Breaking News in Oncologia Medica e Malattie del Sangue

Transcription

1 Breaking News in Oncologia Medica e Malattie del Sangue Aggiornamento 2015 CLAUDIO RUGARLI: TRATTATO DI MEDICINA INTERNA SISTEMATICA Modena, Ottobre 2015 Federico Caligaris-Cappio University Scientific Institute San Raffaele DeptOncoHematology, Div Experimental Oncology

2 Breaking News in Oncologia Medica e Malattie del Sangue A paper with an important message that the media have misinterpreted The issue of premalignancies The tumour microenvironment (TME) and the key issue of novel treatments based upon TME manipulation The issue of intercellular communications Benign Hematology is not lagging behind

3 D Hanahan, RA. Weinberg, Cell 2011

4 Breaking News in Oncologia Medica e Malattie del Sangue An embarassing paper with an important message that the media have misinterpreted

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8 Breaking News in Oncologia Medica e Malattie del Sangue A paper with an important message that the media have misinterpreted The issue of premalignancies

9 The ISSUE of PRE-LEUKEMIA MONOCLONAL B-CELL LYMPHOCYTOSIS (MBL) Chronic Lymphocytic Leukemia (CLL) virtually always preceeded by MBL with CLL cytogenetic abnormalities CLL-like MBL are present in otherwise healthy individuals A seething cauldron for CLL? Will time conquer all? Normal B cell MBL (5% population) CLL (10cases/10 5 /yr) Richter Syndrome (0,1-2% overt CLL) Rawstron et al, 2002; Ghia et al, 2004

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14 Breaking News in Oncologia Medica e Malattie del Sangue A paper with an important message that the media have misinterpreted The issue of premalignancies The tumour microenvironment (TME) and the key issue of novel treatments based upon TME manipulation

15 The Seed and Soil theory Good Seed Good Soil Abundant Harvest The Distribution Of Secondary Growths In Cancer Of The Breast, The Lancet, Volume 133, Issue 3421, 23 March 1889, Pages ,

16 Subverted immune/stromal cells are recruited to constitute the TME Tumour microenvironment (TME) is necessary for tumour growth and progression Ostensibly normal cells (immune/stromal) contribute to acquisition of cancer hallmark capabilities Tumour cells drive the construction of their own pro-tumoural niche (recruitment, activation, programming and persistence of immune/stromal cells) Emerging research: stromal/immune cells signal back and forth to tumour cells but also to each other

17 Johanna A. Joyce & Jeffrey W. Pollard Nature Reviews Cancer 9, (April 2009)

18 The secondary lymphoid organ microenvironment Stromal ECM Lymphoid Secreted B-zone T-zone MRC = marginal reticular cells Extracellular Matrix FDC = follicular dendritic cell B T FRC = fibroblastic reticular cell MΦ e.g. chemokines

19 Inflammation Cytokines Chemokines

20 Fig. 1 Activation of T cells requires two signals. Padmanee Sharma, and James P. Allison Science 2015;348:56-61 Published by AAAS

21 IMMUNE CHECKPOINTS Deactivated T cell When programmed-death receptor (PD-1) on the T cell binds to programmed death-ligand 1 (PD-L1) on the tumour cell, the T cell becomes deactivated, allowing the cancer cell to evade immune attack

22 Tumor cells suppress proximal anti-tumour T-cells via up-regulated immune checkpoint ligand expression T-cells inadvertently up-regulate PD-L1 expression on tumour cells

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27 Reed-Sternberg cells exploit the PD-1 (ProgrammedDeath-1) pathwayto evade immune detection Alterations in Chromosome 9p24.1 Increasethe abundanceof the PD-1 ligand, PDL-1 and promote theirinductionthroughjak-and STAT-signalling

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31 CAR structure, according to signaling domains. Shannon L. Maude et al. Blood 2015;125: by American Society of Hematology

32 Second-generation CAR used in current clinical studies at Penn and CHOP. CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex. Shannon L. Maude et al. Blood 2015;125: by American Society of Hematology

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34 Event-free survival in 30 children and adults treated with CTL019 therapy. Shannon L. Maude et al. Blood 2015;125: by American Society of Hematology

