Download Advances in Cancer Immunotherapy for Solid Tumors

Advances in Cancer
Immunotherapy for
Solid Tumors
Expert Perspectives on The
New Data
Sunday, June 5, 2016
Supported by an independent educational grant from
AstraZeneca
Not an official event of the 2016 ASCO Annual Meeting
Not sponsored or endorsed by ASCO or the Conquer
Cancer Foundation
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data before treating patients or employing any therapies or
strategies described in this educational activity.
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Learning Objectives
1. Evaluate the principles of tumor immunology and the
mechanisms of action of current and emerging cancer
immunotherapies used in solid tumors.
2. Appraise the latest clinical trial data regarding emerging
cancer immunotherapies in SCCHN, NSCLC, mesothelioma,
gastric cancer, melanoma, and other solid tumors,
including use of both monotherapy and combination
regimens.
3. Explore the role of biomarkers in patient selection to
improve targeted use of immune checkpoint inhibitors.
4. Identify practical strategies for using current and emerging
cancer immunotherapies, including prevention, early
detection, and management of immune-related adverse
effects.
Cancer Immunotherapy
in Solid Tumors
Current Concepts
Jeffrey S. Weber, MD, PhD
Deputy Director
Laura and Isaac Perlmutter Cancer Center
Professor of Medicine
NYU Langone Medical Center
New York, New York
Disclosures
• I consult for and have received less than $10000 dollars per
annum from BMS, Merck, Genentech, AstraZeneca, GSK,
Novartis, Nektar Therapeutics, Medivation, Celldex
Therapeutics, cCAM, CytomX, Lion Bioscience, Incyte and
EMD Serono for membership on advisory boards
• I hold equity in Celldex, CytomX and cCAM
• I am not a member of any speakers’ bureau
• My institution, but not me personally, received research
support from BMS, Merck, GSK, Novartis and AstraZeneca
• My laboratory receives research support from Mirati
Therapeutics and Acetylon Pharmaceuticals, Inc.
New Era in Cancer Therapy
Harnessing The Immune System
Reproduced from Immunity, Vol. 39, Daniel S. Chen and Ira Mellman, Oncology Meets Immunology: The Cancer
Immunity Cycle, Page 2, Copyright 2013, with permission from Elsevier via Copyright Clearance Center.
Activation of Antitumor T-Cells
Two Signals Required
Tumor or epithelial cells
No T cell proliferation
1
APC’s (dendritic cells,
macrophages)
T cell proliferation
2
1
Sharma P, et al. Science. 2015.
Cytokines
Antitumor T-Cell Response
How It Happens
3
Perforin
granzyme
Cytokines
(IL-2)
Resting T cell
Tumor
1
T-cell
clonal
Tumor antigen
expansion
Activated T
cell
TCR
MHC
B7
Dendritic cell
2
CD28
Lymph
node
Immune Checkpoints
Inhibitory and Stimulatory Effects
Immune Checkpoints
How Are They Defined?
• Immune checkpoints modulate the duration and
amplitude of the physiologic adaptive immune
response.
• Immune checkpoint signals can be ‘hijacked’ by
cancer cells to allow for tumor growth that is
unchecked by the immune system.
• PD-L1, which binds PD-1, has been found to be
expressed by almost all types of cancers.
• Antibodies that target immune checkpoints can be
used to “disinhibit” T cell responses against cancer.
Immune Checkpoint Blockade
CTLA-4 and PD-1/PD-L1 Inhibitors
Reproduced from N Engl J Med, Antoni Ribas, MD, PhD, Tumor Immunotherapy Directed at
PD-1, Vol. 366, Page 2518. Copyright © 2012 Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society via Copyright Clearance Center.
Tumor Rejection in Mice
Anti-CTLA-4 mAb and GM-CSF Vaccine
Hamster IgG
300
BL6/GM + Hamster IgG
Anti-CTLA4
BL6/GM + Anti-CTLA4
200
100
Day 4 Post-Challenge
Van Elsas A, et al. J Exp Med. 1999.
50
40
30
0
20
(0/5)
10
Mean Tumor Area (mm2)
400
Does Ipilimumab Cure Melanoma?
