Le basi dell’immuno-oncologia nei tumori solidi

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Le basi dell’Immuno-‐Oncologia nei tumori solidi

Michele Maio

Center for Immuno-Oncology

SIENA, ITALY

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Surgery

Radiotherapy

Chemotherapy

Evolving Therapeutic Options for

Cancer Treatment

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Surgery

Radiotherapy

Chemotherapy

Immunotherapy

Evolving Therapeutic Options for

Cancer Treatment

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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 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.

(5)

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-3 MHC

CD28 Activation B7-2 (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

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ü  Tissue samples readily

accessible ü  Adaptable to

tissue culture ü  Amenable to

testing of novel

therapies

Melanoma as a tool for cancer research

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0 1 2 3 4 5 6 7 8 9 10 100

90 80 70 60

0 50 40 30 20 10

O ve ra ll Su rvi va 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

7 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.

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Wolchok JD et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1709684

Kaplan–Meier Estimates of Survival.

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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

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1970s 1980s 1990s 2010s

Spontaneous regressions in melanoma: immune

component?

1 ^st tumour associated an5gen cloned

IL-‐2 approved in the US for

melanoma (1992)

IFN adjuvant melanoma

US (1995)

2011

Ipilimumab approved for advanced

melanoma

2015–2017 An5-‐PD-‐1/-‐PD-‐L1

for metasta5c melanoma, NSCLC,

RCC, Bladder, HNSCC, Hodgkin,

Merkel.

Ipilimumab in adjuvant melanoma.

Nivolumab + ipilimumab, T-‐VEC

in melanoma 2010

Provenge US Coley in 1891:

observa5on of a tumour regression in a

pt who developed a post-‐op infec5on

A historical view of immunotherapy…

Italy 2017

An5-‐PD-‐1 in:

RCC Hodgkin Melanoma

NSCLC

……….

………..

2017

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The evolving Cancer Immunotherapy Landscape

