The Geoffrey P. Herzig Memorial Symposium for Hematological
Malignancies & Bone Marrow Transplantation
Targeting Immune Checkpoint Proteins and
Cells for the Treatment of Cancer
Jason Chesney, Deputy Director
Disclosure of Relevant Financial Relationships
(none impact my ability to present an unbiased talk)
Funding to the UofL for clinical trial testing of ipilimumab (BMS),
nivolumab (BMS), pembrolizumab (Merck), TVEC (Amgen) and PFK-158
(ACT) in cancer patients
Co-inventor of seven issued U.S. Patents on PFKFB3, PFK-158 and MIF
inhibitors for the treatment of cancer (intellectual property owned by
the UofL and Picower Institute)
Regular service on scientific and clinical advisory boards for Novartis,
BMS and Amgen
No participation in pharmaceutical company’s speakers bureaus
How T Cells Kill Cancer Cells
Cytotoxic T cell
Released
cytotoxic
T cell
Perforin
Cancer
cell
Granzymes
1 TCR
Class I MHC
molecule
Target
cell
3
CD8
2
Peptide
antigen
Apoptotic
target cell
Pore
Cytotoxic
T cell
T Cells Have 2 “Brakes” Called Immune Checkpoints:
PD1, CTLA4
These brakes serve to block the activation of T cells
The “feet” that push these brakes are PD-L1 and B7.1/2
Feet:
Brakes:
PD-L1 & B7.1/2
PD1 & CTLA4
Antibodies That Block the Two Brakes Include: aCTLA4
(Ipilimumab) and aPD1 (Nivolumab/Pembrolizumb)
By blocking the brakes, T cells go into overdrive
(Pembrolizumab)
Phase I Trial of an Anti-PD1 In Patients With
Refractory and Terminal Melanoma
Should we Block BOTH Brakes at the Same Time?
Should we Block BOTH Brakes at the Same Time?
Golladay Swartz
Baum
UofL: #2 Accruing Site
WARNING: Autoimmunities From Immune
Checkpoint Inhibitors Can Be Fatal (1-2%)
Majority of autoimmune side effects
resolve with steroids
Immune Checkpoint Inhibitors Should Have
Efficacy Against Multiple Cancer Types
Phase 1 Trial of Nivolumab With Ipilimumab for NSCLC
(Sq+NSq; 4 Arms; 148 patients)
An Open-Label Single Arm Phase 2 Trial of Nivolumab with
Ipilimumab as First-Line Therapy in Stage IV NSCLC
Rios
Perez
Schoenbachler Roberts
Kloecker
Clark
Immune Checkpoint Inhibitors Should Have
Efficacy Against Multiple Cancer Types
*
* *
*
*
Immune Checkpoint Inhibitors and Hematological
Malignancies
PubMed Search:
“immune checkpoint inhibitors” and
“melanoma”, 251 hits
“leukemia”, 21 hits
“lymphoma”, 45 hits
“myeloma”, 10 hits
PD-L1 (B7-H1) Expression Correlates With Poor Survival in
AML
Chen et al. Clinical Significance of B7-H1 (PD-L1) Expression in Human Acute Leukemia.
Cancer Biology & Therapy, 7:5, 622-627, 2008.
Anti-PD-L1 Suppresses AML in Mice
Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune
responses in a murine acute myeloid leukemia model. Blood. 2009 Aug 20;114(8):1545-52
On-Going Clinical Trials of Anti-PD1 in Hem Malignancies
Sehgal, Whiteside and Boyidadzis. PD-1 Checkpoint Blockade in AML. Blood. Expert Opin
Biol Ther, 15(8), 1191-1203, 2015.
First Anti-PD1 Trial for Hematological Malignancies
Response Characteristics and Changes in Tumor Burden in
Patients with Hodgkin's Lymphoma Receiving Nivolumab.
Ansell SM et al. N Engl J Med 2015;372:311-319.
A Study of Pembrolizumab (MK-3475) in Combination With
Lenalidomide and Dexamethasone in Multiple Myeloma
“In the study with 50 heavily pre-treated patients, initial findings from 17
patients who were treated with KEYTRUDA (pembrolizumab) in combination
with lenalidomide and low-dose dexamethasone demonstrated an ORR of 76
percent (n=13/17) (per IMWG 2006), including four very good partial
responses (24%) and nine partial responses (53%).”
