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Raising the Tail of Cancer Survival Curves with Immunotherapy
Siwen Hu-Lieskovan, MD, PhDDirector, Solid Tumor Immunotherapy
Huntsman Cancer Institute at University of Utah
Nevada Cancer Control SummitSep 16, 2019
Disclosures
Consulting: Amgen, Merck, Genmab, Xencor, BMS Research Support: BMS, Merck, Vaccinex Contracted Research: Pfizer, Plexxikon, Genentech, Neon Therapeutics,
Nektar, Astellas, F Star, Xencor
Significant Improvement of Overall Survival for Metastatic Melanomain the Past 10 Years
1. M. Middleton Ann Oncol 2007;18:1691. 2. Hodi FS et al NEJM 2010;363:711. 3. Schadendorf D et al JCO 2015:33:1889. 4. Robert C et al NEJM 2011;364:2517. 5. Maio M et al. JCO 2015; 33:1191. 6. Chapman PB et al Poster presentation SMR 2015. 7. Hauschild A et al Poster presentation ESMO 2014. Abstract 1092. 8. Atkinson V et al Poster presentation SMR 2015. 9. Hodi FS et al Oral presentation AACR 2016. Abstract CT001. 10. Carlino M et al Oral presentation AACR 2016. Abstract CT004. 11. Long GV Lancet Oncol 2016. 12. Ascierto PA et al Lancet Oncol 2016:17:1248. 13. Larkin J et al AACR 2017:1558. 14. Schachter J et al Oral presentation ASCO 2016. Abstract 9504. 15. Flaherty K et al Oral presentation ASCO 2016. Abstract 9502.16. MacArthur GA et al. Poster presentation SMR 2016
25–35%1 56%6 70%7
2012 2013
46%2 47%4
2010 2011
71%8
2014
71%10 Pembrolizumab74%11 Dab + tramd
75%12 Vem + cobi
2015
24%2 29%4 Ipi 45%715%1 53%11 Dab + tram2-year OS
55%14 Pembrolizumab
58% Nivo8
48%12 Vem + cobi
3-year OS
2017
5-year OS
73%13 Nivo + ipi
22%3
1990
35%9 Nivo (ph I)
44%15 Dab + tram
64%13 Nivo + ipi
1-year OS
18%5 Ipi
30%6
©Georgina V Long, MIA
2016
37%16 Vem + cobi
Anti-CTLA-4 and Anti-PD-1/L1 Mechanisms of Action
MHC = major histocompatibility complex; TCR = T-cell receptor; TME = tumor microenvironmentImage adapted from Abril and Ribas, Cancer Cell Snapshot 2017
Dendritic cell
Lymph node
Signal 1
Signal 2
MHC TCR
CD28
CTLA-4B7
Tumor
Tumor cell
MHCTME
Naïve T cellDifferent phase of T cell activation:• Priming phase: anti-CTLA4• Effector phase: anti-PD1
Lymph node
Signal 1
Signal 2
MHC TCR
CD28
CTLA-4B7
Inhibitor of signal 2
Tumor
Tumor cell
MHC
Dendritic cell
Anti-CTLA-4 and Anti-PD-1/L1 Mechanisms of Action
MHC = major histocompatibility complex; TCR = T-cell receptor; TME = tumor microenvironmentImage adapted from Abril and Ribas, Cancer Cell Snapshot 2017
TME
Naïve T cellDifferent phase of T cell activation:• Priming phase: anti-CTLA4• Effector phase: anti-PD1
Lymph node
Signal 1
Signal 2
MHC TCR
CD28B7
Inhibitor of signal 2
Tumor
Tumor cell
MHCTCR
Dendritic cell CTLA-4
Anti-CTLA-4 and Anti-PD-1/L1 Mechanisms of Action
MHC = major histocompatibility complex; TCR = T-cell receptor; TME = tumor microenvironmentImage adapted from Abril and Ribas, Cancer Cell Snapshot 2017
TME
Naïve T cell
Activated T cell
Different phase of T cell activation:• Priming phase: anti-CTLA4• Effector phase: anti-PD1
Increase in TIL in most patients treated with anti-CTLA4 (tremelimumab) regardless of tumor response
GA18
Pre-Tx Biopsies
GA12
GA14
GA29
No
tum
or re
spon
se
Huang… Cochran, Ribas Clinical Cancer Research 2011
40x CD8 IHC
With
tum
or re
spon
se Intratumoral CD8 Infiltration
Pre Post
CD
8 C
ell D
ensi
ty
0
500
1000
1500
2000
2500
3000
Paired t-test p = 0.005
Post-Tx Biopsies
40x CD8 IHC
CTLA4 blockade brings T cells into tumors
CTLA4 blockade diversifies peripheral T cell responses
Ipilimumab
3 mg/kg x 4 doses q3w 10 mg/kg x 4 doses q3w, then q3mo+ dacarbazine
N Engl J Med. 2010 Aug 19;363(8):711-23. N Engl J Med. 2011 Jun 30;364(26):2517-26.
