Tumor cell vaccines

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). 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

VACCINES Vaccines for NSCLC: effective in minimal dz (s/p resection, CCRT, C/T) 

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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 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 7  Cohort 3: 5 ×10 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 Vaccines MAGE-A3 The melanoma-associated antigen-A3 (MAGEA3) expressed melanoma and approximately 35% of NSCLCs 

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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

Target: MUC-1 Target: MUC-1 Target: EGFR

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.

Brahmer, J Clin Oncol. 31(8):1021-8, 2013

CHECK POINT INHIBITORS CTLA-4 pathway is important in early Tcell 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 rate ir-BORR: immune-related BORR DCR: disease control rate ir-DCR: immune-related DCR mWHO: 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

Lynch et al, J Clin Oncol. 30:2046-2054, 2012

mWHO-PFS/OS:

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 Resistance

Present 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

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