Immunotherapy 2017

Sandrine Aspeslagh, MD, PhD

DITEP

Follow @sandrineaspesla

Anti-CTLA-4 can CURE Metastatic Melanoma

Schadendorf D, JCO 2015.

Gentles et al, Nat Med 2015

Immune cells i/t tumor microenvironment

Paradigm Shift in Cancer Therapy

Tumor Cell

Historical Paradigm: Targeting Tumor Cells

Immune cell

New Paradigm: Targeting Immune Cells

Adapted from A. Marabelle

Chemotherapy - 1930s Paul Ehrlich - alkylating agents

1943 nitrogen mustard - lymphoma

Surgery – 1890 Halsted performs first radical mastectomy

Radiotherapy – late 19th - Becquerel and Rontgen, Marie Curie

1898 radium identified, 1903 first successful cancer tx

Pro-tumoral Anti-tumoral

Some immune cells ‘help’ the tumor

Cancer Immunity cycle

Ch

en

an

d M

ellm

an, 2

01

3

http://www.tcells.org/beginners/easy_steps/10.shtml

CD8 T cells: serial killers

Lymphocyte Inhibition

Sharma et al, NRC, 2011

SIGNAL 1

SIGNAL 2

Immune Checkpoint Blockade Therapy

Sharma et al, NRC, 2011

Hui E et al, 2017, Science Kampforst A et al, 2017, Science

Anti-PD1 activates CD28: SIGNAL 2

SIGNAL 1

atezolizumab in RCC

PD(L)1 blockade leads to a CD8+ T-cell anti-tumor response

Herbst RS et al. Nature. 2014

Variable Sensitivity to Immunotherapy

1. Daud A et al. 2014 SMR; 2. Garon EB et al. ESMO 2014; 3. Chow LQ et al. ESMO 2014; 4. O’Donnell P et al. 2015 Genitourinary Cancers Symposium; 5. Muro K et al. 2015 Gastrointestinal Cancers Symposium; 6. Nanda R et al. SABCS

2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR.

90% of patients had a reduction in target lesions

Armand P. et al NEJM 2016

Hodgkin: Highest Efficacy of anti-PD1…

Michot JM et al, in preparation

Hodgkin: increased PDL1/2 expression

PDL1 as a biomarker

Rosenberg et al, Lancet Onco, 2016

Ove

rall

Surv

ival

IC2/3 IC1 IC0

Colon CA MSI high

Le et al 2015, NEJM

GBM

Bouffet et al, 2016, JCO

Snyder A et al, 2015 NEJM

Mutational load: holy graal?

Shin et al, 2017, Cancer Discovery

Colon MSI high cancer: JAK1 loss

Mar

abe

lle A

et

al ,

20

17

, Can

cer

Dis

cove

ry

Koya

ma

et a

l, 2

01

6 N

atu

re c

om

mu

nic

atio

ns

Tim-3 upregulation

AGONISTIC ANTAGONISTIC

Other immune checkpoints to come

Hodi et al 2016, NEJM

Ipilimumab + nivolumab OS in Melanoma

Toxic

Sharma P et al, 2017, Cell

Anti-PD(L)1 resistance

Steidl et al, 2010, NEJM

TAM infiltration

Hodgkin

Hugo et al 2016 Cell

Melanoma

Mantovani A et al 2017, NRC

Macrophage targeting

HDAC-I -Notch inhibition -Taldalafil -CT: Gemci, 5FU, … -IDO-I -TGFbeta-I -Anti-CD47 -Anti-CD40

Anti-CCR2

Noy and Pollard 2014; Immunity

Anti-CCR2

TAM

Zhou et al, 2016, Science Transl Med

?

How to change a cold tumor in a hot tumor

Chen and Mellman, Nature, 2017

Overcome immune checkpoint inhibition resistance w/ immunogenic chemotherapy

Pfirschke C et al 2016 Immunity CD8 Tcells

Overcome ICB R with chemotherapy

TAT 2017 Ghiringelli Dijon

Chemotherapy + anti-PD-1 1st L NSCLC

Langer CJ, et al. Lancet Oncol. 2016

Chemotherapy

Pembrolizumab + Chemotherapy

Trinchieri and Sher, NI 2007

Picibanil

Listeria

monophosphoryl lipid A

BCG

G100

imiquimod

SD101

CpG

IMM 101

Tumeur

chaude

Ongoing Clinical Combinations

Adapted from A. Marabelle

Challenges in 2017

Thank you

Follow @sandrineaspesla