Lymph node
Signal 1
Signal 2
Tumor
MHC TCR
B7
Tumor cell
MHCTCR
IFN-gamma
Dendritic cell
CD28
Inhibitor of signal 2
CTLA-4
Anti-CTLA-4 and Anti-PD-1/L1 Mechanisms of Action
MHC = major histocompatibility complex; TCR = T-cell receptor; TME = tumor microenvironmentImage adapted from Abril and Ribas, Cancer Cell Snapshot 2017
TME
Naïve T cell
Activated T cell
Different phase of T cell activation:• Priming phase: anti-CTLA4• Effector phase: anti-PD1
Lymph node
Signal 1
Signal 2
Tumor cell
Tumor
MHC TCR
MHC
B7
TCR
PD-L1PD-1
IFN-gamma
Dendritic cell
CD28
Inhibitor of signal 2
CTLA-4
Anti-CTLA-4 and Anti-PD-1/L1 Mechanisms of Action
MHC = major histocompatibility complex; TCR = T-cell receptor; TME = tumor microenvironmentImage adapted from Abril and Ribas, Cancer Cell Snapshot 2017
TME
Naïve T cell
Activated T cell
Different phase of T cell activation:• Priming phase: anti-CTLA4• Effector phase: anti-PD1
Lymph node
Naïve T cellSignal 1
Signal 2
Tumor cell
Tumor
MHC TCR
MHC
B7
TCR
PD-L1PD-1
Activated T cell
IFN-gamma
Dendritic cell
CD28
Inhibitor of signal 2
CTLA-4
Anti-CTLA-4 and Anti-PD-1/L1 Mechanisms of Action
MHC = major histocompatibility complex; TCR = T-cell receptor; TME = tumor microenvironmentImage adapted from Abril and Ribas, Cancer Cell Snapshot 2017
TME
Different phase of T cell activation:• Priming phase: anti-CTLA4• Effector phase: anti-PD1
NEJM 2015 Jan 22; 372: 320-30. NEJM 2015, Jun 25; 372: 2521-2532
Response to anti-PD1 Therapy requires both CD4 and CD8 cellsPre-existing CD8 cell infiltration
TCR clonality
Tumeh, .., Ribas. Nature 2014
4HT to skinactivates Cre Recombinase
Male C57 BL/6JBRAFV600EPTEN-/-
i.p. ISO or aPD1
Hu-Lieskovan, et al. ASCO 2018
Both CD4 and CD8 cells are required in the response to PD1 blockade in a syngeneic murine melanoma model
Pembrolizumab Nivolumab
Atezolimumab
Avelumab
Anti-PD1
Anti-PD-L1
DurvalumabAvelumab
Hodgkin’s (65-85%)
Melanoma (35-40%, 60% w combo)
NSCLC (20-25%)
Merkel CC (32%)
MSI-H or dMMRSolid tumors (40%)
HNSCC (15%)
Bladder Ca (15%)
Renal CC (20%, 42% w combo)
Esophageal SCC (30%, PDL1>1%)Ovarian Ca (15%)
FDA Approved Indications
Activities seen in other tumors types
Gastric CA (14%)
HCC (14%)
Clinical Success of PD-1 Checkpoint Blockade ---Durable Responses but only in a Minority of Patients
SCLC (12%)
Cemiplimab
TNBC (18%)
How to help the “Non-Responders”?
Years
OS
(%)
100
The Clinical Challenge
Met
asta
tic C
ance
rs
1 2 3
Sharma, Hu-Lieskovan, Wargo, Ribas. Cell, 2017Hu-Lieskovan and Ribas. Cancer Journal. 2017
Intrinsic Mechanisms Extrinsic Mechanisms
Resistance Mechanisms to Immunotherapy
Tumor CellsTurn on Engine
Neoantigen QuantityChemoRadiationEpigenetic Modulation
Neoantigen QualityTAA VaccineNeoantigen VaccineEngineered specificity
Antigen Presentation/ T Cell PrimingDC vaccineOncolytic virusTLR/STING agonistsCytokinesAnti-CTLA4Anti-CD40
Fuel the TankAnti-GITRAnti-41BB/CD137Anti-OX40Anti-ICOS
Take Away BarrierIDO InhibitorCSF1R inhibitorAdenosine R inhibitorTGFβ inhibitorVEGF inhibitorPI3Kg inhibitor
Block the Stop SignAnti-PD-1/L1Anti-TIM3, anti-LAG3Anti-TIGIT
T Cells
Strategies To Overcome Resistance
Heterogenous Immune Escape Mechanisms in Each Patient
Each Object is Symbolic of a Patient
Sort Patients Based on Biology before Combo Testing
Heterogenous Immune Escape Mechanisms in Each Patient
Each Object is Symbolic of a Patient
Correlation between Tumor Mutational Burden and Objective Response Rate with Anti–PD-1 or Anti–PD-L1 Therapy in 27 Tumor Types (p<0.001). Yarchoan, Hopkins, Jaffee, NEJM 2017
Three Patterns of Response to Immunotherapy
Progression free survival (PFS), n = 57, median not reached, range = 1.2 -56 months
Overall survival (OS), N = 57, median not reached, range = 3.6 – 64 months
High Response Rate To PD-1 Blockade In Patients With Desmoplastic Melanoma
Best ORR = 70%(Median f/u 18mon, CI 57-82%)
18 CR (none progressed)22 PR (9 progressed later)5 SD (2 progressed later)
12 PD
3 pts w/ isolated PD (2 PR, 1 PD) received surgical resection and had NED for 1.8, 5.2 and 5.3 years)
Estimated 1 year OS 85% (CI 78-98), 2 year OS 73% (CI 62-88).
Eroglu, Zaretsky, *Hu-Lieskovan,*Ribas, etc. Nature, 2018* Corresponding authors
• Ten Academic Centers
• Over 1000 cases of advanced melanoma
• 57 patients with advanced DM who received anti-PD-1/L1 therapy identified.
S1512: A Phase II Trial of PD-1 Blockade With Pembrolizumab in Patients With Resectable or Unresectable Desmoplastic Melanoma (DM)
Baseline 3 weeks later 5 months later
Antoni Ribas, MD, PhDGrace Cherry, NP
S1512: A Phase II Trial of PD-1 Blockade With Pembrolizumab in Patients With Resectable or Unresectable Desmoplastic Melanoma (DM)
Study Chair: Kari Kendra, MDTranslational Lead: Siwen Hu-Lieskovan, MDStatisticians: James Moon; Mike Wu, PhDProtocol Coordinator: Danae Campos
https://www.cancer.gov/news-events/cancer-currents-blog/2018/desmoplastic-melanoma-checkpoint-inhibitors?cid=eb_govdel
1) Confirm efficacy of pembrolizumab in desmoplastic melanoma patients2) Explore the possibility of using this effective treatment early before the surgery, even if the disease
is considered resectable, to reduce morbidity and overall clinical outcome.
Cohort A - Resectable DM. Primary endpoint: pCR rate with neoadjuvant pembrolizumab.Cohort B - Unresectable DM. Primary endpoint: CR rate with pembrolizumab
Open at Huntsman!
