Anna Maria Di Giacomo Medical Oncology and Immunotherapy Center for Immuno-Oncology SIENA, ITALY Immuno-Oncologia: verso una immunoterapia di precisione? MEDICINA E ASSISTENZA DI PRECISIONE Firenze – 22 Novembre 2017
Anna Maria Di GiacomoMedical Oncology and Immunotherapy
Center for Immuno-OncologySIENA, ITALY
Immuno-Oncologia:verso una immunoterapia di precisione?
MEDICINA E ASSISTENZA DI PRECISIONEFirenze – 22 Novembre 2017
Cancer immunotherapy, a very long standing concept
Venuti A. J Exp Clin Cancer Res. 2009.
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 whichwould 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.
Surgery
Radiotherapy
Chemotherapy
Evolving Therapeutic Options forCancer Treatment
Surgery
Radiotherapy
Chemotherapy
Immunotherapy
Evolving Therapeutic Options forCancer Treatment
5
Adapted from Pardoll DM 2012.
APC/Tumor
T cell
CD40 CD40L
CD137
OX40
CD137L
OX40L
Activation
Activation
Activation
PD-1
B7-1 (CD80)
PD-L1
PD-L2
LAG-3MHC
CD28 ActivationB7-2 (CD86)
B7-1 (CD80) CTLA-4 Inhibition
TCR
Inhibition
Inhibition
Inhibition
These pathways can be blocked via I-O agents to counteract tumor-mediated inhibition
These pathways can be activated via I-O agents to counteract tumor-mediated inhibition
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.
T-cell Checkpoint and Co-stimulatory Pathways
Tissue samples readily accessible
Adaptable to tissue culture
Amenable to testing of novel therapies
Melanoma as a tool for cancer research
0 1 2 3 4 5 6 7 8 9 10
100
90
80
70
60
0
50
40
30
20
10
Ove
rall
Sur
viva
l (%
)
Years
IPI (Pooled analysis)1
NIVO Monotherapy (Phase 3 Checkmate 066)3
N=210
NIVO Monotherapy (Phase 1 CA209-003)2
N=107
N=1,861
8
Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma
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.
Immune Checkpoint Pathways
CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 ; MHC = major histocompatibility complex; PD-1 = programmed death-1;PD-L1 = programmed death ligand 1; TCR = T-cell receptor.
CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)
Wolchok JD et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1709684
Kaplan–Meier Estimates of Survival.
A
B
C
D
* *
F
* * *
*
C E
Baseline 3 weeks after the first dose 20 weeks after the first dose
Baseline 9 weeks after the first dose 20 weeks after the first dose
Danielli R et al, unpublished
Immunotherapy in solid tumors with immunomodulating antibodies
www.ImmunOncologia.org
ASCO 201613
CI = confidence interval; HR = hazard ratio
NSCLC Kaplan–Meier Estimates of OS(3 Years Minimum Follow-up)
292
194
148
112
82 58 49 39 7 0
290
195
112
67 46 35 26 16 1 0
135
86 57 38 31 26 21 16 8 0
137
69 33 17 11 10 8 7 3 0
CheckMate 057 (non-SQ NSCLC)CheckMate 017 (SQ NSCLC)
No. of patients at risk
Nivolumab
Docetaxel
No. of patients at risk
Nivolumab
Docetaxel
0 6 12 18 24 30 36 42 48 54
Δ10%
Nivolumab (n = 135) Docetaxel (n = 137)
1-y OS = 42%
2-y OS = 23%
3-y OS = 16%1-y OS = 24%
2-y OS = 8% 3-y OS = 6%
HR (95% CI): 0.62 (0.48, 0.80)
100
80
60
40
20
0
OS
(%)
Months
Δ18%
Δ15%
0 6 12 18 24 30 36 42 48 54
Months
1-y OS = 51%
2-y OS = 29%
3-y OS = 18%
1-y OS = 39%
2-y OS = 16%
3-y OS = 9%
Nivolumab (n = 292) Docetaxel (n = 290)
HR (95% CI): 0.73 (0.62, 0.88)
100
80
60
40
20
0
OS
(%)
Δ12%
Δ13%
Δ9%
Felip E, ESMO 2017Felip E, ESMO 2017
Presented By Julie Brahmer at 2017 ASCO Annual Meeting
Lawrence et al, Nature 2013
Mutational landscape of tumor according to Clinical Benefit from ipilimumab therapy (Snyder et al., 2014)
Le DT et al. N Engl J Med 2015; 372:2509‐2520.
