Modulation of T cell response by targeting the PI3K Akt...
Transcript of Modulation of T cell response by targeting the PI3K Akt...
Modulation of T cell response by targeting the PI3K‐Akt pathway
John Janik, M.D.Samir Khleif LaboratoryAugusta University
PI3KδPI3Kδ PI3KβPI3KβPI3KαPI3Kα PI3K
PI3K-Akt Signaling Pathway in T cells
Conventional T cells
Regulatory T cells
?
Normal Cell
T‐Cell
Tregs
T‐Cell
Tregs
CD4+Foxp3‐
CD4+Foxp3+
PI3K
PIP2 PIP3
PTEN, SHIP‐1 and ‐2
Akt
PIP3
PDK‐1PP
T308S473
mTOR
S6K1/2
P
S6
Proliferation
TCR
Stimulation
Effects of PI3K‐Akt pathway inhibition in Tregs vs. Tconv cells
PI3K
PIP2 PIP3
PTEN, SHIP‐1 and ‐2
WM
Akt
PIP3
PDK‐1PP
T308S473
mTOR
S6K1/2
P
S6
TCN
Proliferation
TCR
Stimulation
Effects of PI3K‐Akt pathway inhibition in Tregs vs. Tconv cells
PI3K
PIP2 PIP3
PTEN, SHIP‐1 and ‐2
WM
AktPIP3
PDK‐1PP
T308S473
mTOR
Effects of PI3K‐Akt pathway inhibition in Tregs vs. Tconv cells
TCR Stimulation ‐ + + +Treatment None None DMSO WM
Tconv
Treg
TCR
StimulationpAkt 473
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
US NT DMSO WM
pAkt 473/A
ktCD25‐ (Tconv)CD25+ (Treg)
S6K1/2P
S6
S6 phosphorylation is diminished in mouse Treg in presence PI3K/AKT inhibitors
Abu Eid R.et al, CIR, 2014
Effects of PI3K‐Akt pathway inhibition on the TCR/IL2 Induced proliferation of Tregs vs. Tconv cells
PI3K
PIP2 PIP3
PTEN, SHIP‐1 and ‐2
WM
AktPIP3
PDK‐1PP
T308S473
mTOR
S6K1/2P
S6
TCN
Proliferation
TCR
Stimulation
Effects of PI3K‐Akt pathway inhibition on the TCR/IL2 Induced proliferation of Tregs vs. Tconv cells
PI3K
PIP2 PIP3
PTEN, SHIP‐1 and ‐2
WM
AktPIP3
PDK‐1PP
T308S473
mTOR
S6K1/2P
S6
TCN
Proliferation
TCR
Stimulation
Abu Eid R.et al, CIR, 2014
Inhibition of PI3K‐Akt pathway in vivo
PI3K/ Akt pathway is essential for the in vivo maintenance of Treg in naïve tumor free mice
Abu Eid R.et al, CIR, 2014 ‐7 ‐5 ‐3 0
WM/TCN/MK2206 Collect splenocytes
PI3K/ Akt pathway is essential for the in vivo maintenance of Treg in naïve tumor free mice
Abu Eid R.et al, CIR, 2014 ‐7 ‐5 ‐3 0
WM/TCN/MK2206 Collect splenocytes
PI3K/ Akt pathway is essential for the in vivo maintenance of Treg in naïve tumor free mice
Abu Eid R.et al, CIR, 2014 ‐7 ‐5 ‐3 0
WM/TCN/MK2206 Collect splenocytes
PI3K‐Akt pathway inhibition indirectly decrease tumor growth
CT26 tumor growth
0
100
200
300
400
500
600
700
3 7 10 13 17 20 24
Days post tumor inoculation
Tumor size (m
m2)
PBS
0
Tumor implantation
Abu Eid R.et al, CIR, 2014
CT26 tumor growth
0
100
200
300
400
500
600
700
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 )
PBSPC61
‐4 0
Tumor implantationPC61
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition indirectly decrease tumor growth
CT26 tumor growth
0
100
200
300
400
500
600
700
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 ) PBSPC61DMSO
‐4 0
Tumor implantationPC61
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition indirectly decrease tumor growth
CT26 tumor growth
0
100
200
300
400
500
600
700
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 )PBSPC61DMSOWM
‐7 ‐5 ‐3 0
Tumor implantationWM
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition indirectly decrease tumor growth
CT26 tumor growth
0
100
200
300
400
500
600
700
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 )PBSPC61DMSOWMTCN
‐7 ‐5 ‐3 0
Tumor implantationTCN
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition indirectly decrease tumor growth
0 Tumor size
EL4
0
100
200
300
400
500
600
700
800
900
3 7 10 13 17 20 24Days post tumor implantation
Tum
or S
ize
(mm
2)NT-PBS
NT‐PBS
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition of tumor growth is Treg‐dependent
‐7 ‐5 ‐3 0 Tumor size
EL4
WM
0
100
200
300
400
500
600
700
800
900
3 7 10 13 17 20 24Days post tumor implantation
Tum
or S
ize
(mm
2)NT-PBSWM-PBS
* p<0.01
NT‐PBS
WM‐PBS
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition of tumor growth is Treg‐dependent
‐4 0 Tumor size
PC61 EL4
0
100
200
300
400
500
600
700
800
900
3 7 10 13 17 20 24Days post tumor implantation
Tum
or S
ize
(mm
2)NT-PBSPC61-PBSWM-PBS
* p<0.01
NT‐PBSPC61‐PBSWM‐PBS
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition of tumor growth is Treg‐dependent
‐4 0 4 Tumor size
PC61 EL4 Treg
0
100
200
300
400
500
600
700
800
900
3 7 10 13 17 20 24Days post tumor implantation
Tum
or S
ize
(mm
2)NT-PBSPC61-PBSWM-PBSPC61-Treg
* p<0.01
NT‐PBSPC61‐PBSWM‐PBSPC61‐Treg
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition of tumor growth is Treg‐dependent
‐7 ‐5 ‐3 0 4 Tumor size
EL4 Treg
WM
0
100
200
300
400
500
600
700
800
900
3 7 10 13 17 20 24Days post tumor implantation
Tum
or S
ize
(mm
2)
NT-PBSPC61-PBSWM-PBSPC61-TregWM-Treg
* p<0.01
NT‐PBSPC61‐PBSWM‐PBSPC61‐TregWM‐Treg
Any effects on vaccine efficacy in vivo?