Long term evaluation of biomarkers for PD-1 Blockade in NSCLC
Hu-Lieskovan, Lisberg, Zaretsky, Rizvi, Hellman, Ribas, Garon. Clin Can Res, in press
Characteristics LTB (n=5) All others (n=33) p-valueMutational Load 173 (104-261) 83 (48.5-235) 0.530CD8 9.5 (5.5-15) 4 (2-8.5) 0.106PD-L1 72 (55-77) 16 (6.5-45.5) 0.029CD4 2 (1.05-14) 3.2 (1-8) 0.763Age 59 (59-68) 68 (60-74) 0.424Male 4 (80.0%) 18 (54.5%) 0.374EGFR Mutations 0 (0.0%) 9 (28.1%) 0.553Ever smoker 3 (60.0%) 18 (54.5%) 1.000Squamous 1 (20.0%) 7 (21.2%) 1.000At Least One Line Therapy 3 (60.0%) 27 (81.8%) 0.279
TMB CD8 PD-L1 CD4PFS
(days)OS
(days) Smoking EGFR SquamousTMB Spearman 1.000 0.125 0.191 0.072 0.365 0.021 .517** -0.333 -0.221
p-value 0.591 0.406 0.758 0.072 0.920 0.008 0.104 0.289
N 25 21 21 21 25 25 25 25 25
CD8 Spearman 0.125 1.000 .660** .396* .490** .354* 0.342 -0.287 0.121
p-value 0.591 <0.001 0.025 0.004 0.047 0.055 0.111 0.508
N 21 32 32 32 32 32 32 32 32
PD-L1 Spearman 0.191 .660** 1.000 .487** .547** .445* .366* -0.201 .395*
p-value 0.406 <0.001 0.005 0.001 0.011 0.040 0.271 0.025
N 21 32 32 32 32 32 32 32 32
CD4 Spearman 0.072 .396* .487** 1.000 0.277 0.212 -0.003 0.177 -0.031
p-value 0.758 0.025 0.005 0.125 0.245 0.985 0.334 0.865
N 21 32 32 32 32 32 32 32 32
LTB: Long Term Benefiter (OS>3yr with No Next Line)
Correlation Analysis
Patterns More Prevalent in
Unique Considerations
Strategies Examples
I: TMB High &Inflammation High
MelanomaCutaneous SCCMMR-d Cancers
• Plenty of neoantigens but may not be high quality
• Exhausted T cells• PD-1 is not the
main checkpoint• Intrinsic mutations
• Increase quality of neoantigens
• Decrease T cell Exhaustion• Other immune checkpoints• Tumor Intrinsic Resistance
(JAK1/2, B2M, WNT)• Improve TME• Microbiome?
Neoantigen vaccine
aCD137, aOX40,aGITR, aICOSaTIGIT, aTIM3, aLAG3TLR9 agonists? PEG IL2?
VEGFi, MAPKi, PI3Kgi, IDOi, …
II: TMB Medium &Inflammation Low to Medium
NSCLCHNSCCHCCGastric CA
• Not enough high quality neoantigens
• Defects in priming
• Increase quantity of neoantigens or exposure
• Increase T cell priming• Improve TME• Microbiome?
Oncolytic virus, TLR/STING agonists, hypomethylation agents, …aCTLA4, aCD40VEGFi, MAPKi, PI3Kgi, IDOi, …
III: TMB Low &Inflammation Low to None
MMR-p CRCPancreatic CAProstate CA
• Low or no neoantigens to trigger anti-tumor response
• All of the above• Engineered specificity• Improve TME• Microbiome?
All of the abovebi-specific, TCR/CAR ACTVEGFi, MAPKi, PI3Kgi, IDOi, …
Patterns of TME Biology and Potential Strategies
Patterns More Prevalent in
Unique Considerations
Strategies Examples
I: TMB High &Inflammation High
MelanomaCutaneous SCCMMR-d Cancers
• Plenty of neoantigens but may not be high quality
• Exhausted T cells• PD-1 is not the
main checkpoint• Intrinsic mutations
• Increase quality of neoantigens
• Decrease T cell Exhaustion• Other immune checkpoints• Tumor Intrinsic Resistance
(JAK1/2, B2M, WNT)• Improve TME• Microbiome?
Neoantigen vaccine
aCD137, aOX40,aGITR, aICOSaTIGIT, aTIM3, aLAG3TLR9 agonists? PEG IL2?
VEGFi, MAPKi, PI3Kgi, IDOi, …
II: TMB Medium &Inflammation Low to Medium
NSCLCHNSCCHCCGastric CA
• Not enough high quality neoantigens
• Defects in priming
• Increase quantity of neoantigens or exposure
• Increase T cell priming• Improve TME• Microbiome?
Oncolytic virus, TLR/STING agonists, hypomethylation agents, …aCTLA4, aCD40VEGFi, MAPKi, PI3Kgi, IDOi, …
III: TMB Low &Inflammation Low to None
MMR-p CRCPancreatic CAProstate CA
• Low or no neoantigens to trigger anti-tumor response
• All of the above• Engineered specificity• Improve TME• Microbiome?