Clinical Benefit of Pembrolizumab Treatment According to Mismatch-Repair Status
1970s 1980s 1990s 2010s
Spontaneous regressions in
melanoma: immune component?
1st tumour associated
antigen cloned
IL‐2 approved in the US for melanoma (1992)
IFN adjuvant melanoma US (1995)
2011Ipilimumab approved
for advanced melanoma
2015–2017Anti‐PD‐1/‐PD‐L1 for metastatic
melanoma, NSCLC, RCC, Bladder,
HNSCC, Hodgkin, Merkel, MSI‐H.
Ipilimumab in adjuvant
melanoma. Nivolumab +
ipilimumab, T‐VEC in melanoma
2010 Provenge US
Coley in 1891: observation of a
tumour regression in a pt who developed a post‐op infection
A historical view of immunotherapy…
Italy 2017
Anti‐PD‐1 in: RCC
HodgkinMelanoma NSCLC……….………..
2017
The future of Cancer ImmunotherapyTargeting and modulating multiple compartments
TUMORMICROENVIRONMENT
Antigens
Active T cell
Cancer cell
Dendriticcell
LYMPH NO
DE
BLOOD VESSELS
Apoptoticcancer cell
Active T cell
IMMUNESYSTEM
TUMORMICRO‐
ENVIRONMENT
TUMOR
ICOSGITRLAG34‐1BBOX‐40TIM3…..…..
LAG-3 in T-Cell exhaustion and anti–PD-1 resistance
In therapy-naïve patients, constitutive LAG-3 expression may limit the antitumor activity of PD-1 pathway blockade. Anti–LAG-3 combined with nivolumab may deepen or increase the durability of responses
In patients exposed to PD-1 pathway blockade, adaptive upregulation of LAG-3 expression may lead to treatment resistance and tumor progression. Anti–LAG-3 combined with nivolumab may restore T-cell activation and tumor response
1
2
EffectorCD4+/CD8+
T cell
Acquires resistance
Tumor or other infiltrating cell
+ AntigenPD-L1
Nivolumab
LAG-3
MHC II
Anti–LAG-3 (BMS-986016)
PD-1
PD-1
LAG-3 MHC II
PD-L1
PD-1
+ Nivolumab
+ Nivolumab + Anti–LAG-3
+ Nivolumab + Anti–LAG-3
IO therapy naïve:LAG-3 limits IO response
IO therapy exposed:LAG-3 contributes to resistance
1
2
Study design and endpoints
aTumor response evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v1.110 (investigator assessment). bSafety evaluated per Common Terminology Criteria for Adverse Events v4.011 during treatment and up to 135 days after discontinuation. cLAG-3 and PD-L1 expression (percent of positive cells within invasive margin, tumor, and stroma) evaluated using immunohistochemistry (IHC) assays on formalin-fixed, paraffin-embedded tumor sections. Immune cell LAG-3 expression (≥ 1% or < 1%) determined using mouse antibody clone 17B4; tumor cell PD-L1 expression (≥ 1% or < 1%) determined using Dako PD-L1 IHC 28-8 kit.
BMS-986016 + Nivolumab (N = 212)
Dose-Escalation Phase(advanced solid tumors)
Dose-Expansion PhaseMelanoma After Prior IO (n =
55)(other tumor-specific cohorts)
Endpoints (dose expansion)
• Preliminary efficacya (co-primary)• Safety/tolerabilityb (co-primary)• Pharmacokinetics and pharmacodynamics• Immunogenicity and QTc (secondary)• Biomarkers (LAG-3 and PD-L1;
exploratory)c
Anti-Lymphocyte Activation Gene-3 (anti–LAG-3; BMS-986016) in Combination With Nivolumab in Patients With Melanoma Previously Treated With Anti–PD-1/PD-L1
Ascierto P et al., ASCO 2017
ResultsEfficacy in the Melanoma Prior–IO Cohort
BOR, best overall response; DCR, disease control rate. aAll response-evaluable patients; all progressed on prior anti–PD-1/PD-L1 therapy. bTwo responses were unconfirmed. cOccurred prior to first radiographic scan.
