IL FUTURO DELL’INIBIZIONE DI PD ‐ 1 E PD L1 NELLA NEOPLASIA POLMONARE PD ‐ L1 NELLA NEOPLASIA POLMONARE NON A PICCOLE CELLULE Istituto Nazionale Tumori Regina Elena Istituto Nazionale Tumori Regina Elena Michele Milella Roma
Dr Michele Milella Dr. Michele Milella In ottemperanza alla normativa ECM ed al principio di trasparenza delle fonti di finanziamento e In ottemperanza alla normativa ECM ed al principio di trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario, si informano i discenti che negli ultimi due anni si sono avuti i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: Pfizer, Novartis, AstraZeneca, Merck ‐ Serono, Celgene, BMS
Back to where it all started… (for me at least!!!) (for me at least!!!)
ASCO 2015: Immunotherapy py strikes back! David A. Karnofsky Memorial Award and Lecture: PD 1 Pathway Blockade A Common Denominator for Cancer Therapy Denominator for Cancer Therapy Plenary Session including the Science of Oncology Plenary Session including the Science of Oncology Award and Lecture: Immune Checkpoint Blockade in Cancer I Ch k i t Bl k d i C Therapy: New Insights, Opportunities, py g pp and Prospects for a Cure
Slide 51 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 3 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 4 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Immune checkpoints Immune checkpoints • Various ligand-receptor interactions between T cells and APCs can regulate T-cell responses to antigen • These responses can occur upon initiation of a T-cell response in the LN or tumour microenvironment • CTLA-4 modulates peripheral • CTLA 4 modulates peripheral T-cell expansion post antigen presentation in the LN • PD1 modulates T-cell responses in the periphery the periphery Pardoll DM. Nat Rev Cancer 2012;12(4):252–64 . 8 Mercury: 1506HQ13NP08597 -01-IT Approved Oct 2013; Expires Oct 2015
Ipilimumab Blocks Negative Signaling From CTLA-4 Co stimulation via CD28: Co-stimulation via CD28: CTLA 4 blocks co stimulation: CTLA-4 blocks co-stimulation: Ipilimumab blocks CTLA-4: Ipilimumab blocks CTLA 4: T-cell activation No T-cell activation T-cell activation T cell T cell T cell CTLA4 CTLA4 TCR TCR TCR CD28 CD28 i ili ipilimumab b CD28 CD28 B7 B7 MHC B7 MHC MHC APC APC APC APC APC APC Adapted from Lebbé et al. ESMO 2008 APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor. Adapted from Dooms C., 2012 PILC
Nivolumab mechanism of action Nivolumab mechanism of action Recognition of tumour by T cell through R iti f t b T ll th h P i Priming and activation of T cells through i d ti ti f T ll th h MHC/antigen interaction mediates IFN γ release MHC/antigen and CD28/B7 interactions with and PD-L1/2 upregulation on tumour antigen-presenting cells IFN γ IFN γ R T-cell T cell receptor receptor receptor MHC MHC PI3K Dendritic NF κ B Tumour cell CD28 B7 Other cell ll PD L1 PD-L1 T cell Shp-2 PD-1 PD-L1 PD-1 PD-L2 Shp-2 PD-L2 PD-1 PD-1 Nivolumab PD1 Receptor Blocking Ab 10 Mercury: 1506HQ13NP08597 -01-IT Approved Oct 2013; Expires Oct 2015
Blocking CTLA 4 and PD1 Blocking CTLA-4 and PD1 Tumour microenvironment Activation Activation (cytokines, lysis, proliferation, migration to tumour) TCR TCR MHC MHC +++ +++ +++ D Dendritic d iti Tumour cell B7 CD28 cell +++ T cell T cell PD1 PD-L1 CTLA-4 - - - - - - B7 anti-PD1 anti-CTLA-4 PD1 PD-L2 - - - anti-PD1 PD1 blockade (nivolumab) CTLA-4 blockade (ipilimumab) Ribas A. N Engl J Med 2012;366(26):2517–9. 11 Mercury: 1506HQ13NP08597 -01-IT Approved Oct 2013; Expires Oct 2015
CTLA-4 vs PD1: checkpoint inhibitors CTLA-4 vs PD1: checkpoint inhibitors CTLA-4 PD1 Migrates from intracellular stores to Expressed on cell surface or induced by T cell : APC synapse upon T-cell T cell interaction; redistributes to T cell : activation 1 APC synapse on T-cell activation 1 Inhibits Akt but not PI3K activity 1 Inhibits PI3K and downstream Akt 1 Dual ligands (B7.1; B7.2) 2 Dual ligands (PD-L1; PD-L2) 2 Expressed on activated T cells 1,2 E d ti t d T ll 1 2 E Expressed on a range of immune cells, d f i ll including T cells Ligands broadly expressed on APCs / Ligands expressed on tumours and tissues throughout the body 1,2 tiss es thro gho t the bod 1 2 imm ne cells and to a lesser e tent immune cells and, to a lesser extent, normal tissues 2 Activation through association of APC Activation through association of tumour and T cell in periphery followed by and T cell in periphery followed by and T cell at tumour site and APC and and T cell at tumour site and APC and distribution of activated T cells to tumor T cell in lymph nodes 3 sites 3 K i ME A Keir ME. Annu Rev Immunol 2008;26:677–704. R I l 2008 26 677 704 Korman AJ, et al. Adv Immunol 2006;90:297–339. Parry RV, et al. Mol Cell Biol 2005;25:9543–9553. 