The use of monoclonal antibodies in the setting of HSCT S Montoto, Barts Cancer Institute, London, UK Geneva 3/April/2012 www.ebmt.org
Some definitions of interest: Ab and Ag Antibody (Ab)=Immunoglobulin (Ig): a protein produced by the B-cells of the immune system to identify and neutralize foreign objects Antigen (Ag): a unique part of the foreign target which is recognised by a specific antibody 2
1 antibody for 1 antigen 3
The concept of magic bullet Ehrlich P : On immunity with special reference to cell life Proc. R. Soc. Lond (Biol), 1890 4
Who produces antibodies? The immune system naturally produces antibodies against specific foreign targets (i.e. against a viral protein) to protects us We can artificially produce antibodies in the lab against different self normal cells (i.e. against CDs) or against self malignant cells (i.e. tumour cells) 5
Some definitions of interest: CD Cluster of differentiation (CD): defined subset of surface cell markers present on almost any kind of cell of the body, that identify a specific cell type. They are recognised by antibodies. 6
What are monoclonal antibodies (MoAb)? 7
What do monoclonal antibodies do? Monoclonal antibodies specifically bind to an antigen that is expressed only in certain cells, in order to: Identify these specific cells Selectively kill these cells 8
Cells of interest in HSCT Stem cell: CD34 B-lymphocytes: CD20 T-lymphocytes: CD52 9
Production of MoAb: hybridomas 10
First use of MoAb to treat patients 11
History of the development of MoAb A substance that selectively targets an organism causing disease Genetically modified MoAb to make them more human Mass production of MoAb 12
Rituximab and other anti-cd20 Murine: tositumomab (B1) ibritumomab tiuxetan Chimeric: rituximab Humanised: veltuzumab (2 nd generation) obinutuzumab: GA101 (3 rd generation) Human: ofatumumab (2 nd generation) 13
Types of monoclonal antibodies 14
Types of monoclonal antibodies Naked Immunoconjugates (labeled MoAb) Toxin Radioactive isotope (radiolabeled) 15
Radio-immunotherapy 16
MoAb most frequently used in HSCT Anti-CD52 Anti-CD20 Anti-CD20 Anti-CD33 Anti-CD20 17
How can MoAb be used? Before HSCT Treatment Selection Purging During HSCT GVHD prophylaxis Conditioning After HSCT GVHD treatment Maintenance 18
Before HSCT: salvage therapy Gentuzumab ozogamicin = anti-cd33 Bornhäuser M et al, Clin Cancer Res 2008 19
Before HSCT: salvage treatment rituximab = anti-cd20 Gisselbrecht et al, J Clin Oncol 2010 20
Before HSCT: for selection To collect, pick up the specific cells that we need CD34+ selection: selects stem cells for Purging autologous bone marrow: positive selection T-cell depletion in allogeneic transplants: negative selection 21
Positive/negative selection & purging Stem cell product harvested from patient/donor Stem cells, T- lymphocytes, B- lymphocytes, s malignant cells (if auto). From a donor: we don t want T-cells =T-cell depletion - Positive selection: we select CD34+ cells - Negative selection: we eliminate T-cells From a patient: we don t want malignant cells - Positive selection: we select CD34+ cells - Purging: we eliminate malignant cells 22
Positive selection 23
Before HSCT: for purging To remove the malignant cells that we don t want Purging: eliminates malignant cells In vitro purging In vivo purging 24
In vitro purging: CUP trial Schouten et al, J Clin Oncol 2003 25
In vivo purging: Lym1 RANDOMISATION Group A Group B Group C Group D Rituximab in-vivo purging Rituximab in-vivo purging No purging No purging AUTOLOGOUS STEM CELL TRANSPLANT Rituximab maintenance (375mg/m 2 every 2 months x 4) Observation Rituximab maintenance (375mg/m 2 every 2 months x 4) Observation Pettengell et al, ASCO, 2010 26
During HSCT: conditioning =Zevalin =ibritumomab tiuxetan (anti-cd20) Shimoni et al, Cancer 2012 27
During HSCT: GVHD prophylaxis T-cell depletion: (In vitro: negative selection) In vivo: alemtuzumab/atg 28
During HSCT: GVHD prophylaxis =alemtuzumab (anti-cd52) Norlin et al, European Journal of Haematol 2010 29
After HSCT: treatment of agvhd MoAb against inflammatory molecules (cytokines): Infliximab Etanercept MoAb against T-lymphocytes Alemtuzumab MoAb against B-lymphocytes Rituximab 30
Maintenance after HSCT: Lym1 RANDOMISATION Group A Group B Group C Group D Rituximab in-vivo purging Rituximab in-vivo purging No purging No purging AUTOLOGOUS STEM CELL TRANSPLANT Rituximab maintenance (375mg/m 2 every 2 months x 4) Observation Rituximab maintenance (375mg/m 2 every 2 months x 4) Observation Pettengell et al, ASCO, 2010 31
Conclusions MoAb can be used for many different purposes in the setting of HSCT but the principle is always the same: they identify a specific type of cells..which can then be selected or eliminated depending on the purpose, MoAb can be given before, during or after HSCT. 32
Thank you! Title of the presentation - Author 33