Table 4. Preliminary evidence of antitumor activity
Patients, n (%) Mel Prior IO (n = 48a)BOR
CR 0PRb 6 (13)SD 20 (42)PD 16 (33)Clinical progressionsc 6 (13)
ORR, 95% CIb 6 (13), 4.7, 25LAG-3 ≥ 1% (n = 25) 5 (20), 6.8, 41LAG-3 < 1% (n = 14) 1 (7.1), 0.2, 34
DCR (CR + PR + SD)b 26 (54)LAG-3 ≥ 1% (n = 25) 16 (64)LAG-3 < 1% (n = 14) 5 (36)
ResultsEfficacy in the Melanoma Prior–IO Cohort
Figure 5. Ongoing clinical follow-up
aSix patients had clinical progression prior to their first scan and are not included in the plot. bCensored on last visit. cEvaluations are planned for every 8 weeks.
0 5 1510 2520 3530 4540
Ongoing progression-free survivalb
Time to progression or death
**
*
*
**
*Patients with an objective response
46% (22/48) of patients were still on
treatment at data cutoffa
Weeksc
Melanoma prior-IO cohort
ICOS Mechanism of Action
T cell Priming / Periphery
Local Antigen Re-challenge
ICOSICOS-L
CXCR5, CD40L
Proliferation
IFN-γ
Activation status of T cells
Kaplan Meyer curves of overall survival according to the circulating CD4+ICOS+ in A) metastatic melanoma pts treated with ipilimumab at10mg/Kg within an EAP
Di Giacomo et al CII, 2013
CD4+ICOS+ > 4 fold increase; CD4+ICOS+ ≤ 4 fold increase
mOS = 118 wks
mOS = 27 wks
log-rank test, p = 0.009
A Week 7
• Increased levels of CD4+ICOS+ T cells in patients with different tumor types treated with Ipilimumab
Summary of GSK anti-ICOS agonist antibodyGSK3359609
A humanized, engineered IgG4 anti-ICOS agonist monoclonal antibody (mAb)
For the treatment of cancer
First-in-class ICOS agonist antibody in development
Binds with high affinity to human ICOS
Enhances the proliferation, survival and function of antigen activated effector T cells
Well tolerated safety profile in pre-clinical studies
Strong rationale for combination with other anticancer agents
APC
T cellICOS
ICOS agonist mAb(GSK3359609)
Enhanced survival
and function
Preclinical Evidence of ICOS Agonist Combination Potential
Synergistic combination of surrogate ICOS agonist antibody with checkpoint mAbs in
mouse tumor models
ICOS + PD1
PD1ICOS
CT26 Tumor Model
Combination of GSK3359609 with Pembrolizumab in human PBMCs induces
synergistic IFN-γ production
GSK 204691 (INDUCE-1) Study Design
Part 1A: Monotherapy Dose Escalation
N~36
Multiple selected solid tumors
Part 2B: Combination Expansion
Cohort 1 N~20
Cohort 2 N~20
Cohort 1 N~20
Cohort 2 N~20
Part 2A: Combination Dose Escalation
1
2Multiple selected
solid tumors
N~24
N~24
Biomarker cohort N~30
Steering Committee Decision Points
Cohort 1 N~20
Cohort 2 N~20
Part 1B: MonotherapyExpansion
Cohort 3 N~20
Cohort 4 N~20
Biomarker cohort N~30
TUMOR
MICROENVIRONMENT
Antigens
Active T cell
Cancer cell
Dendriticcell
LYMPH NODE
BLOO
D VESSELS
Apoptoticcancer cell
Active T cell
IMMUNESYSTEM
TUMORMICRO-
ENVIRONMENT
TUMOR
ICOSGITRLAG34‐1BBOX‐40TIM3…..…..
The future of Cancer ImmunotherapyTargeting and modulating multiple compartments
HLA I/IITumor Associated AntigensAntigen Processing MachineryCo‐stimulatory Molecules…..…..
Heritable changes in gene expression not based
on modifications of the DNA sequence
EPIGENETICS
DNA methylation
Histone modifications
MicroRNA gene silencing
EPIGENETIC MODIFICATIONS
PHARMACOLOGICALLY REVERSIBLE
DNMTs inhibitors (DNMTi)
HDAC inhibitors (HDACi)
Maio et al, unpublished
Maio M. et al., CCR 2015
Epigenetic Immunomodulation of Cancer cell
Can epigenetic modulation of neoplastic cells be used to design
novel immunotherapeutic approaches in cancer?