All of the abovebi-specific, TCR/CAR ACTVEGFi, MAPKi, PI3Kgi, IDOi, …
Patterns of TME Biology and Potential Strategies
NEO-PV-01, with anti-PD1, Induces Neoantigen-Specific De Novo Tumor-
Related Immunity in Patients with Advanced Cancer
Siwen Hu-Lieskovan*, Ramaswamy Govindan, Aung Naing, Terence W. Friedlander, Kim Margolin, Jessica J. Lin, Nina Bhardwaj, Matthew D. Hellmann, Lakshmi Srinivasan, Joel Greshock, Melissa Moles, Richard B. Gaynor, Matthew J. Goldstein, and Patrick A. Ott
*David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Steps in production of NEO-PV-01NEO-PV-01 targets a patient’s specific set of tumor neoantigens
• A personal vaccine targeting immune responses against high quality neoantigens unique to each patient
• Up to 20 unique peptides (~14-35mer) + Poly-ICLC adjuvant• Subcutaneous injection
DNA & RNA Sequencing
Tumor Sample& Processing
Bioinformatics
Patient
Personal Peptide Manufacturing
GMP Release NEO-PV-01Personal Neoantigen
Vaccine
Hu-Lieskovan, et al, SITC 2018; AACR 2019
NT-001: Study initiated August 2016Data Cutoff August 31, 2018
30
31 August 2018
Hu-Lieskovan, et al, SITC 2018; AACR 2019
NT-001: Patient Demographics
3131 August 2018
Hu-Lieskovan, et al, SITC 2018; AACR 2019
Per Protocol Set (n = 16)
Response duration (range)
+39.7 weeks(1.0-70.4)
* On study or continuing nivolumab treatment as of recent correspondence
Continued Nivolumab Treatment*
75.0%12/16
Disease stabilization post-progression
% C
hang
e fr
om B
asel
ine
0 20 40 60
0
-50
-100
50
100
150
80Weeks
>
Post-vaccination response
On study
12
> Continued nivo
Observed response
31 August 2018
Melanoma: Tumor Burden Changes During Therapy
Discontinuation rate prior to week 52
21.4%(3/14)
Pre-vaccination
Post-vaccination Total
PR 50.0% (8/16)
37.5% (3/8)
68.8% (11/16)
CR 0% 6.3% (1/16)
6.3% (1/16)
32Hu-Lieskovan, et al, SITC 2018; AACR 2019
NSCLC: Tumor Burden Changes During Therapy
Per Protocol Set (n = 11)
Pre-vaccination
Post-vaccination Total
PR 27.2% (3/11)
25.0% (2/8)
45.5% (5/11)
CR 0% 0% 0% (0/11)
Response duration (range)
+30.6 weeks(8.7-35.0)
* On study or continuing nivolumab treatment as of recent correspondence
Continued Nivolumab Treatment*
63.6%(7/11)
% C
hang
e fr
om B
asel
ine
0 20 40 60
0
-50
-100
50
100
150
Weeks12
>
Post-vaccination response
On study> Continued nivo
Observed response
31 August 201833Hu-Lieskovan, et al, SITC 2018; AACR 2019
Exploratory Analysis of Tumor Responses Post-VaccinationChanges in tumor measurements at week 12 vs. best response post-vaccination
-1
-0.75
-0.5
-0.25
0
0.25
0.5
0.75
1
Increase from Pre-Vaccination
% C
hang
e fr
om P
re-V
acci
natio
n Melanoma NSCLC Bladder
Decrease from Pre-Vaccination
Patients
100
75
50
25
-25
-50
-75
-100
0
31 August 2018
Continuing TreatmentPost-vaccine Response
34
Hu-Lieskovan, et al, SITC 2018; AACR 2019
87% of NEO-PV-01 peptides tested are mutant-specific Durability of immune response at 52 weeks noted in 4 of 6
patients
NEO-PV-01 + nivolumab induces neoantigen immune responses
100% of Patients Exhibit ex vivo Responses Via IFN-γ ELISpot
35Hu-Lieskovan, et al, SITC 2018; AACR 2019
Metastatic Melanoma Patient: M1
NEO-PV-01 induces neoantigen-specific CD8 T Cells that traffic to the tumor
Ex vivo Tetramer and TCR analysis
NEO-PV-01 + Nivolumab
0.17 %
RICTOR Neoantigen
Epitope
TCR 1
TCR 2
TCR 3
RICTOR TCRs in the Tumor Functional Characterization
TCR3 expressed in Jurkat cells is functionalTCR3 is found in the post-vaccine tumor
TCR Frequency %
1 38
2 24
3 21
NEO-PV-01 stimulated multiple neoantigen responses with 9 of the 15 immunizing peptides generating CD4 and CD8 responses in PBMCs post-vaccination.
Single cell TCR sequencing identifies three major RICTOR mutant reactive clones
Major TCR clones
36
• 57y female enrolled with stage M1c melanoma with liver and presacral masses • No prior systemic therapy for metastatic disease• Continues on study with stable disease for > 70 weeks
0 . 0 2 . 0 1 0 . 0
0
5 0
1 0 0
1 5 0
P e p t i d e C o n c e n t r a t i o n u M
IL-
2 (
pg
/ml)
J u r k a t + A 3 7 5 W T
M 1 T C R 3 ( J u r k a t ) + A 3 7 5 - B 5 1 : 0 1
M 1 T C R 3 ( J u r k a t ) + A 3 7 5 W T
Peptide Concentration μM
IL-2
(pg/
ml)
Hu-Lieskovan, et al, SITC 2018; AACR 2019
Neon 003: A Personal Cancer Vaccine (NEO-PV-01) and APX005M or Ipilimumab With Nivolumab in Patients With Advanced Melanoma
PICI0014/MCGRAW: Melanoma Checkpoint and Gut Microbiome Alteration With Microbiome Intervention (To be opened soon)
Immunotherapy Naïve MelanomaOpen Trials at Huntsman
SWOG S1801: A Phase II Randomized Study of Adjuvant Versus NeoAdjuvant MK-3475 (Pembrolizumab) for Clinically Detectable Stage III-IV High-Risk Melanoma
Patterns More Prevalent in
Unique Considerations
Strategies Examples
I: TMB High &Inflammation High
MelanomaCutaneous SCCMMR-d Cancers
• Plenty of neoantigens but may not be high quality
• Exhausted T cells• PD-1 is not the
main checkpoint• Intrinsic mutations
• Increase quality of neoantigens
• Decrease T cell Exhaustion• Other immune checkpoints• Tumor Intrinsic Resistance
(JAK1/2, B2M, WNT)• Improve TME• Microbiome?
Neoantigen vaccine
aCD137, aOX40,aGITR, aICOSaTIGIT, aTIM3, aLAG3TLR9 agonists? PEG IL2?
VEGFi, MAPKi, PI3Kgi, IDOi, …
II: TMB Medium &Inflammation Low to Medium
NSCLCHNSCCHCCGastric CA
• Not enough high quality neoantigens
• Defects in priming
• Increase quantity of neoantigens or exposure
• Increase T cell priming• Improve TME• Microbiome?
Oncolytic virus, TLR/STING agonists, hypomethylation agents, …aCTLA4, aCD40VEGFi, MAPKi, PI3Kgi, IDOi, …
III: TMB Low &Inflammation Low to None
MMR-p CRCPancreatic CAProstate CA
• Low or no neoantigens to trigger anti-tumor response
• All of the above• Engineered specificity• Improve TME• Microbiome?
