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1. Introduction
2. Checkpoint blockade In cancer immunotherapy
3. Two signals are required for naïve T cells activation
4. Many molecules shape the immune response
5. Functional asymmetry of CD28 and CTLA-4
6. Integration of TCR and costimulatory signals
7. Localization of CD28/CTLA-4 in migrating T cells
8. The movement of CD28 and CTLA-4
9. Do B7-1 or/and B7-2 dimerize?
10. B7-1 may dimerizes,while B7-2 appear monomeric
11. CD28 and CTLA-4 signaling complexes
12. Signaling processes on the T cell - APC junction
13. The role of CD28 and CTLA-4 cytoplasmic tails
14. Effect of agonists' strength on CTLA-4 localization
15. CD28 and CTLA- 4 trafficking
16. Differential regulation of T cell responses
17. CTLA-4 preferentially inhibits the best-fit response
18. Models for biological role of CTLA-4
19. How does CTLA-4 broaden responding repertoire?
20. Biological role of CTLA-4
21. Effect of CTLA-4 blockade
22. Effect of anti-CTLA-4 on transplantable tumor
23. Anti-CTLA-4 and GM-CSF synergise
24. Side effects following rejection of B16 melanoma
25. Effect of anti-CTLA-4/GVax
26. CTLA-4 has a cell-autonomous activity
27. Effect of exposure to anti-CTLA-4 in vivo
28. Effect of exposure to anti-CTLA-4 in vitro
29. Anti-CTLA-4 does not block Treg activity in vitro
30. Anti-CTLA-4/GVax increases Teff/Treg ratio
31. Summary: effective combinations of anti-CTLA-4
32. Chimeric murine CTLA-4 transgene
33. Effect of anti-CTLA-4 on MC38 tumor growth
34. MDX-010 (Ipilumumab)
35. Clinical response to a single dose of Ipilumumab
36. MDX-010-05 study design
37. Trial results: complete responder - patient 11
38. Example: CTLA-4 blockade effects on tumors
39. Reversible immune mediated toxicity
40. MDX010-020: Pivotal Phase III Trial
41. Autologous GVAX followed by MDX-010
42. Trial results: melanoma patient 15
43. Ovarian GVAX and Anti-CTLA-4 Ab - single dose
44. Reduction in tumor nodules following MDX-010 Rx
45. “Lupus-like” rash in ovarian cancer
46. Ovarian GVAX and Anti-CTLA-4 Ab effects
47. Research contributors
48. GVAX immunotherapy and Ipilimumab for HRPC
49. Trial results: PSA curves at dose-level 3
50. Trial results: bone scan improvement in patient 8
51. Checkpoint blockade works
52. Many questions still to be answered
53. Acknowledgements
54. Current lab members

Topics Covered

• Activation of naive T-cells
• CD28 and CTLA-4
• Differential regulation of T-cell responses
• Responding repertoire
• Biological role of CTLA-4
• Tumor-specific immune responses
• Treg activity
• CTLA-4/GVax
• Immunotherapies
• Conventional therapies
• Ipilumumab
• Clinical studies: melanoma
• Reversible immune mediated toxicity

Links

Series:

• Monoclonal Antibodies as Therapeutic Agents

Categories:

• Cancer
• Immunology
• Methods

Therapeutic Areas:

• Immunology & Inflammation
• Oncology

Talk Citation

Publication History

• Published on October 1, 2007

Financial Disclosures

• Prof. James Allison has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.