COMBOS
TUMOR
Epigenetic drugs
Modulatetumor immunogenicity
and immune recognitionHOST
Check-point mAb
Improve host’s immune system activity
Epigenetic Epigenetic immunoimmuno--sequencingsequencing
Epigenetic immuno‐sequencing:the NIBIT‐M4 Study
EUDRACT 2015‐001329‐17
W1 W4 W7 W10Ipilimumab4 x q21
W0 W3 W6 W9Guadecitabine5 days q21 WKTA
W12
A.M. Di Giacomo et al. Semin Oncol, 2015
FPFV October 12, 2015
Tumor BiopsyPBMC
Tumor BiopsyPBMC
Tumor BiopsyPBMC
3 pts15mg/m2/die
3 pts30mg/m2/die
3 pts45mg/m2/die
+3 pts30mg/m2/die
≥2 DLT
No DLT
1 DLT
Expand to 16 ptsTo date 11 out of 19 pts enrolled
3 pts60mg/m2/die
No DLT
≥2 DLT
+3 pts60mg/m2/die
1 DLT
Epigenetic immuno‐sequencing: the NIBIT‐M4 Study NCT02608437
Amendment approved Jan 24rd, 2017
Methylome DNA
Transcriptome RNA
ExomeDNA
Epigenetic immuno‐sequencing: the NIBIT‐M4 Study NCT02608437
Phenotipic,functional analyses of
PBMC
IMMUNOSCOREdensity, location, organization and
functional orientation of
tumor‐infiltrating immune cells
FFPE
W1 W4 W7 W10
Ipilimumab4 x q21
W0 W3 W6 W9Guadecitabine5 days q21 WKTA
W12
Tumor biopsyPBMC Tumor biopsy
PBMC
Tumor biopsyPBMC
NGS analysesPerifery and tumorimmunophenotype
The future of Cancer ImmunotherapyTargeting and modulating multiple compartments
TUMOR
MICROENVIRONMENT
Antigens
Active T cell
Cancer cell
Dendriticcell
LYMPH NODE
BLOO
D VESSELS
Apoptoticcancer cell
Active T cell
IMMUNESYSTEM
TUMORMICRO-
ENVIRONMENT
TUMOR
ICOSGITRLAG34‐1BBOX‐40TIM3…..…..
IDOArginaseSuppressor cellsVEGF
IDO‐mediated immunesuppression
IDO1 Inhibition Correlates With Increases in TIL Number and Function
• IDO1 inhibition leads to increased number of TILs and decreased suppressor cells in tumors
• Enhanced IFN-γ secretion from TILs was observed following IDO1 inhibitor treatment
43IFN=interferonKoblish HK, et al. AACR 2015. Poster 1336
Infiltrating cells Cytokines PD-1 expression
Combinations of Epacadostat and Checkpoint Inhibition Showed Synergistic Inhibition in Preclinical Models
• Combinations of epacadostat and checkpoint inhibition were associated with enhanced T-cell proliferation and cytokine secretion in vivo
441. Spranger S, et al. J Immunother Cancer. 2014;2:3. Data on file, Incyte Corporation
Epacadostat + anti–CTLA4 Epacadostat + anti–PD-L1
Days Postinoculation Days Postinoculation
IMMUNE SYSTEM
TUMOR
The future of Cancer ImmunotherapyPatient-tailored immunotherapeutic approaches
TUMOR MICRO-ENVIRONMENT
Targeting and modulating multiple compartments
• Maresa Altomonte• Erika Bertocci• Luana Calabrò• Ornella Cutaia• Riccardo Danielli• Anna Maria Di Giacomo• Carolina Fazio • Ester Fonsatti• Carla Chiarucci• Gianluca Giacobini• Andrea Lazzeri
Medical Oncology and ImmunotherapyCenter for Immuno‐Oncology
University Hospital of Siena ‐ Italy
• Francesca Colizzi• Sandra Coral• Alessia Covre• Elisabetta Fratta• Hugues Nicolay• Luca Sigalotti• Maria Lofiego• Patrizia Tunici• Antonello Lamboglia• Monica Valente• Armida D’Incecco