Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM...
Transcript of Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM...
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Combinations
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MPDL3280A (anti-PD-L1) in metastatic bladder cancer
Powles T et al. Nature 515(7528), 558-562 (2014)
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Targeted Therapy
• Any therapy that targets cancer’s specific
phenotype or genotype – Specific immune generating therapy/vaccines – T cell therapy – Molecular targeted therapy
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NCI Immunotherapy Agent Workshop Proceedings
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Combinational Immunotherapy • Vaccines • Immune Modulators
– Immune Agonists • Stimulatory cytokines (IL-2, IL-12, IL-15, TLR etc..) • Co-stimulatory molecules (OX-40, GITR, 4-1BB)
– Immune inhibitors • Check point inhibitors (CTLA4, PD1/PDL1, LAG3, TIM3, iDO) • Inhibitory cytokines/factors (IL-10, TGFb)
• Standard Therapy – Chemotherapy – Radiation Therapy
• Small Molecules • T cell therapy/CARS
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Challenges
• What pre clinical data would be needed to move with the combination ?
• Type of Combination/Schedule of combination Prediction of response • What clinical trial design ?
– Efficiency – Time
• How to enable combinations from different developers—pharm/bio
• Health Economics, “financial adverse” effect
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Challenges
• What pre clinical data would be needed to move with the combination ?
• Type of Combination/Schedule of combination Prediction of response
– Biology – Activity in preclinical model OPTIMUM RESPONSE
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Treg cell inhibitor-cyclophosphamide (CPM)
Low Dose CPM selectively targets Treg cells, leaving other T cell populations intact (Lutsiak et al, Blood, 2005; Ikezawa et al, J Dermatol Sci, 2005).
E7+aPD-1
CPM
Days 0 7 8 15 22
TC-1
Monitoring of tumor growth and survival
E7+aPD-1 E7+aPD-1
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***P<0.001
0
20
40
60
80
100
120
140
Num
ber
of IF
Nγ
spot
s per
106
sple
nocy
tes
E7 E7 +aPD-1
aPD-1 +CPM
NT E7 +aPD-1 +CPM
E7 +CPM
*** ***
*** ***
E7+aPD-1 CPM TERMINATION
Days 0 7 8 15 21
TC-1 tumor
Vaccine/anti-PD-1/CPM combination induces potent antigen-specific immune responses in tumor bearing mice
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***P<0.001
0
20
40
60
80
100
120
140
Num
ber
of IF
Nγ
spot
s per
106
sple
nocy
tes
E7 E7 +aPD-1
aPD-1 +CPM
NT E7 +aPD-1 +CPM
E7 +CPM
*** ***
*** ***
E7+aPD-1 CPM TERMINATION
Days 0 7 8 15 21
TC-1 tumor
Vaccine/anti-PD-1/CPM combination induces potent antigen-specific immune responses in tumor bearing mice
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 760
20
40
60
80
100
Perc
ent S
urvi
val
Days after tumor implantation 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76
0
20
40
60
80
100
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 760
20
40
60
80
100
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 760
20
40
60
80
100
CPM (n=15) aPD-1 (n=15) E7 (n=14) Non-treated (n=15)
E7 + aPD-1 + CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15)
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Kaplan–Meier Curves for Overall Survival and Progression-free Survival in the Intention-to-Treat Population.
Hodi FS et al. N Engl J Med 2010;363:711-723.
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Vaccines – Peptides, polypeptides – DND/RNA – Viral – Bacterial
• Administered Directly or on DCs
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Vaccines %
of M
DSC
in sp
leen
% o
f Tre
g w
ithin
CD4
Tce
lls
* * *
* * *
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Combination of Lm-LLO-E7 with anti-PD-1 mAb significantly improves therapeutic potency of immunotherapy
Lm-LLO-E7 (5x10e6 CFU) +aPD-1 mAb (50ug)
Monitoring of tumor growth
Days 0 8 15
TC-1 tumor
Tum
or V
olum
e, c
m3
Days after tumor implantation Perc
ent S
urvi
val
Days after tumor implantation Mkrtichyan et al., JITC 2013
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Combinational Immunotherapy
• Vaccines • Immune Modulators
– Immune Agonists • Stimulatory cytokines (IL-2, IL-12, IL-15, TLR etc..) • Co-stimulatory molecules (OX-40, GITR, 4-1BB)
– Immune inhibitors • Check point inhibitors (CTLA4, PD1/PDL1, LAG3, TIM3, iDO) • Inhibitory cytokines/factors (IL-10, TGFb)
• Standard Therapy – Chemotherapy – Radiation Therapy
• Small Molecules • CARS
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PI3K
PIP2 PIP3
PTEN, SHIP-1 and -2
Akt
PIP3
PDK-1 P P
T308 S473
mTOR
S6K1/2
P
S6
Proliferation
TCR
Stimulation
Effects of PI3K-Akt pathway inhibition in Tregs vs. Tconv cells
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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
Akt PIP3
PDK-1 P P
T308 S473
mTOR
S6K1/2 P
S6
TCN
Proliferation
TCR
Stimulation
Abu Eid R.et al, CIR, 2014
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0
50
100
150
200
250
300
350
UT DMSO WM TCN
Spot
s per
mill
ion
E7 re-stim DMSO 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
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Challenges
• What pre clinical data would be needed to move with the combination ?