12 Mercury: 1506HQ13NP08597 -01-IT Approved Oct 2013; Expires Oct 2015
Slide 9 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 10 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 11 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 12 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 13 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 14 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 17 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Slide 18 Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Anti ‐ PD1/PD ‐ L1 in NSCLC: The present
Anti ‐ PD1/PD ‐ L1 in NSCLC: The (near?) future
At what price?
News from ASCO 2015: Nivo in squamous OS and PFS by PD-L1 Expression Presented By David Spigel at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in squamous OS by PD-L1 Expression Presented By David Spigel at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in squamous ORR by PD-L1 Expression Presented By David Spigel at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous CheckMate 057 (NCT01673867) Study Design Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous Overall Survival Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous Treatment Effect on OS in Predefined Subgroups Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous Objective Response Rate Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous Progression-free Survival Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous OS by PD-L1 Expression Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous OS and PFS Hazard Ratios by Baseline PD-L1 Expression Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
News from ASCO 2015: Nivo in non ‐ squamous ORR by PD-L1 Expression Presented By Luis Paz-Ares at 2015 ASCO Annual Meeting
Slide 8 Presented By Marina Garassino at 2015 ASCO Annual Meeting
Slide 11 Presented By Marina Garassino at 2015 ASCO Annual Meeting
Is NIVO more effective in squamous than adenoca? Presented By Marina Garassino at 2015 ASCO Annual Meeting
Overall Survival Presented By Marina Garassino at 2015 ASCO Annual Meeting
News from ASCO 2015: Immuno ‐ Combo Pembrolizumab and Ipilimumab Dosing Presented By Amita Patnaik at 2015 ASCO Annual Meeting
News from ASCO 2015: Immuno ‐ Combo Treatment-Related Adverse Events Observed <br />in ≥ 3 Patients Presented By Amita Patnaik at 2015 ASCO Annual Meeting
News from ASCO 2015: Immuno ‐ Combo Adverse Events of Special Interest (Any Frequency) Presented By Amita Patnaik at 2015 ASCO Annual Meeting
News from ASCO 2015: Immuno ‐ Combo Best Overall Response <br />(RECIST v1.1, Investigator Review) Presented By Amita Patnaik at 2015 ASCO Annual Meeting
News from ASCO 2015: Immuno ‐ Combo Change From Baseline in Tumor Size <br />(RECIST v1.1, Investigator Review) Presented By Amita Patnaik at 2015 ASCO Annual Meeting
…and not just for NSCLC Slide 14 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting
News from ASCO 2015: Atezolizumab Atezolizumab is a Humanized Anti-PDL1 Antibody That Inhibits the Binding of PD-L1 to PD-1 and B7.1 Presented By Alexander Spira at 2015 ASCO Annual Meeting
News from ASCO 2015: Atezolizumab PD-L1 Expression on TC and IC is a Potential Predictive Biomarker for Atezolizumab in NSCLC Presented By Alexander Spira at 2015 ASCO Annual Meeting
News from ASCO 2015: Atezolizumab POPLAR: A Randomized All-comer Phase II Study Presented By Alexander Spira at 2015 ASCO Annual Meeting
News from ASCO 2015: Atezolizumab POPLAR: PD-L1 Expression Subgroups<br />Interim OS Presented By Alexander Spira at 2015 ASCO Annual Meeting
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