Immuno-Oncology: A Colloquium on the State of the Science for Oncology Clinicians

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Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest

Jedd D. Wolchok, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Consultant, Bristol-Myers Squibb Company.

Mary (Nora) L. Disis, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, Bristol-Myers Squibb Company, EMD Serono, Inc., Immunovaccine, Inc., Hoffmann-La Roche, Inc., VentiRX Pharmaceuticals; Contracted Research, GlaxoSmithKline plc.; Ownership Interest, Epigenomics AG.

Charles G. Drake, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Royalty, Amplimmune, Inc., Bristol-Myers Squibb Company; Receipt of Intellectual Property Rights/Patent Holder, Amplimmune, Inc., Bristol-Myers Squibb Company; Consultant, Bristol-Myers Squibb Company, Dendreon Corporation, Pfizer, Inc.; Ownership Interest, Amplimmune, Inc.

John Powderly II, MD, CPI, reported a financial interest/relationship or affiliation in the form of: Receipt of Intellectual Property Rights/Patent Holder, BioCytics®; Consultant, Amplimmune, Inc., Bristol-Myers Squibb Company; Speakers' Bureau, Bristol-Myers Squibb Company; Contracted Research, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech, Inc.; Ownership Interest, BioCytics®.

Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest

Antoni Ribas, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Consultant, Amgen, Inc., Celgene Corporation, Genentech- A member of the Roche Group, GlaxoSmithKline plc., Millennium Pharmaceuticals, Inc., Prometheus.

Scott N. Gettinger, MD, has no real or apparent conflicts of interest to report.

Mario Sznol, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, Anacor Pharmaceuticals, Inc., BeiGene LTD, Bristol-Myers Squibb Company, Genesis Biopharma, Necktar Pharmaceuticals Inc., Prometheus; Ownership Interest, Genesis Biopharma.

5

Welcome and IntroductionWelcome and Introduction

Jedd D. Wolchok, MD, PhDMemorial Sloan-Kettering Cancer Center

Immuno-Oncology: Immuno-Oncology: The Biological FoundationsThe Biological Foundations

Mary L. Disis, MDUniversity of Washington School of Medicine

Immuno-Oncology:Immuno-Oncology:The Biological FoundationsThe Biological Foundations

The immune system

Cancer and the immune system

The basics of immune therapy

CHARACTERISTICS INNATE ADAPTIVE

Specificity Non-Specific Specific

Antigens Not Needed Required

Memory None Generated

Time Course Immediate Slowly Developing

Duration Transient Lifelong

Cell Types MØ, DC, NK, Neutrophil

T Cells, B Cells

T cell (orange) killing a cancer cell (magenta)

First Line of DefenseImmune Sensors

Effectors

The Immune SystemThe Immune System

MØ = macrophages; DC = dendritic cell; NK = natural killer cell.Alberts et al, 2002; Murphy et al, 2008.

Neutrophil

Dendritic Cell

Macrophage

Natural Killer Cell

ADCC = antibody-dependent cell-mediated cytotoxicity; MHC = major histocompatibility center; IFN = interferon; CTL = cytotoxic T lymphocytes.Alberts et al, 2002; Murphy et al, 2008.

Cells of the Innate Immune SystemCells of the Innate Immune SystemPhagocytosis and debris clean upSecrete chemokines that call in other innate immune cells

Potent antigen presenting cells (APC)Uptake and process antigenBoth “class I” and “class II” pathwaysWill stimulate both CTL and T helper (Th) cells

Phagocytosis and cleaning up debris,secrete cytokinesType 1 can turn on adaptive immunityType 2 will limit adaptive immunity

Can directly kill tumor without docking to MHCSecrete high levels of IFN-gamma (critical cytokine)Antibodies can activate them via FC receptor (ADCC)

Cells of the Adaptive Immune SystemCells of the Adaptive Immune System

PMN = polymorphonuclear leukocyt.Kumar, et al 2007.

