DICHIARAZIONE Relatore: Alida Dominietto

DICHIARAZIONE Relatore: Alida Dominietto Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è richiesta la trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario. Posizione di dipendente in aziende con interessi commerciali in campo sanitario NIENTE DA DICHIARARE Consulenza ad aziende con interessi commerciali in campo sanitario NIENTE DA DICHIARARE Fondi per la ricerca da aziende con interessi commerciali in campo sanitario NIENTE DA DICHIARARE Partecipazione ad Advisory Board Azienda Celgene Titolarietà di brevetti in compartecipazione ad aziende con interessi commerciali in campo sanitario NIENTE DA DICHIARARE Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario NIENTE DA DICHIARARE

XII CONGRESSO NAZIONALE SIES 2012 Simposio GITMO CD26, ANTI-CD26 and GVHD Alida Dominietto, Genova IRCCS Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro Largo Rosanna Benzi, 10 16132 GENOVA

Acute GVHD pathophysiology: a three-step model James Ferrara, 1994

Second-Line TX for agvhd and outcome The weighted average 6-month survival estimate across the 25 studies that reported this endpoint was 0.49 P Martin BBMT 2012

Figure 2a GITMO randomized trial CI of TRM non responders (n=61) Responders (n=150) p=0.009 49% 27% days from BMT Figure 2b % of Survval Responders (n=150) non responders (n=61) p=0.007 53% 35% days from BMT Van Lint, BLOOD 2006

No advantage for the use of ATG in steroid refractory acute GvHD in one of the very few prospec:ve randomized trials % of Survval p=0.63 Non ATG (n=33) 36% ATG (n=27) 34% days from BMT 35% is the baseline survival of steroid refractory GvHD (including grade I GvHD non responsers!) Van Lint, BLOOD 2006

Intravenous Monoclonal An:body (BT 5/9) for the Treatment of Acute GraJ- versus- Host Disease Bacigalupo et al., Acta haemat. 73: 185-186 (1985)

Results 5 patients reported alive at the time of publication (1985) Update 25 years later Patient Outcomes Follow-up Clinical Status UPN 77 Alive Days 9810 no GvHD UPN 97 Alive Days 8878 no GvHD UPN 100 Alive Days 7866 no GvHD UPN 999 Alive Days 5430 no GvHD UPN 92 Dead Days 603 Chronic liver GvHD

Antibody binding profile of purified and cell-bound CD26. Designation of BT5/9 and TA5.9 to the CD26 cluster. Immunobiology. 1993 Jun;188(1-2):145-58. University of Antwerp, Belgium

CD26/DPPIV/ADCP2 CD26 (T cell activation antigen) or dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) Ohnuma, 2008

# CD26 is a multifunctional protein expressed on T cells, particularly on CD4+CD45RO+ memory T cells, but also on epithelial cells (liver, kidney, gut) # CD26 has a catalytic activity dipeptidylpeptidase IV (DPP IV), regulates the activity of hormones, neuropeptides, chemokines (RANTES, MDC, SDF-1α and SDF-1β), leading to a co-stimulatory effect # CD26 has a binding activities to adenosine deaminase (ADA) and fibronectin, leading to T-cell activation, proliferation and adhesion to the extracellular mathrix.

Ohnuma, 2008

Fan, 2012

CD26 and HIV the interaction with HIV-1 Tat inhibits the enzymatic activity of CD26 HIV-1 gp120 protein blocks the DPPIV-ADA interaction T-cell activation

CD26 and migration of hematopoietic progenitor cells # SDF-1α or CXCL12 chemoattracts HSCs/HPCs # CD26 binds to CXCL12 and cleaves it into the truncated CXCL12 form # CD26 is expressed on the surface of 75% of Sca-1+c-kit +lin- and Sca-1+c-kit+lin- BM cells

Sca-1+c-kit+lin-BM cells Sca-1+c-kit-lin-BM cells

In mice CD26 inhibitors plus G-CSF reduce the migration of hematopoietic progenitor cells from the bone marrow