>800 clinical combinations with PD-L1/PD-1 inhibitors

Hegde PS, AAADV, Washington DC, 2017

Atezo+chemo+/-bevacizumab Durva+tremelimumab

Nivo+ipilimumab Nivo+BMS-986016 Nivo+capmatinib Nivo+dasatinib Nivo+EGF816

Pembro+azacitidine Pembro+acalabrutinib Pembro+abemaciclib

Nivo+ipilimumab Atezo +chemo Durva+tremelimumab

+/-chemo

Nivo+

ulocuplumab

Nivo+cabiralizumab Nivo+ceritinib

Nivo+crizotinib Nivo+epacadostat Nivo+erlotinib

Nivo+galunisertib Nivo+lirilumab

Nivo+urelumab Nivo+varlilumab

Pembro+AM0010

Pembro+ipilimumab

Pembro+bevacizumab Pembro+epacadostat

Pembro+entinostat Pembro+crizotinib

Pembro+GSK-3174998 Pembro+gefitinib Pembro+erlotinib

Pembro+PEGPH20 Pembro+necitumumab

Pembro+lenvatinib

Pembro+pexidartinib Pembro+ramucirumab Atezo+cobimetinib

Atezo+epacadostat Atezo+erlotinib Atezo+GDC-0919

Atezo+ipilimumab Atezo+varlilumab

Durva+AZD6738 Durva+epacadostat Durva+gefinitib

Durva+ibrutinib Durva+mocetinostat Durva+ramucirumab

Ave+crizotinib Ave+lorlatinib Ave+PF-04518600 Ave+utomilumab

PDR001+LAG525

Nivo+ipilimumab Pembro+epacadostat Pembro+T-VEC

Nivo+BMS-986016 Nivo+cabiralizumab Nivo+epacadostat

Nivo+lirilumab Nivo+urelumab

Pembro+AM0010 Pembro+CAVATAK

Pembro+CMP-001 Pembro+darbafenib+trametinib

Pembro+entinostat Pembro+GSK-3174998

Pembro+LV305

Pembro+IMP321

Pembro+lenvatinib Pembro+pexidartinib Pembro+SD-101

Pembro+X4P-001 Atezo+cobimetinib

Atezo+CPI-444 Atezo+GDC-0919 Atezo+IFN!-2b

Atezo+varlilumab

Durva+dabrafenib+trametinib Durva+epacadostat

Ave+PF-04518600 Ave+utomilumab

PDR001+LAG525

NSCLC

SCLC

Melanoma

Nivo+

Rova-T

Atezo+bevacizumab

Ave+axitinib

Pembro+axitinib / lenvatinib

Nivo+BMS-986016 Nivo+lirilumab Pembro+ipilimumab

Pembro+AM0010 Atezo+CPI-444

Pembro+GSK-3174998 Pembro+epacadostat Atezo+GDC-0919

Atezo+IFNα-2b Atezo+varlilumab

RCC

Atezo+chemo Pembro+chemo

Nivo+ipilimumab Pembro+CAVATAK Pembro+enadenotucirev

Pembro+epacadostat Pembro+GSK-3174998

Pembro+lenvatinib Pembro+pexidartinib

Pembro+ramucirumab Atezo+CPI-444

Atezo+emactuzumab Atezo+GDC-0919 Atezo+varlilumab

Durva+AZD4547 Durva+tremelimumab

Durva+tremelimumab

UC

Nivo+ipilimumab Pembro+chemo / T-VEC

Nivo+BMS-986016 Nivo+cabiralizumab Nivo+epacadostat

Nivo+urelumab

Nivo+varlilumab Pembro+enadinotucirev

Pembro+epacadostat

Pembro+GSK-3174998

Pembro+lenvatinib Pembro+pexidartinib Atezo+CPI-444

Atezo+GDC-0919 Atezo+varlilumab Durva+AXAL Durva+AZD5069

Durva+AZD6738 Durva+AZD9150

Durva+epacadostat

SCCHN

Nivo+BMS-986156 Nivo+BMS-986178

Nivo+mogamulizumab Pembro+MK-1248 Pembro+MK-4166 Pembro+MK-4280

Atezo+bevacizumab

Atezo+MOXR0916 Atezo+MTIG7192A Atezo+RG-7802 Atezo+RG-7813 Atezo+RG-7876 Atezo+vanicizumab Durva+IMC-CS4 Durva+LY2510924

Durva+MEDI0562

Durva+MEDI0680 Durva+MEDI9447 Durva+monalizumab Durva+mogamulizumab Durva+selumetinib

Pembro+demcizumab

Atezo+chemo Pembro+chemo

Pembro+epacadostat

Pembro+GSK-3174998 Pembro+niraparib Nivo+ipilimumab

Atezo+CPI-444 Atezo+emactuzumab

Atezo+entinostat Atezo+GDC-0919

Atezo+T-VEC

Atezo+varlilumab

Durva+tremelimumab Ave+utomilumab

PDR001+BLZ945

TNBC

Ovarian

Ave+chemo Atezo+chemo

Pembro+epacadostat Pembro+niraparib Nivo+lirilumab

Atezo+GDC-0919 Atezo+emactuzumab

Ave+entinostat

Nivo+epacadostat Atezo+rucaparib

Nivo+varlilumab

Pembro+mirvetuximab soravtansine Pembro+pexidartinib Pembro+margetuximab

Atezo+GDC-0919 Atezo+emactuzumab

Pembro+PEGPH20 Pembro+pexidartinib

Pembro+ramucirumab Pembro+trastuzumab

Nivo+BMS-986016 Atezo+bevacizumab

Durva+ramucirumab PDR001+LAG525 Pembro+chemo

Nivo+ipilimumab

Gastric

Atezo+cobimetinib

Nivo+epacadostat

Pembro+enadenotucirev Nivo+cabiralizumab

Atezo+bevacizumab

Nivo+ipilimumab

Pembro+GSK-3174998

Atezo+CPI-444 Atezo+GDC-0919 Atezo+T-VEC Ave+PF-04518699

CRC

Pembro+acalabrutinib Pembro+BL-8040

Durva+tremelimumab

Nivo+cabiralizumab Durva+AZD5069 Durva+epacadostat Durva+galunisertib Durva+ibrutinib

