Espoirs en Oncologie

Immunothérapie anti tumorale : Thérapeutique émergente Oncologie =  45% des études cliniques en cours en France.  Enjeu santé publique.  Enjeu Financier. Années 2000 : Thérapeutiques ciblées ( 15% des cancers du poumon) Surgery Radiation Cytotoxic & targeted therapies I-O

facteur croissance

Correspondances en Onco-Urologie ASCO® GU D’après Freeman G et al., Renal Cancer Keynote Lecture Signal 1 : reconnaissance de l’antigène APC Lymphocyte T Signal 2 : Co-stimulation Activation des lymphocytes T

Correspondances en Onco-Urologie ASCO® GU D’après Freeman G et al., Renal Cancer Keynote Lecture Voie de signalisation PD-1/PD-L1 Cellule Tumorale Lymphocyte T MHCTCR Antigène PD-L1/ PD-L2 PD-1

Correspondances en Onco-Urologie ASCO® GU D’après Freeman G et al., Renal Cancer Keynote Lecture Le blocage de PD-1 ou PD-L1 stimule la réponse immune anti-tumorale CD8+CTL Augmentation de la mort cellulaire IFN-γ Anticorps PD-1 TCR MHC PD-L1 Cellule tumorale Augmentation des cytokines

Correspondances en Onco-Urologie ASCO® GU D’après Freeman G et al., Renal Cancer Keynote Lecture Quel est le lieu d’action du blocage des checkpoints immunologiques Blocage Checkpoint CTLA-4 dans les ganglions PD-1 dans la tumeur APC Lympho T Ganglion IL-6 IL-10 TGF-β IDO Tumeur Lympho T MDSC PD-L1 CTLA-4 PD-L1 APC Celllule stromale PD-L1 PD-1 Treg

Correspondances en Onco-Urologie ASCO® GU D’après Freeman G et al., Renal Cancer Keynote Lecture Deux processus d’évolution dans les cancers : Mutations de l’ADN –rares mutations driver –nombreuses mutations passenger Échappement au frein immunitaire : PD-L1, IDO, TGF-b, IL-10, perte de MHC, autres Cellule normaleCellule tumorale Mutations Néo-antigènes Mutation driver

Proprietary and Confidential15 Tumor antigens released by tumor cells Tumor antigens presented to T cells T cells are activated; they proliferate and differentiate into effector and memory cells Effector T cells recognize tumor antigens T cells kill tumor cells The T-Cell Antitumor Response APC = antigen-presenting cell. 1. Andersen MH, et al. J Invest Dermatol. 2006;126:32–41; 2. Pardoll DM. Nat Rev Cancer. 2012;11:252–264; 3. Mellman I, et al. Nature. 2011;480:480–489; 3. Heemskerk B, et al. EMBO J. 2013;32:194–203; 4. Boudreau JE, et al. Mol Ther. 2011;19:841– 853; 5. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.

MHC-Ag Cancer cell B7.1 CD28 TCR Keir ME et al. Annu Rev Immunol : ; Pardoll DM, Nat Rev Cancer : T cell activation results in tumor destruction (Immunesurveillance by the host) APC T cell Activated T cells APC processes and presents tumor antigen (Ag) on MHC. Activates antitumor immunity Immunesurveillance against Tumors

Tumour escape from the immune response Drake CG,et al. Adv Immunol 2006;90:51–81 Vesely MD, et al. Annu Rev Immunol 2011;29:235–271  Tumors use complex, overlapping mechanisms to evade and suppress the immune system e.g. myeloid-derived suppressor cells, MDSC, regulatory T cells, Tregs, alternatively activated macrophages [M2 Mø] e.g. TGF-B, IDO, IL-10 e.g. down regulation of MHC I and DC/APC defects in antigen processing and presentation e.g. disruption of T-cell inhibitory (‘checkpoint’) and activatory pathways, release of FAS and other death receptor ligands Inhibition of tumor antigen presentation Secretion of immunosuppressive factors Inhibition of attack by immune cells Recruitment of immunosuppressive cell types

Immune Evasion by Tumor via PD-1 MHC-Ag Cancer cell B7.1 CD28 TCR APC T cell Dysfunctional, exhausted T cells (-) PD-L1 PD-1 Cancer cell Cancer cells exploit PD-1 pathway to suppress tumor-directed T cell response. Keir ME et al. Annu Rev Immunol : ; Pardoll DM, Nat Rev Cancer :252-64

Tumours use various mechanisms to escape the immune system Immune escape mechanisms are complex and frequently overlapping Tumour cells CD8 + T cell A. Ineffective presentation of tumour antigens to the immune system Treg MDSC Vesely MD, et al. Ann Rev Immunol 2011;29:235–71. B. Recruitment of immunosuppressive cells (Tregs, MDSCs, others) CD8 + T cell CD4 + T cell TGF-β IL-10 TGF-β ARG1 iNOS C. Release of immunosuppressive factors VEGF APC TGF-β IDO IL-10 D. T cell checkpoint dysregulation PD1 PD-L1 PD1 PD-L1 CTLA-4 TCR MHC

