Immune therapy in NSCLC

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


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


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


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.


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


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


Onging phase III of Ipilimumab


PD-1


Immune ResistancePresent by Julie R. Brahmer MD, at 2013 ASCO Annual meeting

Inhibitors for PD-1/PD-L1


Phase I PD-1 antibody


Patient characteristics

Heavily pretreated patients


Efficacy of PD-1 antibody


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.


Safety of PD-1 antibody


Anti-PD-L1: BMS-936559

Total 207 pts, 75 patients with NSCLC


Clinical activity of BMS-936559


Safety


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.


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Immune therapy in NSCLC

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