All of the abovebi-specific, TCR/CAR ACTVEGFi, MAPKi, PI3Kgi, IDOi, …
Patterns of TME Biology and Potential Strategies
LOF mutation of JAK1/2 and B2M and intrinsic resistance to anti-PD1
Analysis of Mutational Burden and CD8 infiltration in 23 melanoma baseline biopsies treated by pembrolizumab
PDJ AmpliconDepth Ratio
Invasive Margin
Intra-tumoralCD
8D
ensi
ty
Homozygous LoF mutationin JAK1
Shin, et al. Cancer Discovery 2017
PDJ amplicon: PD-L1, PD- L2 and JAK2 amplification Jesse Zaretsky, Hu-Lieskovan
Mutational Burden is notassociated with response to pembrolizumab in cutaneous
melanoma
Melanoma cellor tumor macrophage
Interferon gamma
Summary of 4 Acquired Resistance CasesBaseline Max Response Relapse
Case #1
Case #2
Case #3
Case #4
Zaretsky, et al, NEJM 2016
Genetic Alteration
JAK1 LoF
JAK2 LoF
B2M LoF
Unkn
Melanoma cellor tumor macrophage
Interferon gamma
Melanoma cellor tumor macrophage
Interferon gamma
Slide Curtesy of Dr. Antoni Ribas
Tumor cell
T cell
Role of the Interferon-gamma Receptor Signaling Pathway and Antigen Presentation/B2M
B2MMHC class I
TCR-α TCR-βIFN-γ
P P
IFNGR2
JAK2JAK1
PD-L1
PD-1
GASP
P
Anti-Proliferative Pro-Apoptotic Genes
TAP 1/2 LAMP PSMB 8,9,10
CXCL 9,10,11
MHC
ICAM-1
IFNGR1
STAT1STAT1
PD-L1IRF1
CRISPR screen:Manguso… Haining, Nature 2017Patel… Restifo, Nature 2017
APLNR
PTPN2
Slide Curtesy of Dr. Antoni Ribas
• Siwen Hu-Lieskovan, MD, PhDHuntsman Cancer Institute
• Rene Bernards, PhDThe Netherlands Cancer Institute
Interrogation of Resistance Mechanisms to Checkpoint Inhibitors Using Functional Genomics
Approach/Current Status
Baseline Biopsy
DNA extractionWES – Baseline Mutation
DNA extractionWES - Normal
Research BloodProgression
Biopsy
DNA extractionWES – Additional Mutation
PD-1 checkpoint inhibitors
Acquired Resistance Gene Screening
Step 1 – Acquired Resistance: • 14 cases of paired melanoma
samples • Initial response then progression• Compare mutations at progression
to baseline• 197 genes were identified by priority
score criteria 1-3 and sent to RenePriority Scores:
• 1: Mutation occurred more than once at progression (28)
• 2: Mutation occurred only at progression and are homozygous (33)
• 3: Mutations that were heterozygous at baseline and become homozygous on progression (136)
Generate custom CRISPR library1533 gRNAs
197 candidate IO resistance genes
Melanoma cellsco-cultured with T-cells
+ T-cells- T-cells
Identifying the enriched gRNAs
In vitro screen for immune-escape genes:Testing candidates from sequenced patient samples
197 candidate genesin vitro screen
28 top hit genes
In vivo screen
Patterns More Prevalent in
Unique Considerations
Strategies Examples
I: TMB High &Inflammation High
MelanomaCutaneous SCCMMR-d Cancers
• Plenty of neoantigens but may not be high quality
• Exhausted T cells• PD-1 is not the
main checkpoint• Intrinsic mutations
• Increase quality of neoantigens
• Decrease T cell Exhaustion• Other immune checkpoints• Tumor Intrinsic Resistance
(JAK1/2, B2M, WNT)• Improve TME• Microbiome?
Neoantigen vaccine
aCD137, aOX40,aGITR, aICOSaTIGIT, aTIM3, aLAG3TLR9 agonists? PEG IL2?
VEGFi, MAPKi, PI3Kgi, IDOi, …
II: TMB Medium &Inflammation Low to Medium
NSCLCHNSCCHCCGastric CA
• Not enough high quality neoantigens
• Defects in priming
• Increase quantity of neoantigens or exposure
• Increase T cell priming• Improve TME• Microbiome?
Oncolytic virus, TLR/STING agonists, hypomethylation agents, …aCTLA4, aCD40VEGFi, MAPKi, PI3Kgi, IDOi, …
III: TMB Low &Inflammation Low to None
MMR-p CRCPancreatic CAProstate CA
• Low or no neoantigens to trigger anti-tumor response
• All of the above• Engineered specificity• Improve TME• Microbiome?
All of the abovebi-specific, TCR/CAR ACTVEGFi, MAPKi, PI3Kgi, IDOi, …
Patterns of TME Biology and Potential Strategies
Taking advantage of effective systemic therapy
Combination with Chemotherapy/VEGF inh/MAPKi:• Keep up with rapid tumor growth• Expose more tumor antigen• Modulate tumor immune environment
Decreased immune suppressive factor release
(IL1, IL6, IL8, VEGF)
Activation of T cells and increased homing
Koya, Mok et al. Cancer Res 2012Callahan et al. Cancer Imm Res 2014
BRAFi
Knight et al. J Clin Inv 2013Liu et al. Clin Cancer Res 2013
DC
Increased antigen Cross-presentation
Increased direct antigen presentation
How can BRAF targeted therapy increase the activity of tumor immunotherapy?