Tumours use various mechanisms to escape the immune system Immune escape mechanisms are complex and frequently overlapping Tumour cells CD8 + T cell A. Ineffective presentation of tumour antigens to the immune system Treg MDSC Vesely MD, et al. Ann Rev Immunol 2011;29:235–71. B. Recruitment of immunosuppressive cells (Tregs, MDSCs, others) CD8 + T cell CD4 + T cell TGF-β IL-10 TGF-β ARG1 iNOS C. Release of immunosuppressive factors VEGF APC TGF-β IDO IL-10 D. T cell checkpoint dysregulation PD1 PD-L1 PD1 PD-L1 CTLA-4 TCR MHC

Cancer cell B7.1 CD28 TCR MHC-Ag APC T cell (-) PD-L1 PD-1 Cancer cell Nivolumab Nivolumab revitalizes exhausted tumor-specific T cells by PD-1 blockade Revitalized T cells Keir ME et al. Annu Rev Immunol : ; Pardoll DM, Nat Rev Cancer : Nivolumab Restores T cell Functions

Résultats Nivolumab ( OPDIVO ) Ipilimumab ( YERVOY) 25% de réponses ( stades IV métastatiques) réponses prolongées : mélanome > 10 ans Poumon : recul insuffisant, 20% > 3 ans. Qualité de vie : idem sujets sains +++ Mélanome, Poumons…30 organes, hémopathies.

Avril 2015Août 2015 post chimio Novembre 2015 post anti PD1

TTT Ciblées Anti EGFR Février 2013 échec chimio

Juillet 2014 Xalkori Anti ALK

Immunothérapie versus TTT Ciblées Tous les patients quasiment Réponses 20 à 30 %. Réponses prolongées +++ Tolérance excellente. Pas de toxicité cumulée. < 20% Patients : EGFR, ALK, ROS1, BRAF Réponses > 70%. Échappement constant…2°G, 3°G Tolérance >> chimio.

toxicité similaire. Fréquence variable. Qualité de vie +++

Gestion effets secondaires selon grades toxicité. Abstention. TTT symptomatique Corticoides ( suspension traitement), anti TNF, IS. Arrêt définitif immunothérapie. CI : Maladies auto immunes ? greffes organes ?

Parlons sous ! 45% études cliniques en cours. 20 à 30% des nouvelles AMM. 300 Millions € / an Mélanome. 3 Milliards € / an / cancer poumon !!! Sujet politique : G20. Seuil £ /an…Kadcylla €/ an. Pr JL Harousseau : il n’est pas exclu que nous n’arrivions pas à résoudre l’équation.

Parlons Futur

T cell activation can be augmented by targeting immune checkpoints Adapted from Mellman, et al. Nature, 2011:480;481-9 Pardoll DM. Nat Rev Cancer 2012;12:  T-cell responses are regulated though a complex balance of inhibitory (“checkpoints”) and activating signals  Tumors can dysregulate checkpoints and activating pathways, and consequently the immune response  Targeting checkpoints and activating pathways is an innovative approach to cancer therapy, designed to promote an immune response PD-1 CTLA-4 Inhibitory receptorsActivating receptors TIM-3 LAG-3 Blocking antibodies Agonistic antibodies T-cell stimulation CD28 OX40 CD137

T cells are activated via the integration of signals from both co-stimulatory and co-inhibitory receptors Peggs KS, et al. Clin Exp Immunol 2009;157:9–19. Keir ME. Annu Rev Immunol 2008;26:677–704.

How does immunotherapy differ from chemotherapy? ChemotherapyImmunotherapy Direct cytostatic or cytotoxic effects on tumour cells Aims to destroy tumour cells by enhancing the body’s own immune response 1 Antitumour activity is expected soon after exposure to the agent Antitumour response may develop over time or after initial progression 2–4 AEsChemotherapy affects rapidly dividing cells – e.g. tumour cells and also normal cells such as blood cells, hair and cells of the GI tract. AEs typically include neutropenia, hair loss and nausea/vomiting AEs associated with immunotherapy are drug-specific and typically a consequence of the enhanced immune response and can include rash, colitis and hypophysitis 5 1. Finn OJ. N Engl J Med 2008;358:2704– Hoos A, et al. J Immunother 2007;30:1–15 3. Margolin K. Commun Oncol 2008;5:367– Gattinoni L, et al. Tumori 2003;89:476– Fong L, Small EJ. J Clin Oncol 2008;26:5275–5283

ONCHQ14NP02079 Potential Investigational Immunotherapeutic Approaches as Treatment Options for Lung Cancer 1–3 42 CTLA-4 = cytotoxic T-lymphocyte antigen-4; PD-1 = programmed death-1; PD-L1 = programmed death ligand accessed November 6, 2013; 2. NCCN Guidelines®. NSCLC. V2.2013; 3. Peters S, et al. Ann Oncol. 2012;23:vii56–vii64. Therapeutic Vaccines Enhancing Immune Cell Function Adoptive Antitumor mAbs Bavituximab Necitumumab Adoptive Cell Transfer Modulate T-cell Function Cytokines GSK A TG4010 Belagenpumatucel-L Tergenpumatucel-L Racotumomab CTLA-4 inhibition PD-1 inhibition PD-L1 inhibition Passive (Adoptive) Designed to act on the tumor, might use immune-based mechanism Active Designed to act on the immune system itself Immunotherapy