Proportion Alive
Long-Term OS Data
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Median OS (95% CI): 11.4 mos (10.7–12.1)
3-year OS Rate (95% CI): 22% (20–24%)
Ipilimumab
CENSORED
0
Patients at Risk
Ipilimumab 1861
12
24
36
48
839
370
254
192
60
72
84
96
108
120
170
120
26
15
5
0
Months
Hodi S, et al. ECC. 2013; Schadendorf D, et al. J Clin Oncol. 2015.
Clinical Challenge
When to Hold ‘em, When to Fold ’em?
• Unique patterns of response are seen with
checkpoint inhibitory immunotherapies
− Traditional RECIST response with regression at
week 12
− Slow response with prolonged SD followed by
response
− Progression followed by regression, with or
without the development of new disease
− Mixed response with regression in some disease
and development of new disease followed by
regression of the new disease
Clinical Challenge (cont.)
When to Hold ‘em, When to Fold ’em?
• It is acceptable to continue therapy past
week 12 with checkpoint inhibition if:
− No decrease in performance status
− No worsening of labs by more than one grade
− No symptomatic worsening of disease
− No major increase in disease burden (>50%)
• I suggest getting an interim scan 6 weeks after
continuing
• If there is worsening of any of the above, or
another 25% worsening in disease burden, time
to fold ’em!
• Otherwise, hold ’em and continue to week 24
Immune Checkpoint Blockade
irAEs and Outcomes
• Preclinical melanoma tumor models using CTLA-4
knock-outs have demonstrated enhanced immunemediated tumor rejection AND immune related
depigmentation, but not irAEs as seen in patientsa
• Although still somewhat controversial, irAEs do not
seem to correlate with response;b,c irAEs do seem
to correlate with response with PD-1 and PD1/CTLA-4 combinationsb-e but poorly with CTLA-4
blockade aloneb,c
JS, et al. J Clin Oncol. 2012; bSpain L, et al. Cancer Treat Rev. 2016;
cHorvat TZ, et al. J Clin Oncol. 2015; dDowney SG, et al. Clin Cancer Res. 2007;
eFreeman-Keller M, et al. Clin Cancer Res. 2016.
aWeber
irAEs
General Issues
• Infections and other etiologies should be ruled out
or deemed unlikely as contributing to the irAEs.
• Most irAEs occur during the first 3-4 months.
− Late irAEs, however, also can occur (eg, one episode
has been seen at month 47 during maintenance
phase of therapy).
− Each irAE has different kinetics of onset and some can
wax and wane, particularly colitis.
• Steroids can be used to manage almost all irAEs.
− Prolonged steroid tapers are required
Weber JS, et al. J Clin Oncol. 2012; Weber JS, et al. ASCO. 2015; Weber JS, et al. J Clin Oncol. 2015.
irAEs
Colitis
Focal Active Colitis
Ulceration in Descending Colon
Alterations in Crypt Epithelium
Maker AV, et al. Ann Surg Oncol. 2005.
T-Cell Tumor Immunity
Adaptive Resistance
Chen L, Han X. J Clin Invest. 2015.
PD-1 Pathway
Mechanisms of Immune Suppression
Chen L, Han X. J Clin Invest. 2015.
PD-1 Pathway
Mechanisms of Immune Suppression
B16BL6 Melanoma
Antibody Rx + Cellular Vaccine
MC38 Colon Cancer
Antibody Rx Only
3000
2000
1000
0
0
10
20
30
Days
40
50
anti-PD-1
1/12 Tumor Free
3000
2000
1000
0
0
2000
1000
0
0
10
20
30
Days
40
50
20
30
Days
40
50
9/12 Tumor Free
3000
2000
1000
0
0
10
20 30
Days
40
50
75
50
25
0
B
Untreated
GVAX αCTLA-4
GVAX αCTLA-4/αPD-1
100
0
25
50
Days
75
100
100
Percent survival
0/12 Tumor Free
10
anti-PD-1+ anti-CTLA-4
Tumor Volume (mm³/2)
Tumor Volume (mm³/2)
anti-CTLA-4
3000
A
Percent survival
0/12 Tumor Free
Tumor Volume (mm³/2)
Tumor Volume (mm³/2)
mlgG
125
Untreated
FVAX αCTLA-4
FVAX αPD-1
FVAX αCTLA-4/αPD-1
75
50
25
0
0
25
50
75
Days
100
125
Korman A, et al. J Immunol. 2007; Selby M, et al. ASCO. 2013; Curran, et al. PNAS USA. 2010.
