Los días 15 y 16 de octubre de 2014, la Fundación Ramón Areces y la Real Academia Nacional de Farmacia, en colaboración con la Fundación de la Innovación Bankinter, reunieron en Madrid a algunos de los mayores expertos mundiales en nuevas terapias contra el cáncer. El Simposio Internacional, coordinado por la profesora y académica María José Alonso, analizó el momento actual de la lucha contra esta enfermedad. También fue un punto de encuentro para científicos de los más innovadores institutos de investigación en oncología, quienes debatieron sobre tres grandes temas: la Medicina Personalizada contra el cáncer, los nanomedicamentos en la terapia del cáncer y las terapias basadas en la inmunomodulación.
2. Dendritic Cell Vaccines
CANCER IMMUNOTHERAPY:
= EX VIVO DENDRITIC CELL (DC)
MANIPULATION
Goal: Sufficient numbers of activated DCs to prime
specific T-cell responses at LNs
Current therapy:
- ~4 month extension of life
- $100,000
- Complex technology, regulation
7. GM-CSF Enriches DCs In vivo
GM-CSF promotes DC infiltration
Ali et al., Nature Materials 2009
8. Mimicking Infection?
• Toll like receptors (TLRs): pattern
recognition receptors recognize
molecules broadly shared by
pathogens
• CpG: DNA where cytosine occurs next
to a guanine nucleotide in linear
sequence of bases (Ahmed NP, Eur J Immunol, 2002)
9. TEM Imaging of Par ticles
PEI-condensed CpG
PEI Shell
CpG-ODN
(stained black)
(uranyl acetate stain)
Day 0 Day 3 Day 7
Day 14 Day 20 Day 28
Day 35 Day 42
In vivo CpG-ODN 1/2 life= 13.1 days Bolus Injection:
~63% loss in 27 hours
13. Efficacy: correlation with CD8(+) DCs,
plasmacytoid DCs (pDCs), and local cytokines
R^2 Corr
Mo IL-1a (53) 0.09
Mo IL-2 (19) 0.00
Mo IL-1B (36) 0.02
Mo IL-3 (18) 0.15
Mo IL-4 (39) 0.13
Mo IL-5 (52) 0.16
Mo IL-6 (38) 0.70
Mo IL-9 (33) 0.12
Mo IL-10 (56) 0.08
Mo IL-12(p40) (76) 0.94
Mo IL-12(p70) (78) 0.79
Mo IL-13 (37) 0.15
Mo IL-17 (72) 0.11
Mo Eotaxin (74) 0.62
Mo G-CSF (54) 0.96
Mo GM-CSF (73) 0.17
Mo IFN-g (34) 0.21
Mo KC (57) 0.13
Mo MCP-1 (51) 0.02
Mo MIP-1a (77) 0.01
Mo MIP-1b (75) 0.01
Mo RANTES (55) 0.00
Mo TNF-a (21) 0.11
(VACCINE SITE)
(Ali et al., Cancer Research 2014)
14. CD8 DCs Required for Efficacy
(Batf3–/– mice described in Hildner K, Science, 2008
WT CD8 DC KO
CD3(+)
Trp2 Tetramer
1.47 0.62
(Ali et al., Cancer Research 2014)
15. Therapeutic Vaccination With different TLR agonists
(2X vaccinated)
100
80
60
40
20
0
CpG
P(I:C)
MPLA
Control
0 20 40 60 80 100
Time (days)
8 104
1.4 106
7 104
1.2 106
6 104
1 106
5 104
8 105
4 104
6 105
3 104
4 105
2 104
2 105
0
**
**
1
**
**
*
**
*
*
**
**
Con CpG MPLA P(I:C)
CD8(+) Trp2 Tetramer (+) Splenocytes
(cell #)
1 104
0
CD8CD107a
CD8 IFN-g
Naive Con CpG MPLA P(I:C)
CD8(+) tumor infiltrating leukocytes
6
(Tcell number per 10
tumor cells)
(Ali et al., Cancer Research 2014)
(TUMOR)
18. Wyss Institute and DFCI:
WDVax (therapeutic melanoma vaccine)
IND Filed Jan. 2013 (Hodi and Dranoff)
FDA Approval February 2013
First patient enrolled: August 2013
Cell Activating Scaffold in Melanoma - Full Text View... http://clinicaltrials.gov/ct2/show/NCT01753089?term=wdvax&...
This study is currently recruiting participants.
Verified June 2013 by Dana-Farber Cancer Institute
Sponsor:
Dana-Farber Cancer Institute
Information provided by (Responsible Party):
F. Stephen Hodi, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01753089
First received: December 17, 2012
Last updated: June 12, 2013
Last verified: June 2013
History of Changes
A service of the U.S. National Institutes of Health
Trial record 1 of 1 for: wdvax
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Dendritic Cell Activating Scaffold in Melanoma
19. From Polymers
to Injectable Cryogels
50 μm
(Khoshy et al., Biomaterials 2014)
26. Therapeutic Melanoma Study (B16-F10)
1 Gel Vax
G-VAX
Control
2 Gel Vax
2 Gel Vax
B16-F10 (melanoma)
vaccinate
(unpublished data)
27. Microparticles Spontaneously Create 3D
Mesoporous silica (MPS) microparticles
Self-Assembly Self-Assembly DC Recruiting DC Recruiting
t=1 hr
Subcutaneous injection
Subcutaneous 3D space
t=0 hr
7 nm
Scheme from Tang, AM, 2012
Scaffold In Vivo?
28. MPS microparticles form 3D scaffold in vivo
80-120um particles
with 7nm pores
A
20um
B
*subcutaneous pocket apparent for 30 days
Synthesized with pluronic
copolymer template
10um 10um
32. OVA specific CD4+ T cell clonal expansion
APC Thy1.2
PE-CY7 CD4
CFSE
Count
MPS+Lysozyme MPS+Ovalbumin MPS+GMCSF+CpG+
Ova
naive
Recipient mouse Thy1.1+
Vaccinate
Donor OT-II
Mouse Thy1.2+
CFSE-Labeled
Splenocytes
dLN analysis
proliferation proliferation proliferation proliferation
33. MPS vaccine induces antigen specific blood serum IgG1
and IgG2a antibodies
1.0E+07
1.0E+06
1.0E+05
1.0E+04
1.0E+03
0 100 200 300
Days post vaccination
1.0E+07
1.0E+06
1.0E+05
1.0E+04
1.0E+03
MPS Vax
MPS Ova
Soluble Vax
Soluble Ova
0 100 200 300
Serum IgG1 antibody
Th2 response
Serum IgG2a antibody
Th1 response
Antibody titer
Single vaccination
IgG2a antibody has been implicated in ADCC and has been
shown to be upregulated in patients who respond to tumor
immunotherapy
Kim et al., Nature Biotechnol. In press
34. TH1 and TH2 responses
Serum IgG1 antibody
(TH2 response)
Serum IgG2a antibody
(TH1 response)
- 1 application MSR better than traditional prime-boost
35. Biomaterial Immunotherapeutics
Platform for Cancer Vaccines:
•Demo therapeutic effect
•Molecular/cellular blueprint
•Effective multiple types cancer
Broad Platforms Immune Diseases?
particles
Control timing/spatial interaction
target cells with modulators
- Enrich cells at device