57th American Society of Hematology Annual Meeting, 2015
Real Utility of Immune Checkpoint Inhibitors May
Come From Combination Trials With CAR T Cells
Th17 Cells, Tregs and MDSCs Suppress T Cells Just
Like Immune Checkpoint Proteins
Th17
Treg
OFF
4
DC
MHC/II
MHC/I
TCR
TCR
8
PDL1
PD1
MHC/I
Cancer
OFF
PD1
PDL1
MDSCs
Th17 Cells, Tregs and MDSCs Suppress T Cells
Th17
Treg
4
TCR
8
MHC/I
Cancer
MDSCs
Th17 and MDSCs Require High
Glycolysis Via Hypoxia
Inducible Factor-1a (HIF-1a)
and 6-Phosphofructo-2-Kinase
Th17
Treg
4
TCR
8
MHC/I
Cancer
HIF-1a
PFKFB3
Glycolysis
MDSCs
Th17 Cell Differentiation and MDSC ImmunoSuppression (& PFKFB3) Require HIF-1a
Th17 Differentiation
Lewis Z. Shi et al. J Exp
Med 2011;208:1367-1376
MDSC T Cell Suppression
Cesar A. Corzo et al. J Exp
Med 2010;207:2439-2453
PFKFB3 Expression
Obach et al. JBC. 279,. 51,
53562–53570, 2004
PFK-158 Is A Potent and Specific Small
Molecule Inhibitor of PFKFB3
PFK-158 = (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one
Inhibition, IC50 (mM)
rec PFKFB3
Glucose
Uptake
F2,6BP
Cell
proliferation
0.14+0.01
0.85+0.19
1.3+0.9
0.33+0.01
SPECIFICITY
Does not inhibit enzymes involved in glycolysis including phosphoglucose
isomerase (PGI), hexokinase (HK), or 6-phosphofructo-1-kinase (PFK-1)
No cross-reactivity in a panel of 96 kinases (KinomeScan)
PFK-158 Is A Potent and Specific Small
Molecule Inhibitor of PFKFB3
PFK-158 = (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one
PFK158
Will Selective Inhibition of PFKFB3
With PFK-158 Attenuate the
Immunosuppressive Functions of
Th17 Cells and MDSCs?
Th17
Treg
4
TCR
8
MHC/I
Cancer
MDSCs
Will Selective Inhibition of PFKFB3
With PFK-158 Attenuate the
Immunosuppressive Functions of
Th17 Cells and MDSCs?
PFK158
Th17
Treg
4
TCR
8
MHC/I
Cancer
MDSCs
PFK158
And Facilitate Activation of
Cancer Immunity?
Th17
Treg
MDSCs
OFF
4
DC
MHC/II
MHC/I
TCR
TCR
8
PDL1
PD1
MHC/I
Cancer
OFF
PD1
PDL1
Antigen
Release
Th17 Cells and MDSCs Require PFKFB3
Differentiation
of Th17 Cells:
T Cells
MDSC Function:
+PFK-158
5 mM
2.5 mM
+MDSCs
+MDSCs
+MDSCs
+aCD3/CD28 +aCD3/CD28 +aCD3/CD28 +aCD3/CD28
PFK-158 Depletes B16 Tumor Th17 Cells & MDSCs
+PFK-158
IL-17
Th17
IL-17
Vehicle
CD4
IL-17
IL-17
CD4
gdT17
71%
GR1
GR1
CD11b
IFN-g
IFN-g
CD11b
CD8+/IFNg+
62%
gdT
gdT
MDSC
60%
CD8
78%
CD8
PFK158
Combine PFK-158 With Anti-CTLA4?
Th17
Anti-CTLA4
Treg
MDSCs
OFF
4
DC
MHC/II
MHC/I
TCR
TCR
8
PDL1
PD1
MHC/I
Cancer
OFF
PD1
PDL1
Antigen
Release
PFK-158 Increases the Anti-Tumor Activity of
Anti-CTLA4 Against B16 Melanoma
Phase 1 Safety Study of PFK-158 in Patients
With Advanced Solid Malignancies
James Graham Brown Cancer Center, University of Louisville
Lombardi Comprehensive Cancer Center, Georgetown University
MD Anderson Cancer Center
UT Health Science Center at San Antonio
•
Solid tumor patients who have failed at least one previous regimen
•
24 mg/M2 - 650 mg/M2 delivered IV QOD x 3 weeks followed by 1 week
rest repeated every 4 weeks until disease progression or high toxicity
•
27 patients enrolled > 18 patients completed 2 cycles thus far and were
evaluated by diagnostic imaging after 2 months of treatment
• No drug-related SAEs
• 6/18 patients experienced clinical benefit
% Baseline
PFK-158 Depletes Th17 Cells & MDSCs in Patients
0
Th17
gd-17
Treg
MDSC
-50
-100
1
% Baseline
15
22
PFK158 Dosing
400
CD4+/
CD69+
300
200
100
0
1
8
15
22
PFK158 Dosing
700
% Baseline
8
CD8+
CD69+
600
300
200
100
0
1
8
15
PFK158 Dosing
22
CD8+
IFNγ+
CD8+CD27CD28-CD57+
CD8+
CD137+
PFK-158 Markedly Increases Memory Effector CD8+
T Cells
Patient 01-10 (Breast Ca)
Healthy Donor
Post-PFK-158 C1D22
IFN-g
IFN-g
Pre-Dose C1D1
CD8
CD8
CD8
+PFK-158 x 3 Weeks
PFK-158 Depletes Th17 Cells & Activates CD8+ T Cells
