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
Breaking News in Oncologia Medica e Malattie del Sangue 2014-2015 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
D Hanahan, RA. Weinberg, Cell 2011
Breaking News in Oncologia Medica e Malattie del Sangue 2014-2015 An embarassing paper with an important message that the media have misinterpreted
Breaking News in Oncologia Medica e Malattie del Sangue 2014-2015 A paper with an important message that the media have misinterpreted The issue of premalignancies
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
Breaking News in Oncologia Medica e Malattie del Sangue 2014-2015 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 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 571-573,
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
Johanna A. Joyce & Jeffrey W. Pollard Nature Reviews Cancer 9, 239-252(April 2009)
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
Inflammation Cytokines Chemokines
Fig. 1 Activation of T cells requires two signals. Padmanee Sharma, and James P. Allison Science 2015;348:56-61 Published by AAAS
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
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
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
CAR structure, according to signaling domains. Shannon L. Maude et al. Blood 2015;125:4017-4023 2015 by American Society of Hematology
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;125:4017-4023 2015 by American Society of Hematology
Event-free survival in 30 children and adults treated with CTL019 therapy. Shannon L. Maude et al. Blood 2015;125:4017-4023 2015 by American Society of Hematology
Breaking News in Oncologia Medica e Malattie del Sangue 2014-2015 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
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 2015 2015 by American Society of Hematology
Breaking News in Oncologia Medica e Malattie del Sangue 2014-2015 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
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
Mechanisms of adaptation in iron deficiency anemia (Camaschella C, N Engl J Med 2015)
Intravenous iron preparations Formulation Approved dose (mg) Maximum safe dose Ferric gluconate 125 (10-60 min) 250 (1 hour) Iron sucrose 100-400 (2-90 min) 300 (2 hours) Iron dextran (LMW) 100 (2 min) 1000 (1-4 hours) Ferrumoxytol 500 (> 1 min) 500-1000 (15-60 min) Ferric carboxymaltose Iron isomaltoside (Europe only) 1000 (15 min) 750-1000 (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)
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)
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. 2013 Feb;41(2):155-166
The eyes see what the mind knows (Goethe): look for the Non-Obvious La ciencia sin conciencia es la ruina del alma (F. Rabelais)
Gene/Microenvironment interactions inblood Cancers: Trying to Herd Cats
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?)
FC3 FC4
Diapositiva 59 FC3 Federico Caligaris; 27/09/2015 FC4 Federico Caligaris; 27/09/2015
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
ActivinRII ligand trap increases terminal erythropoiesis ACE-536 - a modified ACTR ectodomain linked to IgG1 Fc domain (Suragani et al, Nat Med. 2014 Apr;20:408-14)
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