Pancreas

Nivo+

BMS-986016

Durva+

ramucirumab

PDR001+capmetinib Durva+

tremelimumab

Nivo+CC-122

Nivo+galunisertib

Atezo+bevacizumab

Liver

!"#$%&'&()&'*+&

!"#$%&+&

!"#$%&,&

-#).%/%0&

Pembro+chemo Atezo+CPI-444

Pembro+ipilimumab Nivo+varlilumab

Nivo+ipilimumab

Pembro+INCB039110 Pembro+utomilumab PDR001+GWN323

PDR001+MBG453

Nivo+ipilimumab Nivo+ulocuplumab

Pembro+pelareoprep Pembro+pexidartinib Nivo+lirilumab

Nivo+varlilumab

Pembro+iMiD Nivo+iMiD+/-elotuzumab Durva+/-iMiD

Durva+azacitidine Atezo+obinutuzumab+/-iMiD Atezo+obinutuzumab+polatuzumab

Atezo+tazemetostat Atezo+daratumumab+/-iMiD

Atezo+azacitidine

Durva+AZD9150 Durva+ibrutinib Durva+rituximab+iMiD

Durva+rituximab+bendamustine Durva+tremelimumab Nivo+brentuximab vedotin

Nivo+epacadostat

Nivo+ibrutinib Nivo+ipilimumab Nivo+urelumab Pembro+acalabrutinib

Pembro+AFM13 Pembro+epacadostat Pembro+dinaciclib

Pembro+G100 Pembro+dasatinib

Heme Solid

PDR001 + BLZ945 PDR001+MCS110

Nivo+CB-1158

Atezo+codrituzumab

Atezo+BL-8040 Atezo+cobimetinib

+vemurafenib Nivo+NKTR-214

Nivo+CV-301

Pembro+CAVATAK PDR001+canakinumab

PDR001+CJM112 PDR001+EGF816

PDR001+trametinib Nivo+NKTR-214

PDR001+LAG525

PDR001+dabrafenib+trametinib

Pembro+acalabrutinib

Nivo+NKTR-214

Pembro+B-701

Atezo+PEGPH20

Ave+defactinib Nivo+JTX-2011

PDR001+CJM112

Pembro+pexidartinib PDR001+canakinumab PDR001+EGF816

Adapted from Vanessa Lucey of CRI by Gergely Jarmy

Chen and Mellman, Nature 2017

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a

Tumor-permissive Tumor non-permissive

Mutational load

angiogenesis, MDSC, immunosuppressive

reactive stroma

Low MHC I

Adapted from Hedge PS, et al. Clin Cancer Res 2016; 22(8) 1865-1874.

Immune desert tumors pre-existing immunity T-cell migration defect

TILs

CD8 T cells/IFNγ PD-L1 &

checkpoints

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HLA class I downregulaAon in diﬀerent tumor lesions

Courtesy of S. Ferrone

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Why some pa5ents do not respond to immunotherapy?

The gene expression proﬁle of the tumor microenvironment as an approach to the iden7ﬁca7on of mechanisms of resistance to immune checkpoint blockade

HLA-‐I

regressing lesion

HLA-‐I

progressing lesion

Courtesy of Andrea Anichini, INT Milano

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Zaretsky JM et al, NEJM, 2016

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Targe5ng and modula5ng mul5ple

compartments

TUMOR MICROENVIRONMENT

AnAgens

AcAve T cell

Cancer cell DendriAc

cell

ApoptoAc cancer cell AcAve

T cell

IMMUNE SYSTEM

TUMOR MICRO-‐

ENVIRONMENT

TUMOR ICOS

GITR LAG3 4-‐1BB OX-‐40 TIM3

…..

(17)

Co-‐sAmulatory pathways

(18)

T cell Priming / Periphery

Local AnAgen Re-‐challenge

ICOS ICOS-‐L

CXCR5, CD40L

ProliferaAon

IFN-‐γ

ICOS Mechanism of Ac5on

(19)

GSK 204691 (INDUCE-‐1) Study Design

Dose

Level GSK3359609

(mg/kg) Design

1 0.001 Accelerated

Titra5on

2 0.003 Accelerated

Titra5on

3 0.01 Accelerated

Titra5on

4 0.03 mTPI

5 0.1 mTPI

6 0.3 mTPI

7 1.0 mTPI

8 3.0 mTPI

Part 1A: Monotherapy Dose Escalation

Part 2A: Combination Dose Escalation

N≈36

Multiple selected solid tumors

N≈24

Multiple selected solid tumors

1 2

Part 1B: Monotherapy Expansion

Part 2B: Combination Expansion Cohort 1 (N≈20) Cohort 2 (N≈20) Cohort 3 (N≈20) Cohort 4 (N≈20) Biomarker cohort (N≈30)

Cohort 1 (N≈20) Cohort 2 (N≈20)

Cohort 1 (N≈20) Cohort 2 (N≈20) Biomarker cohort (N≈30)

•  Steering Commieee Decision Points

(20)

peripheral blood

pharmacodymamic biomarkers

(21)

Kaplan Meyer curves of overall survival for circulating CD4+ICOS+ T cells at day 30 of 1st cycle (A), or for circulating Neutrophil/CD4+ICOS+T cells ratio

at d14 of 2nd cycle (B)

A Mesot-trem-2008* B Mesot-trem-2012**

* Calabrò et al, Lancet Oncol 2013

** Calabrò et al, Lancet Resp Med 2015

(22)

Overall survival by median levels of circulating CD4+ICOS+ T cells in metastatic melanoma patients treated with ipilimumab

