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
Chen and Mellman, 2013
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
Ov er all Sur viv al 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
Marabelle A et al , 2017, Cancer Discovery
Koyama et al, 2016 Nature communications
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