PFK-158 Reduces PD-1 Expression in CD8+ T Cells
PD1+
37.7%
6.5%
6.7%
5.9%
PFK-158: Clinical Benefits
Of the 18 evaluable patients, 6 experienced clinical benefit:
Patient
Disease
Status
01-05
Ocular melanoma
SD until Cycle 6
02-01
Ser ovarian adenocarcinoma
SD through Cycle 6
01-10
Breast adenocarcinoma
SD until Cycle 4
03-03
Adenoid cystic carcinoma
SD, in Cycle 11
01-13
Renal cell carcinoma
SD, in Cycle 8
04-02
Pancreatic adenocarcinoma
Until Cycle 2
Ocular Melanoma Patient 01-05
CT scans (screening, end of Cycles 2, 4 and 6 ) showing an
example of a liver met that became necrotic and regressed
Total Tumor Mass (gm)
Ruth,
Ruth, A
A nthony
nthony K
K
1000
PP age:
age: 1
18
8 of
of 1
10
03
3
IIM
M :2
:20
0 SE
SE :6
:6
1
0.1
lizu
m
br o
10
IIM
M :: 1
19
9 SE
SE :: 7
7
Pe
m
100
IIM
M :: 1
18
8 SE
SE :: 7
7
ab
PP age:
age: 1
19
9 of
of 1
10
06
6
Ob
se
rva
ti
Ipi on
lim
um
ab
PP age:
age: 2
20
0 of
of 1
11
10
0
PFK-158
0 2 4 6 8 10 12 14 16 18 20
Months
PP age:
age: 1
15
5 of
of 1
10
02
2
IIM
M :: 1
15
5 SE
SE :: 7
7
Ovarian Cancer Patient 02-01:
CT scans confirmed peri-gastric tumor regression
Longest diameter: 42 mm at screening, down to 39 and 26 mm at Cycles
2 and 4 respectively (38% decrease at Cycle 4)
Product of perpendicular diameters: 1596 mm2 at screening down 1044
and 546 mm2 at Cycles 2 and 4 respectively (75% decrease at Cycle 4)
Screening
+ PFK-158
+ PFK-158
End of Cycle 2
End of Cycle 4
Breast Cancer Patient 01-10:
Bony Mets: Stable
Baseline
Liver Mets:
Necrotic
Baseline
+PFK158
+PFK158
Renal Cell Carcinoma Patient 01-13:
Screening
+ PFK-158
Cardiophrenic
nodule
21.8 mm
-- mm
Right upper lobe
lung nodule
10.8 mm
4.6 mm
Diaphragmatic
nodule
47.7 mm
Stable Disease: Cycle 8
26.7 mm
End of Cycle 2
Adenoid Cystic Carcinoma Patient 03-03:
+ PFK-158
+ PFK-158
Stable Disease On-Going: Cycle 14
Pancreatic Cancer Patient 04-02:
70% decrease in CA19-9 levels after 1 cycle of PFK-158
Date
Cycle
CA19-9
9/8/15
-
66,121
9/28/15
-
167,050
11/2/15
C1D1
275,427
11/21/15
C1D19
83,166
12/11/15
C2D12
120,000
Increased bilirubin levels during Cycle 2 and restaged at Cycle 2
“ ..Multiple hepatic lesions, which now appear more cystic, the
largest of which in segment II/III now measuring up to 11.7 cm X
9.0 cm X 7. 4 cm (previously 9.5 X 7.5 X 6.6 )…”
Pancreatic Cancer Patient 04-02:
70% decrease in CA19-9 levels after 1 cycle of PFK-158
Date
Cycle
CA19-9
9/8/15
-
66,121
9/28/15
-
167,050
11/2/15
C1D1
275,427
11/21/15
C1D19
83,166
12/11/15
C2D12
120,000
+ PFK-158
Parent Compounds of PFK-158 (3PO+PFK15)
Suppress Growth of Leukemia Cells
HL-60 PML Cells
Jurkat T-ALL Cells
HEL AML Cells
Clem et al. Molecular Cancer
Therapeutics, 7(1):110-20, 2008
Clem et al. Molecular Cancer Therapeutics 12(8),
1-10, 2013
Reddy et al. Leukemia.26(3):481-9, 2012
Immune Checkpoint Inhibitors Are Going to Markedly
Reduce the Annual Cancer-Related Death Rate
• Immune Checkpoint Inhibitors Have Clinical Activity In Multiple
Solid Tumor Types & Certain Hematological Malignancies
• Responses Are Typically Durable With Clear Improvements in
Overall Survival
• On-Going Immuno-Oncology Combination Trials Are Yielding
Synergistic Increases in Clinical Activity
• Targeting Immunosuppressive Cells With Drugs Like PFK-158 May
Be Able to Override the ”Cellular Immune Checkpoint” and Increase
the Activities of Anti-PD1 and Anti-CTLA4 in Hematological
Malignancies
Key Collaborators in the Immuno-Oncology Program
Division of Medical Oncology and Hematology
Miller
Riley Sharma Mandadi Rojan Rios
Redman
Perez
Brown Cancer Center Clinical Trials Office
Immunotherapeutics
Kloecker
Yaddanapudi
Coldwell
Radiology
Potts
Schoenbachler Golladay Clark
Smolenkov
Roberts
Ellis
BMT
Tse
Carter Hall Baum
Mitchell
Van Meter