The use of monoclonal antibodies in the setting of HSCT

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1 The use of monoclonal antibodies in the setting of HSCT S Montoto, Barts Cancer Institute, London, UK Geneva 3/April/2012

2 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

3 1 antibody for 1 antigen 3

4 The concept of magic bullet Ehrlich P : On immunity with special reference to cell life Proc. R. Soc. Lond (Biol),

5 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

6 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

7 What are monoclonal antibodies (MoAb)? 7

8 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

9 Cells of interest in HSCT Stem cell: CD34 B-lymphocytes: CD20 T-lymphocytes: CD52 9

10 Production of MoAb: hybridomas 10

11 First use of MoAb to treat patients 11

12 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

13 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

14 Types of monoclonal antibodies 14

15 Types of monoclonal antibodies Naked Immunoconjugates (labeled MoAb) Toxin Radioactive isotope (radiolabeled) 15

16 Radio-immunotherapy 16

17 MoAb most frequently used in HSCT Anti-CD52 Anti-CD20 Anti-CD20 Anti-CD33 Anti-CD20 17

18 How can MoAb be used? Before HSCT Treatment Selection Purging During HSCT GVHD prophylaxis Conditioning After HSCT GVHD treatment Maintenance 18

19 Before HSCT: salvage therapy Gentuzumab ozogamicin = anti-cd33 Bornhäuser M et al, Clin Cancer Res

20 Before HSCT: salvage treatment rituximab = anti-cd20 Gisselbrecht et al, J Clin Oncol

21 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

22 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

23 Positive selection 23

24 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

25 In vitro purging: CUP trial Schouten et al, J Clin Oncol

26 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,

27 During HSCT: conditioning =Zevalin =ibritumomab tiuxetan (anti-cd20) Shimoni et al, Cancer

28 During HSCT: GVHD prophylaxis T-cell depletion: (In vitro: negative selection) In vivo: alemtuzumab/atg 28

29 During HSCT: GVHD prophylaxis =alemtuzumab (anti-cd52) Norlin et al, European Journal of Haematol

30 After HSCT: treatment of agvhd MoAb against inflammatory molecules (cytokines): Infliximab Etanercept MoAb against T-lymphocytes Alemtuzumab MoAb against B-lymphocytes Rituximab 30

31 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,

32 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

33 Thank you! Title of the presentation - Author 33

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