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.

1. A
Biomaterial Based,
Therapeutic Cancer Vaccines

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

3. Cell Therapies

4. Can We Bypass Ex Vivo Cell Manipulation?

5. Implantable Polymer Vaccine
1 of 1 Huebsch and Mooney, Nature, 2009

6. VACCINE SYSTEM
Bioactive molecule
Shea et al., Nature Biotechnol. 1999
(tradename Leukine)

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

10. PEI-CpG: DC Activation and LN Homing

11. Patient-specific Antigen (Biopsy)
freeze
dried
powder
Patient biopsy

12. Therapeutic Effect
B16-F10 (melanoma)
vaccinate
(Ali et al., Science Translational Medicine, 2009)

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)

16. Broadly Useful in Cancer?
Glioblastoma
Memory

17. Combination with Blockade Antibodies
(single vaccination)
100
80
60
40
20
0
Vax+CTLA4
Control Vax
0 20 40 60 80 100
Survival (%)
Time (days)
Vax+ PD1
3 105
2.5 105
2 105
1.5 105
1 105
5 104
0
CD8CD107a
CD8 IFN-g
Control Vax +PD-1 +CTLA4
Activated CD8+ Tumor infiltrating leukocytes
(cell number 106 tumor cells)
**
* *
**
**
**
(submitted)

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
Previous Study | Return to List | Next Study
Dendritic Cell Activating Scaffold in Melanoma

19. From Polymers
to Injectable Cryogels
50 μm
(Khoshy et al., Biomaterials 2014)

20. Shape memory for minimally invasive
delivery

21. GVAX: GM-CSF Transfected Cancer Cells
(The Scientist March 15, 2004)
Can we bypass need for genetic modification
in GVAX, and increase efficacy?

22. Cancer Cell-loaded Cryogel Vaccines
Conclusion
6hr incubation (before vaccination)
50 μm 100 μm
Irradiated cancer cells on RGD-Alginate
Cryogel Vaccine
24hr incubation
Irradiated cancer cells on RGD-Alginate
Cryogel Vaccine

23. 50 μm
Cryogels Carry, Localize Cells
(Bioluminescent cells)
Scaffold
Imaging
(day 2)
(Bencherif et al., PNAS 2012)

24. Controlled Release of Immunodulators
GM-CSF
MA-Alginate
CPG-ODN
CRYOGELATION
4 mm
RGD
GM-CSF
CpG-ODN
GM-CSF
CpG-ODN

25. GM-CSF Enhance Cellular Infiltration
Harvard University
NO GM-CSF
10 μm
10 μm
GM-CSF

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

29. Nanopores and Macropores Both Play Key Role
Filling of nanopores
Elimination of Macropores

30. Recruited DCs uptake antigen, deployed to dLN
1 hour 1 Day 10 Days
A
OVA*
OVA*
+MPS
MPS MPS+OVA+GM+CpG
CD11c
B
SIINFEKL-MHCI
0.567% 3.88%
3.54% 7.33%

31. B cell expansion/Germinal Center formation in dLN
A Self-Assembly DC Recruiting
B
C

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

36. Collaborators
Glenn Dranoff (DFCI)
Edward Doherty (Wyss)