35 Breaking News in Oncologia Medica e Malattie del Sangue A paper with an important message that the media have misinterpreted The issue of premalignancies The tumour microenvironment (TME) and the key issue of novel treatments based upon TME manipulation The issue of intercellular communications

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39 CLL-derived exosomes have a paracrine effect on stromal cells residing in the TME. The transfer of exosomal cargoes (mirna and proteins) to target cells (bone marrow, BM-MSCs, and endothelial cells) induces an inflammatory CAF phenotype in these cells Intercellular communications and microenvironment reprogramming J. Poggetti et al, Blood 2015 B. Apollonio and A. G. Ramsay Blood by American Society of Hematology

40 Breaking News in Oncologia Medica e Malattie del Sangue A paper with an important message that the media have misinterpreted The issue of premalignancies The tumour microenvironment (TME) and the key issue of novel treatments based upon TME manipulation The issue of intercellular communications Benign Hematology is not lagging behind

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42 What s new in Iron deficiency Anemia (IDA)? Absolute iron deficiency Reduction of total body iron Low hepcidin iron absorption optimal Responds to oral iron Functional iron deficiency Reduction of iron for erythropoiesis (Chronic disease, e.g. CKD, inflammatory disorders). Usually high hepcidin no oral iron absorption. Responds only to iv iron

43 Mechanisms of adaptation in iron deficiency anemia (Camaschella C, N Engl J Med 2015)

44 Intravenous iron preparations Formulation Approved dose (mg) Maximum safe dose Ferric gluconate 125 (10-60 min) 250 (1 hour) Iron sucrose (2-90 min) 300 (2 hours) Iron dextran (LMW) 100 (2 min) 1000 (1-4 hours) Ferrumoxytol 500 (> 1 min) (15-60 min) Ferric carboxymaltose Iron isomaltoside (Europe only) 1000 (15 min) (15 min) 20mg/Kg (15 min) 20mg/Kg (15 min) (Adapted from Auerbach & Ballach, Am Soc Hematol 2010; Powers & Buchanam, Hematol Oncol Clin North Am, 2014)

45 INEFFECTIVE ERYTHROPOIESIS Adult Hemoglobin Hemichromes & apoptosis α α Heme β β Mutations that reduce ß-globin synthesis α α α Heme ß-thalassemias: Heterogeneous Disorders Variable levels of Hb synthesis Transfusion vs non-transfusion dependent Iron overload Abnormal bone metabolism, thrombosis, etc ß-thalassemia Major and ß-thalassemia Intermedia or Non-Transfusion Dependent Thalassemia (NTDT)

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47 Activin Receptor-II Trap Ligands improve ineffective erythropoiesis by targeting GDF11 ACE-011 or ACE-536 FAS/FASL Decreased Increased apoptosisof of erythroid precursors ROS & GDF11 SMAD 2/3 Decreased Increased erythroid cell differentiation Red cells Iancu-Rubin C et al, Exp Hematol Feb;41(2):

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53 The eyes see what the mind knows (Goethe): look for the Non-Obvious La ciencia sin conciencia es la ruina del alma (F. Rabelais)

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55 Gene/Microenvironment interactions inblood Cancers: Trying to Herd Cats

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58 Novel iron preparations on the market Effective in all sets. Dose control (override absorption) Single infusion of high dose (up to 1 g) in short time (15 min) No important side effects (hypersensitivity reactions minimal with some stable preparation) Long term effects unknown (infections? ROS increase?)

59 FC3 FC4

60 Diapositiva 59 FC3 Federico Caligaris; 27/09/2015 FC4 Federico Caligaris; 27/09/2015

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62 Deactivated T cell When programmed-death receptor (PD-1) on the T cell binds to programmed death-ligand 1 (PD-L1) on the tumourcell, the T cell becomes deactivated, allowing the cancer cell to evade immune attack

63 ActivinRII ligand trap increases terminal erythropoiesis ACE a modified ACTR ectodomain linked to IgG1 Fc domain (Suragani et al, Nat Med Apr;20:408-14)

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65 Fig. 2 Blockade of immune checkpoints to enhance T cell responses. Padmanee Sharma, and James P. Allison Science 2015;348:56-61 Published by AAAS