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)


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




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
Thank you for listening!