Humoral Immunity Cellular Immunity

Extracellular microbes (e.g., bacteria)

B lymphocytesB

B

TSecretedantibody

Neutralization

Lysis (complement)

Phagocytosis(PMN, macrophage)

Intracellular microbes (e.g., viruses)

Antigen-presenting cell

HelperT-cell

T-cellreceptor

Processed and presented antigen

Cytokines

CytokinereceptorProliferation and

activation of effector cells

(cytotoxic T-cells, natural killer cells,

macrophages)

Lysis of infected cell

Critical Link Between Innate and Critical Link Between Innate and Adaptive ImmunityAdaptive Immunity

TCR = T cell receptor; TLR = Toll-like receptors.Bevan, 2004.

Apoptotic cell

Necrotic cell

Pathogen

Immaturedendritic cell

Immaturedendritic cell

TLR

Activation

Activation

Maturedendritic cell

CD8

CD8+T-cell

CD4+T-cell

CD4TCRMHC II

CD40L

CD40MHC I

• Activation• Proliferation• CTL generation

IL = Interleukin; TNF = tumor necrosis factor; TGF = transforming growth factor.DeNardo et al, 2010.

The Immune System Is All About The Immune System Is All About ““Checks and BalancesChecks and Balances””

NK/NKT TH1 TH17 TH17 B cell TH2 TREG

Tumor Regression Tumor Progression

Angiostatic Pro-angiogenic

Directcytotoxicity

Tissueremodeling

Immunesurveillance

Immunesuppression

Myeloid Phenotype

Regulatory loops

IL-12, IL-2, IFN-g, TNF-a IL-4, IL-5, IL-10, TGF-b

N2 M2 DC2DC1 M1 N1


The immune system



Steps in Stimulating Cancer Specific ImmunitySteps in Stimulating Cancer Specific Immunity

Melanoma

“Danger”e.g. HSP

IFN-α

MAGE IMARTI(TAAs)

Immature DC

Activated mature DC

Migration to lymph node

Lymph node

Migration fromlymph node

CD8CD4

DC

CD4TH

CD8CTL

APCCD40

CD40

B7

TCR

MHC I

CD28 CD40

CD40L

TCRMHC II

CD40L

CD40

B7CD28

Helpe.g. IL-2

MIP-1α= macrophage inflammatory protein 1α.Vanderlught et al, 2002.

Epitope Spreading Is the Endpoint of an Epitope Spreading Is the Endpoint of an Effective Immune Response in CancerEffective Immune Response in Cancer

237 breast cancers MVA: Density of Treg+ in ER+ tumors predictor of survival

Type I Inflammation Modulation of Self-Regulation

186 advanced ovarian cancers MVA: Intratumoral T cells independent predictor survival

High Density of T CellsPenetrating Tumor

75 colorectal cancers 7 gene classifier Inverse correlation of gene expression and relapse

MVA = multivariate regression analysis; ER+ = estrogen receptor positive; Treg = regulatory T cells.Galon et al, 2006; Zhang et al, 2003; Bates et al, 2006.

What Is Needed for Clinical Effective What Is Needed for Clinical Effective Antitumor Immunity?Antitumor Immunity?

Murine breast tumor

after activating the

Immune system

Murine TNBC

Murine ER+ BC

CD4

FO

XP

3

Murine TNBC

Murine ER+BC

VEGF = vascular endothelial growth factor; CT = center; IM = invasive margin.Bindea et al, 2010.

Optimal Immune ReactionOptimal Immune Reaction

Many cancer patients have demonstrated an “optimal immune reaction”

Lake et al, 2005; Cheever et al, 2009.

Foreign Antigens

Self Antigens

LMP2 HER2 GD2

HPV WT1 CEA

HepB MUC1 MART-1

MAGE A2 gp100

NY-ESO-1 PR1

PSMA Tyrosinase

PSA PAP

PSCA NA17

Antigens Associated With Clinical Response

What Does the Immune System What Does the Immune System See in Cancer?See in Cancer?

Dangerous• Cell damage (uric acid)• Innate immunity activated• TLRs triggered • Inflammation• Cytokines• CD40 signals• Others

Weak• No danger signals• No CD40 signals• Pro- inflammatory cytokines

Tolerizing• None of these signals

Cell and Self Protein Only

Cell and Tumor Antigen

Cell and Virus

Why Do Most Tumors Evade Why Do Most Tumors Evade Immune Recognition?Immune Recognition?

Murphy et al, 2008.

