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