• Type of Combination/Schedule of combination Prediction of response
– Biology – Activity in preclinical model OPTIMUM RESPONSE
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Challenges
• What pre clinical data would be needed to move with the combination ?
• Type of Combination/Schedule of combination Prediction of response • What clinical trial design ?
– Efficiency – Time
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• Reviewed all cancer vaccine trials on PubMed
• Phase 1, phase1/2, and pilot studies in therapeutic cancer vaccines
• Reported from 1990 through 2011
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What is the rate of vaccine-related toxicity in relation to the number
of vaccinated patients?
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Rahma et al, Clin Cancer Research, 2014
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Rahma et al, Clin Cancer Res, 2014
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What is the rate of vaccine-related toxicity in relation to the number
administered vaccines?
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Rahma et al, Clin Cancer Res, 2014
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Rahma et al, Clin Cancer Res, 2014
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Questions in Early Cancer Vaccine Development
Does dose escalation determine MTD?
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Rahma et al, Clin Cancer Res, 2014
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Rahma et al, Clin Cancer Res, 2014
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Trials with DLT Trial Vaccine Toxicity DLT
Dols et al. 2003
Allogeneic HER2/neu(+) breast cancer cells (SC) with GM-CSF or BCG
Nausea/Vomiting
1 patient at 250 µg/m2 GM-CSF
Maciag et al. 2009
L. monocytogenes secreting HPV-16 E7 fused to Lm listeriolysin O (IV)
Hypotension
3 patients at highest dose level
Guthmann et al. 2004
GM3 ganglioside with N. meningitidis outer
membrane (IM)
Hypotension
1 patient at highest dose level
Rahma et al, Clin Cancer Res, 2014
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Conclusion
• Dose escalation design has no role in defining – The maximum tolerated dose (MTD)
– Except for bacterial vector vaccines
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Questions in Early Cancer Vaccine Development
Does dose escalation determine BAD?
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Trials with Dose Related Cellular Immune Response
Vaccine Category
No. Trials
Dose Related Cellular Immune Response
Autologous 32 0 Allogeneic 4 0 Synthetic 80 0
Total 116 0
Rahma et al, Clin Cancer Res, 2014
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Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
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Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
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Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
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Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
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Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
![Page 40: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/40.jpg)
Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
![Page 41: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/41.jpg)
Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Step 2. Combination Design “Vaccine + X” (X is an immune modulator, chemotherapy or targeted agent)
X had no DLT X had a DLT X’ DLT is unknown
Use the same dose Use the dose below MTD Proceed to traditional phase 1
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
![Page 42: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/42.jpg)
Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Step 2. Combination Design “Vaccine + X” (X is an immune modulator, chemotherapy or targeted agent)
X had no DLT X had a DLT X’ DLT is unknown
Use the same dose Use the dose below MTD Proceed to traditional phase 1
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
![Page 43: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/43.jpg)
Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Step 2. Combination Design “Vaccine + X” (X is an immune modulator, chemotherapy or targeted agent)
X had no DLT X had a DLT X’ DLT is unknown
Use the same dose Use the dose below MTD Proceed to traditional phase 1
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
![Page 44: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/44.jpg)
Alternative Clinical Trial Design For Combination Immune Therapy
Step 1. Determining a starting dose of a vaccine
Step 2. Combination Design “Vaccine + X” (X is an immune modulator, chemotherapy or targeted agent)
X had no DLT X had a DLT X’ DLT is unknown
Use the same dose Use the dose below MTD Proceed to traditional phase 1
Vaccine class and toxic (e.g., bacterial vector)
Vaccine class non-toxic (e.g., peptide)
Vaccine class that is not used before & not expected to be toxic
Proceed to traditional phase 1 trial
Use Immune Active Dose (IAD) from previous clinical trials
One Patient Escalation Design (OPED)
Rahma et al, Clin Cancer Res, 2014
![Page 45: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/45.jpg)
Challenges
• What pre clinical data would be needed to move with the combination ?
• Type of Combination/Schedule of combination Prediction of response • What clinical trial design ?
– Efficiency – Time
• How to enable combinations from different developers—pharm/bio
![Page 46: Khleif – Combinations › en › documents › presentation › present… · E7 + aPD1 -+ CPM (n=20) aPD-1+CPM (n=15) E7+CPM (n=14) E7+aPD-1 (n=15) Kaplan–Meier Curves for Overall](https://reader033.fdocuments.us/reader033/viewer/2022060422/5f1880af7f55eb716f2ba07e/html5/thumbnails/46.jpg)
Challenges
• What pre clinical data would be needed to move with the combination ?
• Type of Combination/Schedule of combination Prediction of response • What clinical trial design ?
– Efficiency – Time
• How to enable combinations from different developers—pharm/bio
• Health Economics, “financial adverse” effect