pembro+AM0010 Pembro+AM0010 PDR001+LAG525
Pembro+azacitidine Pembro+IMP321 Atezo+CPI-444
Atezo+ipilimumab Nivo+cabiralizumab Pembro+bevacizumab Pembro+acalabrutinib Pembro+epacadostat
Atezo+bevacizumab Atezo+varlilumab Nivo+NKTR-214 Atezo+GDC-0919
Nivo+ceritinib Pembro+abemaciclib Atezo Atezo+cobimetinib Pembro+GSK-3174998
Solid Atezo+BL-8040
Ave+crizotinib Nivo+crizotinib
Nivo+BMS-986016 +chemo +vemurafenib Atezo+IFNα-2b Nivo+ipilimumab
Atezo+MOXR0916 Nivo+capmatinib Pembro+CAVATAK
Ave+lorlatinib PDR001+dabrafenib+trametinib Atezo+varlilumab
Atezo+MTIG7192A Atezo+RG-7802 Nivo+dasatinib Pembro+chemo Nivo+ipilimumab
Atezo+vanicizumab Pembro+enadenotucirev Nivo+NKTR-214
Atezo+RG-7813 Atezo+RG-7876 Nivo+EGF816 Atezo+chemo+/-bevacizumab Pembro+epacadostat Atezo+bevacizumab Atezo+CPI-444 UC
Pembro+epacadostat
Durva+IMC-CS4 Durva+MEDI0680 Pembro+T-VEC Pembro+axitinib / lenvatinib Atezo+emactuzumab
Durva+LY2510924 Durva+tremelimumab
Durva+monalizumab Pembro+GSK-3174998
Durva+MEDI0562 Nivo+ipilimumab Atezo+GDC-0919
Durva+MEDI9447 Nivo+ipilimumab Nivo+ipilimumab Atezo+chemo
Durva+mogamulizumab Nivo+JTX-2011 Ave+axitinib Pembro+lenvatinib Pembro+B-701
Durva+selumetinib Pembro+chemo Atezo+varlilumab
Nivo+BMS-986156 Nivo+CB-1158 Pembro+pexidartinib
Nivo+BMS-986178 Durva+tremelimumab Pembro+acalabrutinib
Durva+AZD4547 Pembro+ramucirumab
Nivo+mogamulizumab Pembro+MK-1248 Pembro+MK-4166 Pembro+iMiD Durva+tremelimumab Nivo+ipilimumab
Pembro+MK-4280 Pembro+demcizumab Pembro+INCB039110 Nivo+iMiD+/-elotuzumab Atezo+CPI-444 Durva+AZD9150
Pembro+chemo / T-VEC Pembro+epacadostat
PDR001+GWN323 Pembro+utomilumab Atezo+chemo Atezo+GDC-0919
Durva+/-iMiD Durva+AXAL
Atezo+cobimetinib Ave+chemo Pembro+enadinotucirev
PDR001+MBG453 Atezo+azacitidine Pembro+chemo Atezo+varlilumab
Durva+azacitidine Pembro+chemo Durva+epacadostat
PDR001+MCS110 Atezo+daratumumab+/-iMiD Atezo+chemo Durva+AZD5069 Nivo+BMS-986016 Pembro+GSK-3174998
Durva+ibrutinib Atezo+obinutuzumab+/-iMiD Atezo+bevacizumab Nivo+ipilimumab
Atezo+CPI-444 Durva+AZD6738 Nivo+cabiralizumab
Durva+rituximab+iMiD Atezo+obinutuzumab+polatuzumab Pembro+BL-8040
Atezo+emactuzumab Nivo+epacadostat Pembro+lenvatinib
Pembro+acalabrutinib Durva+AZD9150 Atezo+tazemetostat Pembro+acalabrutinib
Durva+ Nivo+urelumab
Durva+rituximab+bendamustine Atezo+entinostat Atezo+T-VEC
Pembro+AFM13 Durva+tremelimumab tremelimumab Pembro+pexidartinib
Atezo+emactuzumab Atezo+GDC-0919 PDR001+BLZ945
Pembro+epacadostat Durva+tremelimumab
Nivo+brentuximab vedotin
Atezo+CPI-444 Atezo+PEGPH20
Atezo+bevacizumab Atezo+GDC-0919 Atezo+varlilumab PDR001+CJM112
Nivo+varlilumab
SCCHN
Pembro+dinaciclib Atezo+GDC-0919
Nivo+epacadostat Atezo+T-VEC Durva+AZD5069 Nivo+CC-122 Atezo+rucaparib PDR001+EGF816 PDR001+canakinumab
Pembro+dasatinib Atezo+emactuzumab
Ave+PF-04518699 Durva+epacadostat Ave+entinostat Ave+utomilumab Pembro+epacadostat
Heme Pembro+G100
Nivo+ipilimumab
Nivo+cabiralizumab Nivo+
Atezo+GDC-0919 Ave+defactinib Nivo+ipilimumab Pembro+niraparib
Nivo+urelumab Durva+galunisertib BMS-986016 Durva+ramucirumab Nivo+epacadostat Pembro+pexidartinib
Nivo+ipilimumab
Nivo+ibrutinib Nivo+epacadostat Durva+ibrutinib PDR001+LAG525 Nivo+lirilumab Pembro+GSK-3174998
Nivo+lirilumab Nivo+galunisertib Nivo+varlilumab Durva+tremelimumab
