immune therapy in nsclc
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Immune therapy in NSCLC
Presentation –劉惠文Supervisor – 劉俊煌教授
IntroductionImmunotherapy’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
CTLA-4 and PD-1 pathway
Brahmer, J Clin Oncol. 31(8):1021-8, 2013
VACCINESVaccines 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
Tumor Cell VaccinesBelagenpumatucel-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
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
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
CHECK POINT INHIBITORSCTLA-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
Phase II Ipilimumab
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Abbreviation:irPFS: immune-related progression-free survival.BORR: best overall response rateir-BORR: immune-related BORRDCR: disease control rateir-DCR: immune-related DCRmWHO: radiologic review committee by using modified WHO criteria
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
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
mWHO-PFS/OS:Lynch et al, J Clin Oncol. 30:2046-2054, 2012
Historlogy
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Onging phase III of Ipilimumab
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
PD-1
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Immune ResistancePresent by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Inhibitors for PD-1/PD-L1
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Phase I PD-1 antibody
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Patient characteristics
Heavily pretreated patients
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Efficacy of PD-1 antibody
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
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
Safety of PD-1 antibody
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Anti-PD-L1: BMS-936559
Total 207 pts, 75 patients with NSCLC
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Clinical activity of BMS-936559
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
Safety
Present by Julie R. Brahmer MD, at 2013 ASCO Annual meeting
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
Thank you for listening!
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