Inhibition of CD26 impairs migration of T cells # Inhibition of CD26 preserves pancreatic islet transplants through a pathway involving modulation of splenic CD4(+) T-cell migration in mice. Diabetes 2010; 59(7):1739-50 # Inhibition of CD26 down regulates activated T cells and prevents lung graft rejection in rats. J Heart Lung Transplant 2006; 25(9):1109-16 # Inhibition of CD26 suppresses autoimmune encephalomyelitis (EAE) in mice. J Immunol 2001; 166(3): 2041-8

From the bench to the bedside # The use of DDPIV inhibitors in type II diabetes shows a benefit on glucose metabolism control, but is associated to an increased risk of infection complications # The use of DDPIV inhibitors in autoimmune diseases is controversial, despite the observation that high levels of CD26+ T cells are detected in biological fluids or blood of patients with autoimmune disorders (MS, Graves s disease, RA) # In the allogeneic HSCT setting the intravenous monoclonal antibody anti CD26, named BT5/9, was sussessfully used for the first time in 1985 for the treatment of steroids refractory acute GvHD.

BEGEDINA the murine monoclonal antibody against CD26 for steroid-refractory acute GvHD: the first pilot study EUDRACT code : 2007-005809-21 14 pts treated between December 2010 and February 2012, 12 evaluable All patients received more than 2 lines of treatment for agvhd grade III-IV Dosage 2 mg/day for 5 consecutive days i.v. Primary endpoint is to evaluate the efficacy and safety SIB/ALT 2/10 PB/BM 3/9

Response to Begedina 12 pts agvhd grade III-IV CR=2 ncr/vgpr=8 PR=1 NR=1 Alive 5/12 Relapse=4 Couse of death: relapse = 3 GvHD = 4 median follow up of 433 days (range: 211-575 days) disease free survival Survival 1,000 0,750 0,500 0,250 45% Cumulative Inc of TRM Historic controls 60% TRM 35% 0,000 0,0 200,0 400,0 600,0 800,0 days from transplant

Average % CD26 + cells in vivo, during treatment with BEGEDINA (anti- IgG 2B mouse fluor monoclonal) 30 25 20 15 Serie1 10 5 0 0 2 4 6 8 10 12

BEGEDINA dose finding phase 2 clinical study for patients with steroid resistant acute GvHD after allogeneic HSCT The primary end point of the ongoing study is the interaction of BEGEDINA with at least 80% of circulating CD26+ cells, with the aim of delivering an effective dose to modulated CD26+ cells. EUDRACT code : 2012-001353-19

Begedina dose-finding: inclusion criteria Age > 18 yy and < 65 yy SIB or ALT donor Acute GvHD according to Glucksberg criteria Patients treated with the first line therapy: methylprednisolone 2 mg/kg GVHD resistant to standard therapy with steroides diagnosed in the face of the impossibility of reducing the dose after 5 days

Dose finding study Primary end point > 80% CD26+ cells with anti-mouse in vivo Cohorts of 3 patients /group median % CD26+ 1 st dose 2 mg /m^2 completed 40% 2 nd dose 3 mg /m^2 completed 60% 3 rd dose 4.5 mg/m^2 2 pts 75%

Conclusions CD26 is a multifunctional protein expressed on T cells, but also on epithelial cells (liver, kidney, gut) CD26 is involved in cell migration Anti-CD26 may be relevant in autoimmune disease anticd26 in vivo (Begedina) is safety and efficacy for the treatment of steroid refractory acute GvHD The Phase II study to optimize the dosage of Begedina is ongoing Future comparative studies with other second line treatments of agvhd to confirm the phase I-II results are needed

Genova BMT Unit A Bacigalupo AM Raiola R Varaldo M T Van Lint S Bregante C di Grazia F Gualandi T Lamparelli Data Managers R Oneto B Bruno A Camboni Stem Cell Lab S Pozzi E Tedone S Geroldi NURSING TEAM IBMDR N Sacchi