Foxp3 = forkhead box P3.Fridman et al, 2011; Disis, 2010a.

Multiple Factors Impact the Multiple Factors Impact the Tumor Immune Microenvironment Tumor Immune Microenvironment

Pro-Tumorigenic Inflamation

AnticancerImmunosurveillance

Cell Types M2 macrophagesMyeloid-derived suppressor cells NeutrophilsFoxp3+ T reg. Th17 cells

Dendritic cellsM1 macrophagescytotoxic CD8+ T cells with a memory effector phenotype

Cytokine Profiles

Th2, Th17 Th1CX3CL1CXCL9, CXCL10

Distribution Peritumoral Intratumoral, close to cancer cells, as well as in the invasive front

Associated Features

Stat3 phosphorylation High endothelial venules

Functional Impact

Negative prognostic impact Positive prognostic and predictive impact


The immune system



PASSIVE ACTIVE

Transferred Generated

Ready Made Must Be Developed

Immediate Protection Takes Time

No Memory Long Lived

Immune System May Function Poorly

Requires Functional Immune System

Ig Infusions, Some MoAB Therapy, T-Cell Transfer

Vaccines, Anti-CTLA-4

Types of Types of ImmuneImmune Therapy Therapy

Ig = immunoglobulins; MoAB = monoclonal antibody; CTLA-4 = cytotoxic T-lymphocyte antigen-4. Murphy et al, 2008.

HER-2/neu = human epidermal growth factor receptor 2.Ferris et al, 2010; Taylor et al, 2007; Ladoire et al, 2011.

Monoclonal Antibody Therapy: TrastuzumabMonoclonal Antibody Therapy: Trastuzumab

Time (Weeks)

50% response rate20/93 complete responders

Adoptive T Cell TherapyAdoptive T Cell Therapy

TIL = tumor-infiltrating lymphocytes; CR = complete response; PR = partial response; NR = no response; MART-1/ Melan-A = melanomaantigen recognized by T-cells, gp100 = glycoprotein 100; NY-ESO-1 = immunogenic peptide derived from the cancer-testis antigen.Topalian et al, 2011; Rosenberg et al, 2011.

Objective Response

34%-50%

49%-72%

13%-30%

0%-11%

Diversity

Specificity

Unfractionated TIL

Selected tumor- reactive TIL

TCR gene transfer (MART-1/Melan-A, gp100,NY-ESO-1)

Individual T cell clones (MART-1/Melan-A, gp100,NY-ESO-1)

po

lyclon

al

mo

no

clon

al

Factors Associated With Clinical Response

Tx = treatment.Disis, 2010b.

Immuno-Oncology: Immuno-Oncology: The Biological FoundationsThe Biological Foundations

T1

T2

Key TakeawaysKey Takeaways Innate immunity, our first responders that don’t require antigen recognition,

can support and enhance the efficacy of adaptive immunity cells that are specific to an invader

Therapeutic immunity can be either passive (supplying an antibody response) or active (vaccinating to create your won antibody response) which requires your immune system to do the work

There is strong evidence that most cancers stimulate the immune system

Efficacy of cancer-induced immunity is limited by both factors secreted by the tumor and stroma, but also normal defense mechanisms activated to prevent autoimmunity

Our improved understanding of tumor-immune system interactions has led to design of therapeutic approaches that both stimulate immunity and address mechanisms of immune escape

There are now several promising immunologic agents that have demonstrated significant antitumor efficacy in advanced stage clinical trials or have been approved for standard of care use

Audience Q&A:Audience Q&A:The Biological FoundationsThe Biological Foundations

of Immunotherapyof Immunotherapy


Immuno-Oncology: Immuno-Oncology: Genitourinary CancersGenitourinary Cancers

Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer

Center at Johns Hopkins

OutlineOutline

Cancer “Vaccines”

– Sipuleucel-T

– ProstVac VF

– Argos AGS-003

Immune Checkpoint Blockade

– Anti-CTLA-4, ipilimumab

– Anti-PD-1, BMS-936558 (MDX-1106)

– Phase III trial design

Combination Immunotherapy

– With androgen-ablation

– With TKIs

Integrating immunotherapy into the current (and future) prostate cancer treatment paradigm

PD-1 = programmed cell death protein-1; TKIs = tyrosine kinase inhibitors.

