Dr. David Mooney - Simposio Internacional 'Terapias oncológicas avanzadas'
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The document discusses the development and efficacy of biomaterial-based therapeutic cancer vaccines, particularly dendritic cell vaccines and their potential to enhance cancer immunotherapy. It highlights methods to improve dendritic cell manipulation, bioactive molecules to promote immune responses, and provides data on the correlation of various cytokines with therapeutic outcomes in melanoma treatment. Additionally, it explores innovative delivery systems such as microparticles and cryogels that may bypass traditional genetic modifications while enhancing vaccine efficacy.
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Dr. David Mooney - Simposio Internacional 'Terapias oncológicas avanzadas'
- 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
- 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)