ematology and Medical Oncology “L. e A. Seràgnoli” Bologna I ta matologia “CAR and Beyond CAR” New insights in Chimeric Antigen Receptor 2 settembre BiTE in Hematological Malignancies Aula Magna Ematologia “M. T. Chian Policlinico S. Orsola – Ma Pad. 8 – Ematologia e Oncologia M Ore 9.30 – Cristina Papayannidis, MD, PhD Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Bologna, 2 Settembre 2014 PROGRAM 0 9 .3 0 – 0 9 .5 0G .M a r tin e lli– F .B o n ifa z i Introduction and Workshop purpose Agenda  Background  Blinatumomab • Mode of action • Clinical Trials  AMG 330  Take home messages The BiTE antibody principle Baeuerle P A and Reinhardt C Cancer Res 2009 Hallmarks of BiTE Antibodies • Highly potent redirected lysis of target cells by polyclonal T cells • Rapid and strictly target cell-dependent activation of resting T cells • Proliferation of BiTE-activated T cells • Serial killing by BiTE-activated T cells Baeuerle PA et al, Cancer Res 2009; Nagorsen D et al, Exp Cell Res 2011; Portell CA et al, Clin Pharmacol 2013 CD19 and Blinatumomab  CD19 is a highly specific B-cell marker that is expressed throughout B-cell development and in >90% of B-cell lineage cancers  Blinatumomab, a 55kDa investigational bispecific T-cell engager Antibody, is designed to redirect CD3+ cytotoxic T cells to CD19+ malignant B cells Nagorsen D et al, Pharmacology & Therapeutics 2012 Key Milestones Nagorsen D et al, Pharmacology & Therapeutics 2012 Mode of action Nagorsen D et al, Pharmacology & Therapeutics 2012 Pharmacokinetics • Short serum half-life of 1-3 h Allows for control of adverse events • Css is reached within 24 h after infusion start • Continuous i.v. administration leads to constant Css throughout the maintenance phase Klinger M et al. Blood 2012 Complete and sustained B-Cell Depletion Klinger M et al. Blood 2012 T-Cell Kinetics Klinger M et al. Blood 2012 Effect of Blinatumomab on Cytokine Release Klinger M et al. Blood 2012 Take Home messages (I)  Rapid, complete and sustained B-cell depletion  Swift T-cell redistribution and activation, followed by a potential T-cell expansion due to proliferation of memory T cells  Transient dose-dependent cytokine release predominantly in treatment cycle 1 which can be mitigated by dose-step approach and Dexamethasone premedication Clinical Experience Patients Response Response Rate 80% Adverse Events Disease Free Survival Follow up Median Follow-up: 33 months Hematologic RFS estimate of 61% Blood 2012 ASH 2012 (Topp M. et al, abstract # 670) • • • • 36 patients, relapsed/refractory 26 (72%) CR or CRi 24 Molecular response Responses more frequent in patients in first relapse compared with those in more advanced stages of relapse • Median survival of all 36 patients: 9.0 months • 13 patients proceeded to Allo SCT Ongoing Trials • TOWER 00103311 A Phase III, Randomized, Open Label Study investigating the Efficacy of the BiTE Antibody Blinatumomab vs Standard of Care Chemotherapy in Adult Subjects with Relapsed/Refractory Bprecursor ALL • ALCANTARA 20120216 A Phase II, Single Arm, Multicenter Trial, to evaluate the Efficacy of the BiTE Antibody Blinatumomab in Adult Subjects with Relapsed/Refractory Philadelphia positive B-precursor ALL AMG 330: CD3/CD33 BiTE Laszlo G. Blood Rev 2014 Preclinical Data • Like the CD19/CD3-bispecific BiTE antibody, the CD33/CD3-bispecific AMG 330 showed a dose-dependent activation of T cells as was evident by upregulation of CD69 and CD25 at low picomolar concentrations, which was dependent on the presence of target cells. • T-cell activation by AMG 330 also involved transient release of inflammatory cytokines with individual kinetics. • With some AML lines, like SKM-1, the potency of AMG 330 was low at the beginning but dramatically increased during the first day of coculture, suggesting that T cells may require some time to ramp up their level of granzymes and perforin or that there is a time-dependent increase in the ability of T cells to form cytolytic synapses. Laszlo G. Blood 2013 Take Home Messages and Open Questions • Innovative and promising therapeutic tool • Good tolerability and safety profile • Mechanisms of resistance? • Best timing in the therapeutic path? Acknowledgments Clinical Team Maria Chiara Abbenante Chiara Sartor Stefania Paolini Francesca Volpato Prof Giovanni Martinelli Data Manages/Project Managers Silvia Piccari Federica Frabetti Elisa Lani Gabriele Galli Paolo Mariotti Cytogenetics Nicoletta Testoni Carmen Baldazzi Simona Luatti Giulia Marzocchi Prof Michele Cavo Molecular Biology Team Ilaria Iacobucci Simona Soverini Emanuela Ottaviani Anna Ferrari Viviana Guadagnuolo Claudia Venturi Margherita Perricone Valentina Robustelli Eugenia Franchini Elisa Zuffa Giorgia Simonetti Caterina de Benedittis Teresa Bocchicchio Antonella Padella