Cancer Vaccines:Cancer Vaccines:An Immunological MOAAn Immunological MOA

CD4 T Cell

TCR

CD8 T Cell

TCR Cytokines = HELP

Activated CD8 T Cells Traffic to Tumor and Lyse Tumor Cells

Class II MHC

Class I MHC

ActivatedDendritic Cell

Tumor Antigen

MOA = mechanism of action. Burch et al, 2000; Small et al 2000; Fong et al, 1997.

Patient WBC Harvested

Short-Term Culture With Protein “Cassette”

Shipping

Cells Infused BACK Into Patient (IV)

GM-CSF

PAP

Active Cellular Immunotherapy Active Cellular Immunotherapy Sipuleucel-TSipuleucel-T

WBC = white blood count; GM-CSF = granulocyte-macrophage colony stimulating factor;PAP = prostatic acid phosphatase; IV = intravenous.Burch et al, 2000; Small et al, 2000.

D9902B – IMPACTD9902B – IMPACTImmunotherapy Prostate Immunotherapy Prostate

Adenocarcinoma TreatmentAdenocarcinoma Treatment

Patients: Asymptomatic or minimally symptomatic mCRPC Primary end point: OS Secondary end point: TTP

mCRPC No Visceral

Mets N = 512

Sipuleucel-T q2wks x 3

RANDOMIZE

PROGRESSION

Physician’s Discretion

Eligible forSipuleucel-Ta

aPrepared from cryo-preserved lymphocytes.mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; TTP = time to progression.Kantoff et al, 2010a.

Placebo q2wks x 3

IMPACT OS: Primary End Point IMPACT OS: Primary End Point ITT PopulationITT Population

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Per

cent

Sur

viva

l

Survival (Months)

p = .032 (Cox model)HR = 0.775 [95% CI 0.614, 0.979]

Median Survival Benefit = 4.1 mos

Sipuleucel-T (n = 341)Median Survival = 25.8 mos

Placebo (n = 171)Median Survival = 21.7 mos

ITT = intent-to-treat; HR = hazard ratio; CI = confidence interval.Kantoff et al, 2010a.

PSA

LFA-3 ICAM-1 B7-1

Co-Stimulatory Molecules

Target Antigen

Plasmid DNA

Vaccinia VirusFowlpox Virus

rV-PSA-TRICOMrF-PSA-TRICOM

Packaging Cell Line

Vaccine

A Viral Vaccine Approach: ProstVac VFA Viral Vaccine Approach: ProstVac VF

DNA = deoxyribonucleic acid; PSA = prostate-specific antigen.Madan et al, 2009; Sonpavde et al, 2011.

Viral Vaccines – Same Idea:Viral Vaccines – Same Idea:But Starting At A Different StepBut Starting At A Different Step

ProstVac VFCD4 T Cell

TCR

CD8 T Cell

TCR

Class II MHC

Class I MHC

Epithelial Cells

Cell Death - Necrosis

ACTIVATED

CD8 T Cell

Madan et al, 2009; Sonpavde et al, 2011.

TBC-PRO-002 Survival DataTBC-PRO-002 Survival Data

CRPC = castration-resistant prostate cancer; TTP = time to progression.Kantoff et al, 2010b.

Design: Nearly identical to IMPACT but NO crossover

Patients: mCRPC with either no or minimal symptoms

Primary end point: TTP

Time (mos)

Prospect Trial: Design (SPA)Prospect Trial: Design (SPA)Phase III Global (US-CAN-AUS/WE/EE/Latin America) Phase III Global (US-CAN-AUS/WE/EE/Latin America)

Non/Minimally Symptomatic

mCRPC

Non/Minimally Symptomatic

mCRPC

PROSTVAC-(V)(F) TRICOM + Low-Dose Adjuvant GM-CSF

PROSTVAC-(V)(F) TRICOM + Low-Dose Adjuvant GM-CSF

Vector PlaceboAdjuvant Placebo Vector PlaceboAdjuvant Placebo

SURVIVAL

SURVIVAL

No Crossover

PROSTVAC-(V)(F) TRICOMAdjuvant Placebo

PROSTVAC-(V)(F) TRICOMAdjuvant Placebo

Standard of Care

Primary End Point: OS

SPA = special protocol assessment.US NIH, NCT01322490.

