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Immune therapy in NSCLC

Immune therapy in NSCLC. Presentation – 劉惠文 Supervisor – 劉俊煌教授. Introduction. Immunotherapy’s evaluation has expanded into other solid tumors than melanoma (Ipilimumab).

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Immune therapy in NSCLC

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  1. Immune therapy in NSCLC Presentation –劉惠文 Supervisor –劉俊煌教授

  2. Introduction • Immunotherapy’s evaluation has expanded into other solid tumors than melanoma (Ipilimumab). • Most patients present with advanced disease and are immune suppressed as documented by reports of decreases in peripheral and tumor lymphocyte counts seen in this patient population. • Regulatory T cells (Tregs-CD4) play a key role in suppressing tumor immune surveillance, found high level in NSCLC. Brahmer , J Clin Oncol. 31(8):1021-8, 2013

  3. CTLA-4 and PD-1 pathway Brahmer, J Clin Oncol. 31(8):1021-8, 2013

  4. VACCINES • Vaccines for NSCLC: effective in minimal dz (s/p resection, CCRT, C/T) • Tumor cell vaccines: advantage of exposing the host’s immune system to a myriad of tumor antigens • Antigen-based vaccines: expose the host’s immune system to a specific antigen expressed on the tumor cell Brahmer, J Clin Oncol. 31(8):1021-8, 2013

  5. Tumor Cell Vaccines • Belagenpumatucel-L: an allogeneic tumor cell vaccine with four irradiated NSCLC cell lines (H460, H520, SKLU-1, and RH2) modified with transforming growth factor β2 (TGF-β2) antisense plasmid. • Cohort 1: 1.25 ×107 cell/injection • Cohort 2: 2.5 ×107 cell/injection • Cohort 3: 5 ×107 cell/injection • High-dose cohorts had a significantly improved OS (p=0.0069) Nemunaitis J et al, J Clin Oncol.  24:4721-4730, 2006

  6. Antigen-Specific VaccinesMAGE-A3 • The melanoma-associated antigen-A3 (MAGE-A3) expressed melanoma and approximately 35% of NSCLCs • Tumor recurrence rate: 30.6% in vaccine vs 43.3% in placebo • Disease-free interval, OS: NS • Positive gene signature group had a 43% relative risk reduction of cancer recurrence with vaccine treatment vs 25% in unselective group. • Phase III MAGRIT: ongoing Brahmer, J Clin Oncol. 31(8):1021-8, 2013

  7. Others • One dose of cyclophosphamide (300 to 600 mg/m2) was given 3 days before the first vaccine to inhibit Tregs to enhance the immune response. • BLP-25 Phase III: START and INSPIRE trial. Target: MUC-1 Target: MUC-1 Target: EGFR Brahmer, J Clin Oncol. 31(8):1021-8, 2013

  8. CHECK POINT INHIBITORS • CTLA-4 pathway is important in early T-cell activation. • Ipilimumab blocks the interaction between CTLA-4 and its ligands, CD80 and CD86, and showed promise with C/T. Brahmer, J Clin Oncol. 31(8):1021-8, 2013

  9. Phase II Ipilimumab Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  10. Abbreviation: • irPFS: immune-related progression-free survival. • BORR: best overall response rate • ir-BORR: immune-related BORR • DCR: disease control rate • ir-DCR: immune-related DCR • mWHO: radiologic review committee by using modified WHO criteria

  11. Response and Safety • Safety: • Grade 3-4 AEs: control 37%, concurrent 41%, phased 39% • Drug related discontinuation: control 5%, concurrent 10%, phased 6% • Two treatment related death: • Concurrent: 1 septic shock secondary to epideraml necrosis • Control: 1 neutropenic sepsis Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  12. Ipilimumab irPFS: phased vs concurrent • irPFS phased: • HR 0.72, p=0.05 • The immune-related best ORR was nearly doubled for the phased schedule versus chemotherapy alone (32% v 18%) Lynch et al, J Clin Oncol.  30:2046-2054, 2012

  13. Lynch et al, J Clin Oncol.  30:2046-2054, 2012 mWHO-PFS/OS:

  14. Historlogy Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  15. Onging phase III of Ipilimumab Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  16. PD-1 Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  17. Immune Resistance Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  18. Inhibitors for PD-1/PD-L1 Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  19. Phase I PD-1 antibody Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  20. Patient characteristics Heavily pretreated patients Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  21. Efficacy of PD-1 antibody Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  22. Response to anti-PD-1 antibody • Tumor PD-L1 expression may be associated with response. • 36% of patients with tumor PD-L1 expression were objective responders. Brahmer, J Clin Oncol. 31(8):1021-8, 2013

  23. Safety of PD-1 antibody Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  24. Anti-PD-L1: BMS-936559 Total 207 pts, 75 patients with NSCLC Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  25. Clinical activity of BMS-936559 Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  26. Safety Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  27. Conclusion • Immunotherapy may play a role in the future of lung cancer treatment. • Checkpoint inhibitors have promising activity in NCSLC. • Check point inhibitors have a unique set of side effects consistent with immune mechanism of action. • Randomized studies are ongoing. Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

  28. Thank you for listening!

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