L. Calabrò et al., unpublished

CD4+ICOS+ >median CD4+ICOS+ ≤median

p<0.02

(23)

CD4+ICOS+ in melanoma treated with IPI 3mg or 10mg

0 1 2 3 4 5 6 7

Baseline w4 w7 w12 w24

ce ll c ou nt /U L

* * *

p<0.0001

L. Calabrò et al., unpublished

(24)

TUMOR MICROENVIRONMENT

AnAgens

AcAve T cell

Cancer cell DendriAc

cell

ApoptoAc cancer cell AcAve

T cell

IMMUNE SYSTEM

TUMOR MICRO-‐

ENVIRONMENT

TUMOR

Targe5ng and modula5ng mul5ple compartments

HLA I/II

Tumor Associated AnAgens AnAgen Processing

Machinery

Co-‐sAmulatory Molecules

…..

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Blocking the MAPK Signaling Pathway Results in Changes in the Tumor Microenvironment

• 

^a

Adap5ve Technologies, Seaele, WA.

•  1. Frederick D et al. CCR 2013; 2. Ebert P et al. Immunity 2016.

•  Sullivan R et al. presented at 13th Interna5onal Melanoma Congress | SMR 2016-‐11-‐07

MAPK Inhibitor-‐Induced Changes ^1,2

l  Increased melanoma an5gen expression

l  Decreased immunosuppressive cytokine produc5on

l  Increased CD8+ T-‐cell inﬁltra5on

l  Increased T-‐cell clonality ^a

l  Increased PD-‐L1 expression

l  Class I MHC upregula5on Enhanced

Tumor Cell Death

T Cells Are Activated and

Live Longer

Tumor Cells Are More

Visible

Tumors Are More Susceptible

Dual MAPK Pathway Inhibition PD-L1 Inhibition

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vem 960mg BID ^a cobi 60mg QD ^b

atezo 840mg q2w

vem 720mg BID + vem placebo 240mg BID cobi 60mg QD ^b

vem 960mg BID ^a cobi 60mg QD ^b

placebo q2w vem 960mg BID

cobi 60mg QD ^b

Phase III Study of atezo + cobi + vem in BRAF V600 Mutant Melanoma

(NCT02908672)

• 

^a

vemurafenib dose will decrease to 720 mg BID + placebo 240 mg BID beginning day 22 of vem + cobi doublet treatment phase.

• 

^b

cobime5nib administered on 21 days on/7 days oﬀ schedule.

•  IRF, independent review facility; PK, pharmacokine5cs.

•  Sullivan R et al. presented at 13th Interna5onal Melanoma Congress | SMR 2016-‐11-‐07

R 28 days Treatment unAl PD or toxicity

Previously Untreated Advanced Melanoma

•  BRAF V600 muta5on

•  ECOG PS 0-‐1

•  Measurable disease

•  No signiﬁcant history of liver disease

N = 500

•  Primary: investigator-assessed PFS

•  Secondary: PFS (IRF-assessed), OS, ORR, DOR, Safety, PK

(27)

Targe5ng and modula5ng mul5ple

compartments

TUMOR MICROENVIRONMENT

AnAgens

AcAve T cell

Cancer cell DendriAc

cell

ApoptoAc cancer cell AcAve

T cell

IMMUNE SYSTEM

TUMOR MICRO-‐

ENVIRONMENT

TUMOR

IDO Arginase

Suppressor cells

VEGF

(28)

Multiple immune inhibitory and co-stimulatory pathways in the tumor microenvironment are targets of therapeutic manipulation by antibodies or drugs.

Drew Pardoll, and Charles Drake J Exp Med 2012;209:201-209

(29)

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IDO1 Expression Is Associated With

Poor Patient Outcome in Various Tumor Types

•  IDO1 is highly expressed in multiple tumor types

–  Melanoma –  NSCLC

–  Ovarian cancer –  Pancreatic cancer –  CRC

–  Glioblastoma

–  Squamous cell carcinoma –  Endometrial carcinoma –  DLBCL

–  RCC –  TCC –  TNBC

30 Kaplan-Meier survival curves in melanoma based on IDO1 accumulation in the lymph node ¹

IDO negative

IDO positive

TCC=transitional cell carcinoma; TNBC=triple negative breast cancer

1.  Munn DH, et al. J Clin Invest 2004;114(2):280-90

(31)

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

IFN=interferon 31

Koblish HK, et al. AACR 2015. Poster 1336

Infiltrating cells Cytokines PD-1 expression

(32)

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

32 1.  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

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Le basi dell’immuno-oncologia nei tumori solidi