Nivo + Ipi vs Ipi in Advanced Melanoma
OS at 2 Years of Follow-Up
Probability of Overall Survival
All Randomized Patients
1.0
NIVO + IPI
(N=95)
IPI (N=47)
NR
NR
(11.9‒NR)
Median OS,
months (95% CI)
0.9
0.8
64%0.74 (0.43‒1.26)*
HR (95% CI)
*Exploratory endpoint: NR = not reached
73%
0.7
0.6
65%
0.5
54%
0.4
0.3
0.2
0.1
NIVO + IPI
IPI
0.0
0
3
Number of Patients at Risk
NIVO + IPI 95
82
IPI 47
41
6
9
12
77
36
74
33
69
29
15
18
21
24
27
30
67
27
65
26
63
25
57
22
6
3
0
0
Months
30/47 (64%) of patients randomized to IPI crossed over to receive any systemic therapy at progression
Postow M, et al. AACR. 2016.
CTLA-4 Blockade
Durable Responses in Fraction of Patients
Ipilimumab induces durable objective responses in a small fraction of patients
leading to an OS plateau, but no shift of the early portion of the OS curve.
“Hypothetical”
Patients Alive
ICB +
Complementary TX
PD-1/PD-L1 Blockade
CTLA-4 Blockade
1
2
3
Years
Ott PA, et al. Clin Cancer Res. 2013.
4
Boosting Antitumor
Immunity
Targeting Four Nodes
Node 1
Blocking Immune Suppression
PGE2
MDSC
Adenosine
NKG2A KIR
TGF-β
TREG
Immature
dendritic cell
Arginase-1
HIF-1α
VEGF
CCL2
IDO IL-10
Tie2 IL-13
CSF1 IL-23
Smyth MJ, et al. Nat Rev Clin Oncol. 2016.
M2
Paracrine
effect
STAT3 activators
CTLA-4
PD-1
LAG-3
TIM-3
BTLA
VISTA/
PD-1H
TIGIT
CD96
Inhibitory
Node 2
Inducing Immunogenic Cancer-Cell Death
Conventional therapy
TRAIL-R
agonists
• Radiotherapy
• Chemotherapy (eg, anthracycline,
oxaliplatin)
Oncogene inhibitors
HDAC inhibitors
Chemokines to
attract CTL and
TH1
Smyth MJ, et al. Nat Rev Clin Oncol. 2016.
p53 rescue
Vaccines to
generate CTL
and TH1
Proteasome
inhibitors
Node 3
Enhancing APC Function/Adjuvanticity
STING
activator
TLR
agonists
Type I
IFN
GM-CSF
Smyth MJ, et al. Nat Rev Clin Oncol. 2016.
SIRPα
antagonists
CD40
agonists
α-GalCer or
α-C-GalCer
Node 4
Enhancing T/Macrophage Effector Activity
ICOS
CD28
CD137
OX40
GITR
CD27
IL-2
IL-15
IL-21
α-B7-H5
α-B7-H6
α-B7-H4
α-B7-H3
α-CD73
α-CD47
α-CD200
CD30
HVEM
DNAM-1
CD28H
Agonistic
Smyth MJ, et al. Nat Rev Clin Oncol. 2016.
FcγR
CD40
Checkpoint Blockade
Current Concepts and Future Prospects
• Checkpoint blockade is a major advance in cancer
treatment that is supported by extensive murine preclinical data.
• Multiple checkpoints and agonists regulate antitumor
immunity, and their modulation is clinically feasible.
• Unique kinetics of response is associated with
checkpoint inhibitory therapy.
• irAEs typify checkpoint inhibition and may be
associated with benefit.
• Strong scientific rationale for novel combinations raises
the hope for cures in multiple different cancers.
Thank you!
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