raising the tail of cancer survival curves with immunotherapy...2017:1558. 14. schachter j et al...

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



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


Tumor

Tumor cell

MHCTCR

Dendritic cell CTLA-4



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


CTLA-4



TME

Naïve T cell

Activated T cell


Lymph node

Signal 1

Signal 2

Tumor cell

Tumor

MHC TCR

MHC

B7

TCR

PD-L1PD-1

IFN-gamma

Dendritic cell

CD28


CTLA-4



TME

Naïve T cell

Activated T cell


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


CTLA-4



TME


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!

https://www.cancer.gov/news-events/cancer-currents-blog/2018/desmoplastic-melanoma-checkpoint-inhibitors?cid=eb_govdel

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

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


NT-001: Patient Demographics

3131 August 2018


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


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)


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



Strategies Examples









Neoantigen vaccine
















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


Interferon gamma


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


• 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



Strategies Examples









Neoantigen vaccine
















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.


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

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=DD980VZPgN6nfM&tbnid=_ls8Dqr2DtFncM:&ved=0CAUQjRw&url=http://jaxmice.jax.org/strain/002407.html&ei=09owUoKTKaGTiQLW54GYAw&bvm=bv.52109249,d.cGE&psig=AFQjCNGcEFM5XHDwhBGiWE77BgR3sMXWQQ&ust=1379019712922677

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

https://directorsblog.nih.gov/2015/03/31/knocking-out-melanoma-does-this-triple-combo-have-what-it-takes/

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

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

Ch

an

ge F

rom

Ba

selin

e in

Su

m o

fL

on

ges

t D

iam

ete

r o

f Targ

et

Les

ion

, %

0 1 0 2 0 30 4 0 5 0 6 0 70-1 00

-75

-50

-25

0

25

50

75

1 00

T im e , w e e k s

Ch

an

ge

Fro

m B

as

eli

ne,

%

dabrafenib+trametinib+pembrolizumab

vemurafenib+cobimetinib+atezolizumab

Hwu et al. Annals of Oncology 27 (Supp 6); 2016: Abstract 1109PD.


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?



Strategies Examples









Neoantigen vaccine
















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

ge C

hang

e fro

m B

asel

ine

Pembrolizumab

6

T-VEC Intralesional

1 30Wk:

62% objective response rate33% complete response rate


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



Strategies Examples









Neoantigen vaccine
















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

raising the tail of cancer survival curves with immunotherapy...2017:1558. 14. schachter j et al...

Documents