Nivo+varlilumab
Nivo+cabiralizumab
Durva+
Nivo+BMS-986016
Pembro+epacadostat TNBC
Pembro+enadenotucirev Nivo+ipilimumab ramucirumab Pembro+margetuximab
Pembro+niraparib
Pembro+GSK-3174998 Nivo+ulocuplumab Pembro+PEGPH20 Pembro+mirvetuximab soravtansine
PDR001 + BLZ945 Atezo+bevacizumab Pembro+pexidartinib Pembro+pexidartinib
CRC Pembro+pelareoprep Atezo+codrituzumab Pembro+ramucirumab
Pembro+pexidartinib Pembro+trastuzumab
Ovarian
PDR001+capmetinib
Pancreas
Liver Gastric
Adapted from Vanessa Lucey of CRI by Gergely Jarmy
Chen and Mellman, Nature 2017
Hegde PS, AAADV, Washington DC, 2017Inflamed tumor Non-inflamed tumor
pre-existing immunity T-cell migration defect Immune desert tumors
Mutational Load
TILs angiogenesis, MDSC, Low
CD8 T cells/IFNγ immunosuppressive MHC I
PD-L1 & checkpoints reactive stroma
• Adapted from Hegde PS et al. Clin Cancer Res 2016;22(8):1865-1874.Epigenetic Immunomodulation of Cancer cell • Maio M et al. CCR 2015
The Center for Immuno-Oncology
University Hospital of Siena - Italy
Early Phase
Clinical Trials
(2018)
Research Medical Oncology
Laboratories
(2017)
CIO and
Immunotherapy
(2007)
Translational
Laboratories
(2011)Medical Oncology and Immunotherapy
Center for Immuno-Oncology
University Hospital of Siena - Italy
• Maresa Altomonte • Giovanni Amato
• Luana Calabrò • Sara Cannito
• Maria Grazia Daffinà • Carla Chiarucci
• Riccardo Danielli • Sandra Coral
• Anna Maria Di Giacomo • Alessia Covre
• Elisabetta Gambale • Ornella Cutaia
• Santa Monterisi • Carolina Fazio
• Ivan Parla • Simona Mastrandrea
• Giulia Rossi • Gianluca Giacobini
• Monica Valente • Elisa Ibba
• Angela Iacovelli • Andrea Lazzeri
• Sergio Speranza • Fabrizio nardi
• Marilena Piccinelli • Maria Lofiego
• Marica Pierli • Alessia Longo
• Fatma Socrati • Tommaso Vittori
• Roberta Crispino • Patrizia Tunici
• Vincenzo Di Nuzzo • Filomena CisterninoIt takes two to tango
The future of Cancer Immunotherapy
Targeting and modulating multiple compartments
TUMOR
MICRO-
ENVIRONMENT
Active Active
T cell T cell
Dendritic TUMOR
IMMUNE cell MICROENVIRONMENT
SYSTEM
Antigens Apoptotic
cancer cell
Cancer cell
TUMORThe future of Cancer Immunotherapy
Targeting and modulating multiple compartments
TUMOR
MICRO-
ENVIRONMENT
ICOS
Active Active
GITR T cell T cell
LAG3 Dendritic TUMOR
IMMUNE cell MICROENVIRONMENT
4-1BB SYSTEM
OX-40
Antigens Apoptotic
TIM3 cancer cell
…..
…..
Cancer cell
TUMORThe future of Cancer Immunotherapy
Targeting and modulating multiple compartments
TUMOR
MICRO-
ENVIRONMENT
Active Active
T cell T cell
Dendritic TUMOR
IMMUNE cell MICROENVIRONMENT
SYSTEM
Antigens Apoptotic
cancer cell
HLA I/II
Tumor Associated Antigens
Antigen Processing
Cancer cell
Machinery
TUMOR
Co-stimulatory Molecules
…..
…..The future of Cancer Immunotherapy
Targeting and modulating multiple compartments
IDO
Arginase
TUMOR Suppressor cells
MICRO-
ENVIRONMENT Blocking VEGF
Active Active
T cell T cell
Dendritic TUMOR
IMMUNE cell MICROENVIRONMENT
SYSTEM
Antigens Apoptotic
cancer cell
Cancer cell
TUMORThe future of Cancer Immunotherapy
Targeting and modulating
Patient-tailored multiple compartments
immunotherapeutic approaches
IMMUNE SYSTEM
TUMOR
TUMOR MICRO-
ENVIRONMENTYou can also read