BRAF BRAFi
Boni, A., et al. (2010) Cancer Res. Callahan, M. K., et al. (2014) Cancer Immunol Res. Comin-Anduix, B., et al. (2010) Clin Cancer Res. Cooper, Z. A., et al. (2013) Oncoimmunology. Donia, M., et al. (2012) Oncoimmunology. Du, J., et al. (2003) Am J Pathol. Frederick, D. T., et al. (2013) Clin Cancer Res. Gray-Schopfer, V.C et al (2007) Cancer Res. Ho, P. C., et al. (2014) Cancer Res. Hong, D. S., et al. (2012) Clin Cancer Res. Kamata, T., et al. (2013) Mol Cancer Res. Khalili, J. S., et al. (2012) Clin Cancer Res. Knight, D. A., et al. (2013) J ClinInvest. Kono, M., et al. (2006) Mol Cancer Res. Kortum, R. L., et al. (2013) Trends Immunol. Koya, R. C., et al. (2012) Cancer Res. Lindau, D., et al. (2013) Immunology. Long, G. V., et al (2013) Pigment Cell Melanoma Res. Liu, C., et al. (2013) Clin Cancer Res. Oberholzer, P. A., et al. (2012) J Clin Oncol. Robert, C., et al. (2011) Curr Opin Oncol. Sanchez-Laorden, B., et al. (2014) Sci Signal. Sapkota, B., et al. (2013) Oncoimmunology. Schilling, B., et al. (2013) ncoimmunology. Schilling, B., et al. (2014) Ann Oncol. Schilling, B., et al. (2013) IntJ Cancer. Su, F., et al. (2012) N Engl J Med. Vella, L. J., et al. (2014) Cancer Immunol Res. Vosganian, G. S., et al. (2012) J Immunother. Wilmott, J. S., et al. (2014) J Immunol. Wilmott, J. S., et al. (2012) Clin Cancer Res. Yang, L., et al. (2004) Cancer Cell.
Slide Curtesy of Dr. Antoni Ribas
Enhanced in vivo antitumor activitypmel-1 ACT + dabrafenib and/or trametinib
Dabrafenib and trametinib were kindly provided by Drs. Tona Gilmer, Li Liu and Jeff Legos through an MTA with GSK
C57 BL/6 mouse
ACT i.v. activated T cells
w gp100
TBI900 cGy
BMT
D0: SM1 tumors.c.(BRAFV600E)
High dose IL-2 i.p.
Drug Tx, daily oral gavageSix groups (N=6):Pmel ACT+Vehicle (V)Pmel ACT+D30Pmel ACT+T0.6Pmel ACT+D30+T0.6C57 ACT +V C57 ACT +D30+T0.6
C57 BL/6 mice with nonspecific TCR
ACT i.v. activated T cells
w CD3, CD28
Pmel-1 transgenic mice with gp100 TCR
Hu-Lieskovan et al. Science Translational Medicine 2015
Hu-Lieskovan et al. Sci Transl Med. 2015
NIH Director’s Blog*Knocking Out Melanoma: Does This Triple Combo Have What It Takes?Posted on March 31, 2015 by Dr. Francis Collins Comment on: Hu-Lieskovan S, et al. Sci Transl Med. 2015;7:279ra41.
*Available at: https://directorsblog.nih.gov/2015/03/31/knocking-out-melanoma-does-this-triple-combo-have-what-it-takes/. Accessed on August 18, 2016.
Combination of BRAFi+MEKi+Anti-PD-1
Clinical Trials Combining BRAFi+MEKi+anti-PD-1/L1dabrafenib+trametinib
+durvalumab
Ribas et al. J Clin Oncol (Meeting Abstracts) May 2015 vol. 33 no. 15_suppl 3003
Ribas et al. J Clin Oncol 34, 2016 (suppl; abstr 3014).
†
-1 0 0
-8 0
-6 0
-4 0
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8 0
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rom
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0 1 0 2 0 30 4 0 5 0 6 0 70-1 00
-75
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dabrafenib+trametinib+pembrolizumab
vemurafenib+cobimetinib+atezolizumab
Hwu et al. Annals of Oncology 27 (Supp 6); 2016: Abstract 1109PD.
Slide Curtesy of Dr. Antoni Ribas
Combining immunotherapy and targeted therapy?Immunotherapy Targeted therapy
Perc
ent a
live
Perc
ent a
live
1 2 30 1 2 30
Combination
Perc
ent a
live
1 2 30
?
• 1+1=2 or >2?• Double or triple? Quadruple?• Combination upfront or lead in?• Sequenced? • Intermittent?• Safety/Toxicity?
Patterns More Prevalent in
Unique Considerations
Strategies Examples
I: TMB High &Inflammation High
MelanomaCutaneous SCCMMR-d Cancers
• Plenty of neoantigens but may not be high quality
• Exhausted T cells• PD-1 is not the
main checkpoint• Intrinsic mutations
• Increase quality of neoantigens
• Decrease T cell Exhaustion• Other immune checkpoints• Tumor Intrinsic Resistance
(JAK1/2, B2M, WNT)• Improve TME• Microbiome?
Neoantigen vaccine
aCD137, aOX40,aGITR, aICOSaTIGIT, aTIM3, aLAG3TLR9 agonists? PEG IL2?
VEGFi, MAPKi, PI3Kgi, IDOi, …
II: TMB Medium &Inflammation Low to Medium
NSCLCHNSCCHCCGastric CA
• Not enough high quality neoantigens
• Defects in priming
• Increase quantity of neoantigens or exposure
• Increase T cell priming• Improve TME• Microbiome?
Oncolytic virus, TLR/STING agonists, hypomethylation agents, …aCTLA4, aCD40VEGFi, MAPKi, PI3Kgi, IDOi, …
III: TMB Low &Inflammation Low to None
MMR-p CRCPancreatic CAProstate CA
• Low or no neoantigens to trigger anti-tumor response
• All of the above• Engineered specificity• Improve TME• Microbiome?
All of the abovebi-specific, TCR/CAR ACTVEGFi, MAPKi, PI3Kgi, IDOi, …
Patterns of TME Biology and Potential Strategies
Intra-tumoral T-VEC (oncolytic virus) plus systemic pembrolizumab induces high response rates by increases in tumor CD8 infiltration
T-VEC T-VEC+ pembro
Ribas et al. Cell 2017 Sep 7; 170 (6): 1109-1119.e10.
–100
–75
–50
–25
0
25
50
75
100
Stage IV M1c (N = 8)Stage IV M1b (N = 4)Stage IV M1a (N = 2)Stage IIIC (N = 6)Stage IIIB (N = 1)N = 21
Perc
enta
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hang
e fro
m B
asel
ine
Pembrolizumab
6
T-VEC Intralesional
1 30Wk:
62% objective response rate33% complete response rate
Slide Curtesy of Dr. Antoni Ribas
S1607: A Phase II Study of Combining T-VEC and Pembrolizumab in Patients With
Advanced Melanoma Who Have Progressed on Anti-PD1/L1 Based Therapy
• Primary Objective: DRR• Secondary Objectives: ORR, PFS, OS, toxicity
Study Chair and Translational Lead: Siwen Hu-Lieskovan, MD, PhD
Statisticians: Mike Wu, PhD; James Moon
Protocol Coordinator: Danae Campos
Open at Huntsman!
