Update on cell therapy using dendritic cells

Transcription

1 Update on cell therapy using dendritic cells Prof. dr. Evelien Smits UAntwerp, 24 March 2017

2 Hallmarks of cancer (Hanahan and Weinberg, Cell 2000) Hanahan and Weinberg, 2000

3 Extra hallmarks of cancer (Hanahan and Weinberg, Cell 2011) Reprogramming of energy metabolism Evading destruction mediated by the immune system: immune evasion TUMOR IMMUNOLOGY or IMMUNO-ONCOLOGY: studying interactions between tumor cells & immune system 2

4 Concept of immune evasion Finn O. J. Ann Oncol Sep; 23(Suppl 8): viii6 viii9. 3

5 Concept of immune evasion Finn O. J. Ann Oncol Sep; 23(Suppl 8): viii6 viii9. 4

6 Kiss of death

7 Shotton D M, and Attaran A PNAS 1998;95: by National Academy of Sciences 6

8 Antitumor immune response Degli-Esposti and Smyth, Nat Rev Immunol

9 Cancer immunotherapy Using the immune system to control or to eliminate cancer Cancer breakthrough of the year 2013 (editors of Science; Couzin-Frankel, Science 2013) Different ways: 1. Injection of immune effector molecules (e.g. antibodies) 2. Injection of immune effector cells (e.g. activated T cells or natural killer cells) 3. Inducing the immune response in the patient (vaccination) 8

10 Classification of immunotherapy Research ongoing in Antwerp Galluzzi et al, Oncotarget

11 Three signal theory of CD8+ T cell activation 10

12 Center for Cell Therapy and Regenerative Medicine UZA CCRG was founded in 2005 as a multidisciplinary research center for innovative cell therapies Personalized cell therapy using autologous or allogeneic cells Targets: Cancer (DC), Infectious diseases (DC), Autoimmune diseases (DC), Regenerative medicine (Limbal epithelial cells), 3 sterile cell processing units, working according to GMP standards TRANSLATIONAL RESEARCH: from bench to bedside and back

13 Clinical experience 2 decades of worldwide clinical experience with DC vaccines Safety profile: - Common: local reactions at injection site - Extremely uncommon: systemic grade 3-4 toxicity and immune-related adverse events Provenge (DC-based immunotherapy) approved by FDA in

14 Dendritic cell vaccine against cancer Cancer cell Non-active killer cell Active killer cell Cancer cell license to kill vaccine ATTACK Cell death Transfer of cancer marker through gene transfer Dead cancer cell Dendritic cell 13

15 Rationale of WT1-targeted DC vaccine Wilms tumor 1 protein as antigen of choice Overexpressed in AML and in many solid tumors Indispensable for leukemogenesis process Proven immunogenicity in cancer patients

16 Patients and Methods Apheresis WHITE BLOOD CELLS CliniMACS CD14+ cells Intradermal injection WT1 mrna Electroporation MONOCYTES In vitro culture 6 days GM-CSF + IL-4 Maturation cocktail (36-42h): TNF- /PGE2/KLH MATURE DENDRITIC CELLS 15

17 Stap 1: Afname van witte bloedcellen

18 Stap 2: Opzuiveren van monocyten

19 Stap 3: Aanmaak dendritische cellen door kweek van monocyten met rijpingsstoffen

20 Dendritische cellen

21 Stap 4: Dendritische cellen opladen met het kankereiwit

22 Stap 5: Vaccinatie 15 Lymfeklieren oksel Figuur: S. Anguille

23 Acute myeloid leukemia (AML) the facts 5-yr OS: 26.2 % high relapse rate 75% in CR1 relapse <2yr probability CR2 only 25% Relapse prevention is a major therapeutic goal Data from: NCI SEER, cohort

24 Clinical results Conversion of partial remission into complete remission following vaccination with WT1 mrna-electroporated dendritic cells (2/3) Van Tendeloo et al, PNAS

25 Transiently stable disease (SD) in AML patient under DC vaccination (4/30) 24

26 Overall survival 25

27 Immunological effects Positive DTH skin test (induration 2 mm in all patients) Bottom left: KLH/WT1/DC Top left: KLH only Top middle: WT1/DC Bottom middle: NaCl Top right: DC only 26

28 Immunological results Significant increase in WT1-specific IFN and TNF, but not IL-5 producing CD8+ DIL, solely in the long-term survivor group.

29 Solid tumors: Study schedule NCT (ClinicalTrials.gov) Study schedule pre w0 w2 w4 w6 w8 w10 w12 w14 Donor check before apheresis T0 T1 T2 vaccine 1 IM Imaging TM vaccine 2 TM vaccine 3 TM vaccine 4 TM vaccine 5 IM in vitro & in vivo Imaging TM vaccine 6 TM vaccine 7 TM vaccine 8 TM Imaging TM

30 Glioblastoma multiforme 29

31 Metastatic breast cancer Median overall survival: 43.8 months 30

32 Malignant pleural mesothelioma (n=10) Median OS from start of chemotherapy: 35.7 m vs. 22 months (Hillerdal et al, J Thoracic Oncology 2008) 31

33 Anguille et al. Lancet Oncology 2014 Clinical efficacy of DC cancer therapies Clinical benefit in terms of objective clinical responses is real, but limited Where overall survival has been monitored, there is clear evidence that DC immunotherapy can have clinical benefit 32

34 Currently ongoing DC studies at UZA ADDIT-GLIO - Newly diagnosed GBM patients (20 pat) - Combination of standard therapy and DC vaccination MESODEC - Newly diagnosed MPM patients (20 pat) - Combination of standard therapy and DC vaccination WIDEA - Multicentric phase II study to treat AML patients following chemotherapy to prevent or delay relapse 33

35 Center for Cell Therapy and Regenerative Medicine Antwerp University Hospital 34