The Promise of
Immunotherapy for
Cancer Treatment
Julie R. Brahmer, M.D., M.Sc.
Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins
Scott Gettinger 2012
It Takes a Village to Control a T Cell?
Tumor Cell or
Antigen Presenting Cell
T cell
Signal 2
B7.1/2
CD28
Signal 1
HLA
Class II
MHC
B7-H1
(PD-L1)
Others: ICOS, GITR, Tim-3
antigen
CTLA-4
T Cell Receptor
LAG-3
PD-1
Blocking the Immune Checkpoint CTLA4 - Ipilimumab
Signal 2
B7.1/2
(CD80/86)
CD28
CTLA-4
Signal 1
HLA
antigen
T Cell Receptor
T cell
Ipilimumab in Melanoma
Phase III trial:
– 676 patients with chemoresistant metastatic melanoma
– Randomized to ipilimumab +
gp100, or either treatment alone
– Median overall survival of
ipilimumab group 10 months, vs
6.4 months for gp100
Immune-related adverse events in
60% of patients (skin, GI, endocrine,
liver)
FDA decision March, 2011
Hodi et al, NEJM 2010 363:711
Role of PD-1 in Suppressing
Antitumor Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
B7.1
MHC-Ag
Tumor
CD28
TCR Signal 1
APC: Antigen presenting cell
TCR: T-cell receptor
MHC-Ag: Major Histocompatibility Complex-Antigen
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Role of PD-1 in Suppressing Antitumor
Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
B7.1
MHC-Ag
CD28
TCR Signal 1
(-)
(-)
(-)
PD-1
PD-L1
Tumor
Inhibition
Tumor
(anergy, exhaustion, death)
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Role of PD-1 in Suppressing Antitumor
Immunity
Activation
(cytokines, lysis, prolif., migration)
APC
T cell
B7.1
MHC-Ag
CD28
TCR Signal 1
(-)
(-)
(-)
AntiPD-1
PD-1
PD-L1
Tumor
Inhibition
Tumor
(anergy, exhaustion, death)
Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012
Clinical Development of Inhibitors of PD-1
Immune Checkpoint
Target
Antibody
Development
stage
PD-1
NivolumabBMS-936558
Phase III
Pembrolizumab
MK-3475
Approved 9/4/14
for unresectable
or metastatic
melanoma
MedI-4736
Phase III
MPDL-3280A
Phase III
PD-L1
Durable Responses to Anti-PD-1 OFF THERAPY
Pt 22013
0
Pt 14033
CR Stop Rx
1 yr
Stop Best
Rx resp.(PR)
Latest evaluation: CR
2yr
3 yr
? new brain met on MRI
resected: - no viable tumor
4 yr
5 yr
Latest evaluation: CR
Sustained PR
0
1 yr
Pt 13019
2 yr
3 yr
Stop Best
Rx resp.(PR)
4 yr
Restart
New mets a-PD1
5 yr
PD after
2 yr reRx
Sustained PR
0
1 yr
2 yr
3 yr
4 yr
Lipson E et al Clin Cancer Res 2012
Pembrolizumab in Melanoma
Phase Ib trial: 24% response rate in patients
with melanoma. Responses lasting for
months 1.5-8.4 months. 1 yr survival rate of
58%.
6th drug for melanoma approved since 2011
Ribas A, ASCO 2014, FDA 2014
Broad Activity of PD-1 or PD-L1
Inhibitors
Lung Cancer- in Phase 3 trials
Kidney Cancer – in Phase 3 trials
Bladder Cancer
Head and Neck Cancer
Ovarian Cancer
Multiple cancers are being studied
S1400: MASTER LUNG-1:
Squamous Lung Cancer- 2nd Line Therapy
Biomarker
Profiling (NGS/CLIA)
CT*
Biomarker
Non-Match
Multiple Phase II- III Arms with “rolling” Opening & Closure
PiK3CA Mut
PI3Ki
CT*
Endpoint
PFS/OS
CCND1, CCND2,
CCND3, cdk4 ampl
CDK 4/6i
CT*
Endpoint
PFS/OS
FGFR ampl,
Mut, Fusion
FGFRi CT*
Endpoint
PFS/OS
C-MET Expr
HGFi+E
E*
Endpoint
PFS/OS
CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib
PI: V. Papadimitrakopoulou (SWOG)
Steering Committee Chair: R. Herbst (YALE, SWOG)
Lung Committee Chair: D. Gandara
Translational Chair: F. Hirsch
Statistical Chair: M. Redman
S1400 Master Protocol Unique PrivatePublic Partnerships with the NCTN
Alliance
SWOG
S1400
Master
Protocol
NCI-C
ECOGAcrin
NRG
Conclusions
Immunotherapy agents have promising antitumor activity in multiple cancers
Many key questions need to be answered.
– How best should these agents be used (by themselves
or in combination)?
– Who will most likely benefit from these agents
(personalize treatment)?
Phase 3 trials are ongoing in order to make
immunotherapy a reality for the treatment of
cancer.