Kidney Cancer Sample

Leukapheresis Product

Intranodal Injection

TumorRNA Isolation

DC

Manufacture

Load DC With RNAAnd Activate

(AGS-003)

Cryopreserve

Using RNA to Load Dendritic CellsUsing RNA to Load Dendritic CellsArgos AGS-003Argos AGS-003

RNA = ribonucleic acid.Figlin et al, 2012.

ADAPT:ADAPT:Autologous Dendritic Cell Immunotherapy With AGS-003 Autologous Dendritic Cell Immunotherapy With AGS-003

Plus Sunitinib for the Treatment of Advanced RCCPlus Sunitinib for the Treatment of Advanced RCC

Primary end point: OS Secondary end point: PFS (30% increase), ORR, safety FDA approved the SPA for the phase III clinical study of AGS-003 for the treatment of

metastatic RCC Study has initiated and is expected to begin dosing patients in the second half of 2012

Metastatic, Unfavorable Risk Clear Cell RCC

N = 450

RANDOMIZE

AGS-003q3mos

1 Cycle Sunitinib(6 wks)

1 Cycle Sunitinib(6 wks)

Placeboq3mos

AGS-0035 dosesq3wks

Placebo5 dosesq3wks

Ongoing Sunitinib (4 wks on, 2 wks off)

RCC = renal cell carcinoma; ORR = overall response rate; PFS = progression-free survival.US NIH, NCT01582672.

T Cell

HLA

TCR

antigenSignal 1Signal 1

B7.1/2

CD28

Antigen Presenting Cell

Signal 2Signal 2

Normal T-Cell ActivationNormal T-Cell Activation

HLA = human leukocyte antigen.Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.

T Cell

HLA

TCR


B7.1/2

CD28


Signal 2Signal 2

CTLA-4

Immune Checkpoints (CTLA-4) Prevent Normal Immune Checkpoints (CTLA-4) Prevent Normal T-Cell ActivationT-Cell Activation

Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.

T Cell

HLA

TCR


B7.1/2

CD28


Signal 2Signal 2

CTLA-4

CTLA-4

Ipilimumab (Anti-CTLA-4) Blocks the CTLA-4 Ipilimumab (Anti-CTLA-4) Blocks the CTLA-4 Checkpoint, Restoring T-Cell ActivationCheckpoint, Restoring T-Cell Activation

Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.

CTLA-4 Blockade:CTLA-4 Blockade:(Ipilimumab, Tremelimumab)(Ipilimumab, Tremelimumab)

Single-agent activity

– RR = 15%–20%

Regressions = durable

Regressions = delayed

Grade III/IV SAE = 10%–15%

– Colitis

– Hypophysitis

PSA Responses in PC

(N = 200)

– 20%

RR = response rate; SAE = serious adverse event; PSA = prostate-specific antigen; PC = prostate cancer. Saenger et al, 2008; courtesy of Jedd D. Wolchok, MD, PhD.

Ipilimumab in Melanoma: The First Ipilimumab in Melanoma: The First ““DrugDrug”” Ever to Ever to Show a Survival Benefit in a Randomized Clinical TrialShow a Survival Benefit in a Randomized Clinical Trial

Hodi et al, 2010.

Years

Ipilimumab + gp100 (A)Ipilimumab + gp100 (A)Ipilimumab alone (B)Ipilimumab alone (B)gp100 alone (C)gp100 alone (C)

1 2 3 4

Comparison HR Comparison HR PP--valuevalue Arm A vs CArm A vs C 0.680.68 0.00040.0004 Arm B vs CArm B vs C 0.660.66 0.00260.0026 Arm A vs BArm A vs B 1.041.04 0.75750.7575

Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone

1-yr 44% 46% 25%

2-yr 22% 24% 14%

Randomized, Double-Blind, Phase III Trial Comparing Randomized, Double-Blind, Phase III Trial Comparing Ipilimumab Vs. Placebo Following Radiotherapy in Subjects Ipilimumab Vs. Placebo Following Radiotherapy in Subjects

