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731ES13PR06651-01

731ES13PR06651-01. Ipilumumab en tumores sólidos. Luis Paz-Ares Hospital General Universitario Virgen del Rocío. Sevilla. T cell activation by TCR and co-stimulation through CD28. MHC. Antigen. TCR. Dendritic cell. T cell. CD28. B7. CTLA4.

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731ES13PR06651-01

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  1. 731ES13PR06651-01

  2. Ipilumumab en tumores sólidos Luis Paz-Ares Hospital General Universitario Virgen del Rocío. Sevilla

  3. T cell activation by TCR and co-stimulation through CD28 MHC Antigen TCR Dendritic cell T cell CD28 B7 CTLA4

  4. CTLA4 receptors are up-regulatedfollowing T-cell activation MHC Antigen TCR Dendritic cell T cell CD28 B7 CTLA4

  5. CTLA4 negatively modulates T-cell activation MHC Antigen TCR Dendritic cell T cell CD28 B7 CTLA4

  6. Blocking antibodies to CTLA4 allow positive signaling from costimulatory molecules to T-cells MHC Antigen TCR Dendritic cell T cell CD28 B7 CTLA4 Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science.1996; 271: 1734-36.

  7. CTLA-4: Down-regulates T-cell activation. Ipilimumab (Yervoy): Fully human monoclonal antibody. Blocks CTLA-4 receptor. Potentiates T-cell activation. Ipilimumab (Yervoy) in treatment of cancer Korman, Peggs and Allison. Adv. Immunol. 2006; 90:297-339.

  8. Ipilimumab: mechanism of action T-cell activation T-cell inhibition T-cell potentiation CTLA4 T cell T cell T cell CD28 CD28 CTLA4 CTLA4 TCR TCR TCR IPILIMUMAB blocks CTLA-4 B7 B7 B7 MHC MHC MHC APC APC APC

  9. MDX010-20: study design (N=403) Pre-treated Metastatic Melanoma (N=676) (N=137) R A N D O M I Z E (N=136)

  10. Accrual: September 2004 – July 2008. 125 Centers in 13 Countries. Randomized (3:1:1), Double-Blind. Stratified for M-Stage and prior IL-2. Induction: Ipilimumab: 3 mg/kg q 3 weeks X 4 doses. gp100: 1mg q 3 weeks X 4 doses. Re-induction (same regimen) in eligible patients. MDX010-20: study design details

  11. Ipilimumab improves progression free survival compared to control Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) Comparison Hazard Ratio (C.I.) p-value  Arms A vs C 0.81 (0.66–1.00) 0.0464 Arms B vs C 0.64 (0.50–0.83) 0.0007 Arms A vs B 1.25 (1.01–1.53) 0.0371 1 2 3 4 Years = 1st tumor assessment as per protocol F. Stephen Hodi. Et al.The New England Journal of Medicine.. 2010; 10.1056/NEJMoa1003466.

  12. Ipilimumab improves overall survival compared to control F. Stephen Hodi. Et al.The New England Journal of Medicine.. 2010; 10.1056/NEJMoa1003466.

  13. Ipilimumab improves overall survival compared to control Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) 1 2 3 4 Years F. Stephen Hodi. Et al.The New England Journal of Medicine.. 2010; 10.1056/NEJMoa1003466.

  14. What mediates anti-CTLA4-induced durable tumor regressions? Blue: melanoma Durable response > 5 years Brown: CD8+ T cells 2005 Treatment with anti-CTLA4 antibodies The great majority of responses last years without relapses: • Longest responder: Ongoing since May 2001. • Response rate: ~10%.

  15. Ipilimumab: improved survival in all subgroups F. Stephen Hodi. Et al.The New England Journal of Medicine.. 2010; 10.1056/NEJMoa1003466.

  16. Ipilimumab is associated with increased serious adverse effects F. Stephen Hodi. Et al.The New England Journal of Medicine.. 2010; 10.1056/NEJMoa1003466.

  17. Most common immune-related adverse events* (grades 3, 4 and 5) *Across entire study duration F. Stephen Hodi. Et al.The New England Journal of Medicine.. 2010; 10.1056/NEJMoa1003466.

  18. Summary • MELANOMA. • First randomized phase III study to show survival benefit. • EMA approved for second-line therapy • Suggests a long-term survival effect: • 2 year survival rate: 24%. • Some patients alive 10 years disease-free so far. • Immune mediated adverse effects require prompt medical attention and early administration of corticosteroids.

  19. Ipilimumab represents a new class of T-cell potentiators and an important advance for the field of immuno-oncology. Further development of ipilimumab is ongoing. Diversification to a variety of cancer types and settings. Alternative combination regimens. Refinements in dose and schedule. Next generation of anti-CTLA4 antibody? Summary

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