PI3K‐Akt pathway inhibition of tumor growth is Treg‐dependent
Abu Eid R.et al, CIR, 2014
PI3K‐Akt pathway inhibition of tumor growth is Treg‐dependent
0
50
100
150
200
250
300
350
UT DMSO WM TCN
Spots p
er m
illion
E7 re‐stimDMSO re‐stim
‐7 ‐5 ‐3 0 14
E7 Vx Collect splenocytes
No Vx E7 Vx
* *** P<0.05; ** P<0.01
WM/TCN
PI3K‐Akt inhibition enhances vaccine efficacy
Abu Eid R.et al, CIR, 2014
TC1 tumor growth
0
100
200
300
400500
600
700
800
900
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 )
DMSO-DMSO
Inhibition of PI3K‐Akt synergistically enhances anti‐tumor immune responses
Abu Eid R.et al, CIR, 2014
TC1 tumor growth
0
100
200
300
400500
600
700
800
900
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 )DMSO-E7DMSO-DMSO
Inhibition of PI3K‐Akt synergistically enhances anti‐tumor immune responses
Abu Eid R.et al, CIR, 2014
TC1 tumor growth
0
100
200
300
400500
600
700
800
900
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 ) WM-DMSODMSO-E7DMSO-DMSO
Inhibition of PI3K‐Akt synergistically enhances anti‐tumor immune responses
Abu Eid R.et al, CIR, 2014
TC1 tumor growth
0
100
200
300
400500
600
700
800
900
3 7 10 13 17 20 24
Days post tumor inoculation
Tum
or s
ize
(mm
2 )WM-E7WM-DMSODMSO-E7DMSO-DMSO
Inhibition of PI3K‐Akt synergistically enhances anti‐tumor immune responses
Abu Eid R.et al, CIR, 2014
Akt inhibition by MK‐2206 enhances the anti‐tumor therapeutic effect of tumor‐specific vaccine..
Abu Eid R.et al, CIR, 2014
Akt inhibition by MK‐2206 enhances the anti‐tumor immune response of tumor‐specific vaccine
Abu Eid R.et al, CIR, 2014
WM differentially affects proliferation of human Tregs and Tconv cells
Abu Eid R.et al, CIR, 2014
A phase Ib /II trial of pembrolizumab and idelalisibin patients with non‐small cell lung cancer (NSCLC)
Metastatic NSCLC • Progressed on platinum doublets• OR, Not able to tolerate chemo or unwilling to undergo chemotherapy
• OR EGFR, ALK, ROS1 mutations with disease progression on small molecule inhibitors
• may have also failed prior PD‐1/PD‐L1 blockade
Keytruda 200 mg Q3WZydelig 150 mg BID PO
Keytruda 200 mg Q3WZydelig 150 mg BID PO
Phase II(A) 50 PD1N patients (B) 20 PD1P patients
=2/6 DLTone dose lower
For Phase II
lower level if>2/6 DLT
<=1/6 DLT
Phase Ib
A phase Ib /II trial of pembrolizumab and idelalisibin patients with non‐small cell lung cancer (NSCLC)
Clinical Trials• Vaccine in combination with AKT inhibitors• AKT inhibitor in combination with anti‐PD1
•Samir Khleif•Shamim Ahmad•Pandelakis Koni•Mikayel Mkrtichyan•Rajeev Shrimali•Rasha Abu-Eid•Abdeljabar El Andaloussi•Atbin Doroodchi•Zuzana Berong•Mason Webb•Abdulmoneim Algady
•Tanusree Sen•Stephanie Zdaniv•Michiko Shimoda•Raed Samara•Osama Rahma
• Collaborators:– Theresa Whiteside, U Pitt– Jay Berzofsky, NCI– Nadia Tarasova, NCI– Jeff Schlom, NCI– Micheal Schickler, CureTech– Ramy Ibrahim, AZ– Ross Stewart, AZ– Linda Liu, Medimmune– Sol Langerman Medimmune
Acknowledgments