S1607 "A Phase II Study of Combining T-VEC (NSC-785349) and Pembrolizumab (NSC-776864) in Patients with Advanced Melanoma who
have Progressed on Anti-PD1/L1 Based Therapy." (NCT#02965716)
PI: Siwen Hu-Lieskovan, MD, PhD
i.v. anti-PD-1i.t. TVEC
+ i.v. anti-PD-1
10/10/18
12/12/18
Antoni Ribas, Grace Cherry, UCLA
S1607: T-VEC and Pembrolizumab for Melanoma after Anti-PD1/L1
Direct Tumor Lysis
Release of Progeny Viruses
Induced IFN ReleaseUp-RegulatedPD1/PD-L1?
Enhanced Innate Immune Response
Attract DC /Antigen cross-presentation
Acquired Immune Response- Increased CD8 infiltration- Increased CD8 clonality- Increased CD8 activation- Decreased Tregs, Macrophage, MDSC?- Decreased immune suppressive
cytokines? (TGFβ, IL10, etc)
Un-injected Tumor Peripheral Blood
Released Progeny Viruses?
Enhanced Innate Immune Response
Acquired Immune Response- Increased activated CD8 - Increased CD8 clonality- Increased DC?
Injected Tumor
Patterns More Prevalent in
Unique Considerations
Strategies Examples
I: TMB High &Inflammation High
MelanomaCutaneous SCCMMR-d Cancers
• Plenty of neoantigens but may not be high quality
• Exhausted T cells• PD-1 is not the
main checkpoint• Intrinsic mutations
• Increase quality of neoantigens
• Decrease T cell Exhaustion• Other immune checkpoints• Tumor Intrinsic Resistance
(JAK1/2, B2M, WNT)• Improve TME• Microbiome?
Neoantigen vaccine
aCD137, aOX40,aGITR, aICOSaTIGIT, aTIM3, aLAG3TLR9 agonists? PEG IL2?
VEGFi, MAPKi, PI3Kgi, IDOi, …
II: TMB Medium &Inflammation Low to Medium
NSCLCHNSCCHCCGastric CA
• Not enough high quality neoantigens
• Defects in priming
• Increase quantity of neoantigens or exposure
• Increase T cell priming• Improve TME• Microbiome?
Oncolytic virus, TLR/STING agonists, hypomethylation agents, …aCTLA4, aCD40VEGFi, MAPKi, PI3Kgi, IDOi, …
III: TMB Low &Inflammation Low to None
MMR-p CRCPancreatic CAProstate CA
• Low or no neoantigens to trigger anti-tumor response
• All of the above• Engineered specificity• Improve TME• Microbiome?
All of the abovebi-specific, TCR/CAR ACTVEGFi, MAPKi, PI3Kgi, IDOi, …
Patterns of TME Biology and Potential Strategies
Unresectable orMetatastic Melanoma
• Previously untreated
• 945 patients
CA209-067: Study Design CheckMate 067: Study Design
Treat until progression orunacceptable
toxicity
NIVO 3 mg/kg Q2W +IPI-matched placebo
NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO
3 mg/kg Q2W
IPI 3 mg/kg Q3W for 4 doses +
NIVO-matched placebo
Randomize1:1:1
Stratify by:
• BRAF status
• AJCC M stage
• Tumor PD-L1 expression <5% vs ≥5%*
N=314
N=316
N=315
Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone*
*The study was not powered for a comparison between NIVO and NIVO+IPI
Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)
CheckMate 067: Overall SurvivalNivo OR Nivo+Ipi vs Ipi
Tx Naïve Melanoma
AACR 2017 (Checkmate 067)
Caveats:1. Not powered to compare Nivo
arm to Nivo+Ipi arm2. Pts on single agent Nivo arm can
have Ipi after being off trial.
Data suggests:1. Ipi after Nivo might have similar
efficacy but avoid significant toxicity
2. Checkmate 012 in NSCLC suggests combining with lower dose of ipi with less frequency reduces toxicity and might improve efficacy
Grade 3/4 tox:59%21%
28%
S1616: A Phase II Randomized Study of Nivolumab With Ipilimumab or Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD1
or Anti-PD-L1 Agent (NCT03033576)
Study Chair: Ari Vanderwalde, MDStatisticians: Mike Wu, PhD; Michaella Latkovic-TaberProtocol Coordinator: Danae Campos
Primary objective– Combination will be considered superior to single-
agent ipilimumab if PFS is doubled from 3 to 6 months
– 1:3 randomization (to ensure adequate numbers for major secondary objective)
– 63 patients randomized to receive combination, 21 patients randomized to receive ipilimumab alone
– One sided alpha of 10%, power of 90%
Open at Huntsman!
Unique Challenges with Clinical Testing of Combination Immunotherapy
• Unique toxicity profile– Spectrum different from agent to agent– MTD vs MAD? Need to leverage with biological efficacy– Timing of irAE can be late– More challenging when combine with traditional cytotoxic agents or targeted
therapy (different DLT window)
• How to evaluate response, which can be delayed or mixed– RECIST? irRC? iRECIST?– Pt can benefit from treatment after discontinuation due to toxicity
• What is the best measure of clinical outcome/benefit – ORR, PFS? OS, DRR, DCR?
Draft iMATCH Protocol Design
Baseline Biomarker
Assessment TMBhi/Inflammationhi
TMBhi/Inflammationlo
TMBlo/Inflammationhi
TMBlo/Inflammationlo
CR/PR/SD
PDPrimary
Resistance
PDAcquired
Resistance
Anti-PD1
Baseline Biopsy
CPI-naive(Histology-agnostic or Selected tumors)
Regimen 1, 2, …
PD Biopsy
Or Regimen X based on different biomarker(s)
PD Biopsy*
Combo Partners (examples) 1. aCTLA42. TVEC/TLR9/Sting agonist3. Pegylated IL-24. 41BB/OX40 agonists5. VEGF inhibitor6. IDO inhibitor7. Microbiome Modulation8. Bispecific9. Epigenetic modulator10. aLAG3/aTIGIT/aTIM311. Targeted Agents12. ……
Study Entry Study Entry
Study Entry
* For primary resistance, Biomarker triage is based on baseline biopsy sample analysis. PD (progression of disease) biopsy is done for retrospective research.