With CRPC That Have Received Prior Treatment With With CRPC That Have Received Prior Treatment With Docetaxel (CA184-043)Docetaxel (CA184-043)

ICF, Baseline Assessments

Radiotherapy (8 gy) to bone metastases

Day -2 or -1

INDUCTION MAINTENANCE

Placebo Wks 1, 4, 7, 10

Placeboq12wks

Ipilimumab 10 mg/kg Wks 1, 4, 7, 10

Ipilimumab 10 mg/kgq12wks

TA: Wks 12, 24PSA: Wks 7, 12, 18, 24OA: Wks 7, 10, 12, 18, 24

IVRS

Day -28 to -2 Day -2 to Wk 24 Wk 24 to 48+

SCREENING

TA: q12wksPSA: q6wksOA: q12wks

CRPCPriorDocetaxel

N = 800

Completed Accrual 1/2012TA = tumor assessment; OA = outcome assessment; ICF = informed consent form; IVRS = interactive voice response system.US NIH, NCT00861614.

Immune Checkpoint Blockade 2: PD-1Immune Checkpoint Blockade 2: PD-1

T CellTumor Cell or


antigenHLA TCR

CTLA-4

PD-1B7-H1(PD-L1)

Signal 1

B7.1/2 CD28

Signal 2

LAG-3Class II MHC

Others: ICOS, GITR, Tim-3

Weber, 2010; Pardoll, 2012a.

Adaptive Immune Resistance

Tumor

OncogenicPathway

T Cell

TCR

PD-1

MHC + Peptide

PD-L1

Oncogene-Driven PD-L1Expression

Tumor

PD-L1

Adaptive Up-Regulation Of PD-L1 Turns T Cell OFF

Tumor

Interferon g

Immune Resistance: PD-1Immune Resistance: PD-1Innate Immune Resistance

Pardoll, 2012a.

T Cell T Cell

First BMS-936558 (MDX-1106) First BMS-936558 (MDX-1106) Phase I TrialPhase I Trial

PR or CR

Day 160 minute IV infusion 10mg/kgOptional tumor bx

Day 85 2 years Or until PD

SD or mixed response

Follow up every month x 2 then every 2 months,Re-treat on progression

2 doses 4 wks apart, follow 12 more weeks, can repeat

1st Treatment CycleFollow Up or Additional Treatment Cycle(s)

Day 29Optional tumor bx

Day 57

Scans

PR or CR

Day 160 minute IV infusion 10mg/kgOptional tumor bx

Day 85 2 years Or until PD

SD or mixed response

Follow up every month x 2 then every 2 months,Re-treat on progression

2 doses 4 wks apart, follow 12 more weeks, can repeat

1st Treatment CycleFollow Up or Additional Treatment Cycle(s)

Day 29Optional tumor bx

Day 57

Scans

SD = stable disease; MR = mixed response; PD = progression disease.Brahmer et al, 2010.

BMS-936558 (MDX-1106) BMS-936558 (MDX-1106) Phase I: SummaryPhase I: Summary

Toxicities (39 patients)

Grade 1: Pruritis, rash, fatigue

Grade 2:

– Polyarticular arthropathy, 2 patients (3 mg/kg and 10 mg/kg), treated with oral steroids

– TSH elevation, 4 patients (1 patient requiring levothyroxine)

Grade 3: Colitis, 1 patient after multiple doses at 1 mg/kg

Response – MR (2), PR (2), CR (1)

Brahmer et al, 2010.

3.9 cm 2.6 cm 2.4 cm

Pre-Rx 12-wk Post Dose 1 8-wk Post Dose 3

Pre-Rx 4-wk Post Dose 1

Anti-CD8 Anti-CD8 Anti-CD8

4-wk Post Dose 3

Rx = treatment.Brahmer et al, 2010.

PD-1 Blockade: Results in Increased PD-1 Blockade: Results in Increased CD8 T Cells in Tumors CD8 T Cells in Tumors

0 1 yr 2 yr 3 yr 4 yr

CR Stop Rx

Latest Evaluation: CR

Pt 2-2013

0 1 yr 2 yr 3 yr 4 yr

Stop Best Rx resp.(PR) Latest Evaluation: CR

Pt 1-4033

Sustained PR

? new brain met on MRI resected: - no viable tumor

Sustained PR

0 1 yr 2 yr 3 yr 4 yr

Stop Best Rx resp.(PR)

New LN metsPt 1-3019

Restart a PD-1

Durable Responses to Anti-PD-1 Durable Responses to Anti-PD-1 OFF THERAPYOFF THERAPY

MRI = magnetic resonance imaging; LN = lymph node. Brahmer et al, 2010.