Tumor CellsTurn on Engine
Neoantigen QuantityChemoRadiationEpigenetic Modulation
Neoantigen QualityTAA VaccineNeoantigen VaccineEngineered specificity
Antigen Presentation/ T Cell PrimingDC vaccineOncolytic virusTLR/STING agonistsCytokinesAnti-CTLA4Anti-CD40
Fuel the TankAnti-GITRAnti-41BB/CD137Anti-OX40Anti-ICOS
Take Away BarrierIDO InhibitorCSF1R inhibitorAdenosine R inhibitorTGFβ inhibitorVEGF inhibitorPI3Kg inhibitorMicrobiome Modulation
Block the Stop SignAnti-PD-1/L1Anti-TIM3, Anti-LAG3Anti-TIGIT
T Cells
Strategies To Overcome Resistance
Multi-histology IO Trials open at HCIAgency: Astellas (8374-CL-0101)Complete Title: A Phase 1b Study of ASP8374, an Immune Checkpoint Inhibitor, as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors. (Anti-TIGIT + pembrolizumab)
Agency: Xencor (DUET-2)Complete Title: A Phase 1 Multidose Study to Evaluate the Safety and Tolerability of XmAb®20717 in Patients with Selected Advanced Solid Tumors. (Bispecific Antibody: CTLA4-PD1)
Agency: Xencor (DUET-3)Complete Title: A Phase 1 Multiple-Dose Study to Evaluate the Safety and Tolerability of XmAb®23104 in Subjects With Selected Advanced Solid Tumors. (Bispecific Antibody: ICOS-PD1)
Agency: Xencor (DUET-4)Complete Title: A Phase 1 Multiple-Dose Study to Evaluate the Safety and Tolerability of XmAb®22841 Monotherapy and in Combination With Pembrolizumab in Subjects With Selected Advanced Solid Tumors. (Bispecific Antibody: CTLA4-LAG3 + pembrolizumab)
Agency: Merck (MK1454-001)Complete Title: Phase 1 Open-label, Multicenter Study of MK-1454 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas (Sting Agonist MK-1454)
Agency: Merck (3475-001)Complete Title: A Phase 1/1b, Open-label Clinical Study of Intratumoral/Intralesional Administration of V938 in Combination with Pembrolizumab (MK-3475) in Participants with Advanced/Metastatic or Recurrent Malignancies (New Generation Oncolytic Virus)
Agency: BioAtla (BA3011-001)Complete Title: A Phase 1/2 Dose Escalation and Dose Expansion Study of BA3011 in Patients with Advanced Solid Tumors (CAB-AXL-ADC)
Agency: BioAtla (BA3021-001)Complete Title: A Phase 1/2 Dose Escalation and Dose Expansion Study of BA3021 in Patients with AdvancedSolid Tumors (CAB-ROR2-ADC)
Conclusions/Take-Away• Immunotherapy for cancer has the potential to provide durable
benefit to a wide array of patients.
• Successful development of Combination Immunotherapy strategies relies on --• A clear understanding of the heterogeneity of the immune
resistant mechanisms that exists in each patient • Successful development of predictive biomarkers• Collaborative effort of the entire academia, industry and
regulatory authorities
Acknowledgments
Tom G. Graeber, PhD
Roger S. Lo, MD, PhD
Zeynep ErogluMD
Blanca HominMeleno MD
Richard KoyaMD, PhD
Stephen MokPhD
John Glaspy, MD
Robert M. PrinsPhD
Antoni RibasMD, PhD
Edward Garon, MD
Jesse Zaretsky PhD
Jennifer TsoiPhD
Catie GrassoPhD
Ribas Research Group
Clinical Trial Group
Special ThanksOncology Division:Lynn Henry, MD
Saundra Buys, MDNeeraj Agarwal, MDWally Akerley, MD
Ignacio Garrido-Laguna, MDJohn Ward, MD
Elaine VolckmannKaylene, Wayman
Melanoma DOT:Doug Grossman, MDSherry Holman, PhDJohn Hyngstrom, MDKen Grossmann, MD
Ben Voorhies, MDAllie Grossmann, MDTawnya Bowles, MD
Glen Bowen, MDMatthew Van Brocklin, PhD
Mark Hyde, PhD, PA-CElizabeth Flores, PA-C
Mindy Stone
HCIMary Beckerle, PhD
Neli Ulrich, PhDMartin McMahon, PhD
Brad Cairns, PhDJohn Sweetenham, MD
Alana Welm, PhDAshlee BrightLisa AndersonChris Bretones
Matt IsomNia SherarMark Oberg
Andrew IntveldJen HeningerCarolyn Ross
Kimberly SimmonsJoey ParkerElle Oldfield
Dian BretonesDebbie ArnoldMiriam Allen
Melanoma Clinic:Carolyn Lockett, RVN
Jordan McPherson, PharmDDan Sageser, PharmD
Lorena CannonSean Calvert
Christy HortonKimberly LindsaySamantha HoltJulie Nielsen
TCC/BMP:Mikaela Larson
AnnaLeah LarsonAndy Lee
Glenda PeckJames ClineDavid LumPenny Noel
Hu-Lieskovan Lab:Yoko Derose, PhD
Clinical Trial Office:David Gaffney, MD
Theresa Werner, MDJessica Moehle
Elizabeth ConstantzSusan Sharry
Tamara Willis, CRNAndrew Grandemange
Alex JonesCarolynn HunterCristy Johnston
Trevor Gordon, JDAlex Lenzen
IST Team:Kelli Thorne
Jenniffer PearceSusan ClementKarthik SontyLisa Dubler
Grant Office:Callie Martens
Kristi Smith
Acknowledgements
Tower Cancer Research Foundation
Career Development Award
UCLA CTSI KL2 Award
SWOG Dr. Charles Coltman AwardSWOG ITSC Pilot Award
MRA Young Investigator Award
ASCO Young Investigator AwardASCO Career Development Award
SU2C/AACR Phil Sharp Innovation in Collaboration Award