Multidose Phase Ib Trial of Anti-PD-1Multidose Phase Ib Trial of Anti-PD-1(BMS-936558/MDX 1106)(BMS-936558/MDX 1106)

cCR = confirmed complete response; uCR = unconfirmed complete response; uPD = unconfirmed progressive disease; wPD = worsening progressive disease.McDermott et al, 2011.

Efficacy Results: RCC PatientsEfficacy Results: RCC Patients

McDermott et al, 2012.

Changes in Target Lesions Over Time in RCC Patients

Anti-PD-1 (BMS-936558) Dose Anti-PD-1 (BMS-936558) Dose Finding Study CA209010Finding Study CA209010

Arm 1 n = 50BMS-936558 (0.3 mg/kg) IV q3wks

Arm 2 n = 50BMS-936558 (2 mg/kg) IV q3wks


1° end point: PFS as measured by TA2° end points: PFS, ORR, OS

Prior Anti-Angiogenic Tx(1:1:1 Randomization)N = 150

Completed Accrual 12/2011

US NIH, NCT01354431.

Anti-PD-1 (BMS-936558) Biomarker StudyAnti-PD-1 (BMS-936558) Biomarker StudyCA209009CA209009

Treatment Naïve

Arm 1 n = 20BMS-936558 (0.3 mg/kg) IV q3wks



1° end point: Measurement of immunomodulatory activity2° end points: PFS, ORR, safety, and tolerability

Arm 4 n = 20 (treatment naïve arm)BMS-936558 (10 mg/kg) IV q3wks

Prior Anti-Angiogenic Tx(1:1:1 Randomization)N = 80

Treatment NaïveCohort Closed 2/2012Other Cohorts Open


Why Has Immunotherapy Been Why Has Immunotherapy Been Successful in Prostate Cancer?Successful in Prostate Cancer?

Better “Vaccines” ?

– Sipuleucel-T = Ex-Vivo Culture

– ProstVac = Heterologous Prime Boost (+ costimulation)

Better Antigens?

– PAP (no tolerance in animals)

– PSA (role in tumor progression)

Prostate Cancer = Better Target?

– Slow Growing

– Patient Selection (asymptomatic or minimally symptomatic)

– Patients = Castrate

Cha et al, 2011; Makarov et al, 2009.

Effect of Androgen-AblationEffect of Androgen-Ablationon T-Cell Response on T-Cell Response

Drake et al, 2005.

Testing the Optimal Sequencing of Testing the Optimal Sequencing of Androgen-Ablation and Androgen-Ablation and ““VaccinationVaccination””

P10-2P10-2Eligibility• Post Primary Rx (RP or XRT or RP + XRT)• PSADT ≤ 12 mos• Non-Metastatic (bone and CT scan)

Stratification• PSADT ≤ 3 mos or > 3 mos and ≤ 12 mos• RP or XRT or RP + XRT

Primary Objective: To determine whether ADT started before or after sipuleucel-T leads to superior augmentation of immune response

Primary End Point: Immune response, which will be evaluated with an INF-γ ELISPOT specific for PA2024

Treatment Arm 1

Sipuleucel-T ADTN = 30

Treatment Arm 2

ADT Sipuleucel-TN = 30

Immune Response, Safety

18-mos visit

Stu

dy

Par

tici

pat

ion

Co

ncl

ud

es

ADT = androgen deprivation therapy; RP = radical prostatectomy; XRT = radiation therapy; CT = computed tomography;PSADT = prostate-specific antigen double time; ELISPOT= enzyme-linked immunospot; INF= interferon.Antonarakis et al, 2011.

RENCA

Orthotopic

(0.5M Cells)

Treatment Ends

Days -8 -3

Sunitinib 40 mg/kg daily

0

Anti-PD-110 mg/kg

3 6 9 Day 12

Orthotopic RENCA Model Hypoxia High VEGF Levels Growth Inhibition With Sunitinib

Combining PD-1 Blockade Combining PD-1 Blockade With TKIs in RCCWith TKIs in RCC

Courtesy of Hans Hammers, MD, PhD.

Tumor ResponseTumor Response


14x 49x


Antibody ResponseAntibody Response

Phase I Study Combining Anti-PD-1 Phase I Study Combining Anti-PD-1 With Sunitinib or Pazopanib in Patients With Sunitinib or Pazopanib in Patients

With Metastatic RCCWith Metastatic RCC

Primary End Points: Safety, Tolerability, MTD

Metastatic RCC(Prior Pazopanib)

Arm S EscalationSunitinib + BMS-936558

Arm S ExpansionSunitinib + BMS-936558

MTD

Metastatic RCC(Prior Sunitinib)

Arm P EscalationPazopanib + BMS-936558

Arm P ExpansionPazopanib + BMS-936558

MTD

MTD = maximum tolerated dose.US NIH, NCT01472081.

Integrating Immunotherapy Into the Integrating Immunotherapy Into the Prostate Cancer Treatment ParadigmProstate Cancer Treatment Paradigm

Docetaxel Chemotherapy

AndrogenAblation

2004


AndrogenAblation

2010

Sipuleucel-T Sipuleucel-T

20122012


AndrogenAblation

Sipuleucel-T Sipuleucel-T

Cabazitaxel

AbirateroneAbiraterone

and beyond… Enzalutamide (MDV3100)

Iplimumab?

Key TakeawaysKey Takeaways

Sipuleucel-T

– FDA approved in US for CRPC

– Precise MOA under investigation

– T cell and antibody data consistent with an adaptive immune response

In development for prostate cancer

– ProstVac VF

• Phase III ongoing

– Anti-CTLA-4 (ipilimumab)

• Post-Tax phase III trials ongoing

In development for kidney cancer

– AGS-003

• Randomized phase III ongoing

– Anti-PD-1 (BMS-936558)

• Phase II dose finding completed

• Biomarker study ongoing

• TKI combination trial ongoing

Case Study: Prostate CancerCase Study: Prostate Cancer

Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive Cancer

Center at Johns Hopkins

Clinical States ModelClinical States Model

Rising PSAHormone Naive

Non-Metastatic CastrateResistant

Metastatic CastrateResistantAsymptomatic

MetastaticCastrateResistantSymptomatic

PrimaryDisease

Metastatic Disease

(de novo)

MetastaticCastrateResistantPost Docetaxel

Sipuleucel-T

Abiraterone

Cabazitaxel

Enzalutamide (MDV3100)

DocetaxelADT

Modified from Scher et al, 2008.

Case StudyCase Study

64-yr-old man presented with an elevated PSA of 4.5 ng/mL

Negative DRE

Prostate Bx: Gleason 7 (3+4)

4/12 cores positive, all on right

10%–50% of each core involved

Bone scan and CT negative

PMH/PSH: None

DRE = digital rectal exam; PNBx = prostate needle biopsy; PMH = past medical history; PSH = past surgical history.

Question 1Question 1

What would you suggest as primary therapy?

1. RT alone

2. Brachytherapy in combination with RT

3. RT with ADT

4. Primary ADT

5. Radical prostatectomy

6. Cryotherapy

RT = radiation therapy; ADT = androgen deprivation therapy.NCCN, 2012a.

Case Study (cont.)Case Study (cont.)

Patient undergoes radical retropubic prostatectomy

– Gleason 7 (3+4)

– Organ Confined

– Negative Margins

– 5/5 LN negative


Which subsequent therapy would you choose?

1. Observation

2. Adjuvant RT

3. Adjuvant ADT

4. Clinical Trial

NCCN, 2012a.

Case Study (cont.)Case Study (cont.)Course of TreatmentCourse of Treatment

Observed

3 yrs later presents with rising PSA

– Post-surgery nadir = 0.1

– 0.2, 0.2, 0.5

Referred to radiation oncology

Salvage RT (66 Gy over 8 wks)

– Well tolerated

NCCN, 2012a.

Case Study (cont.)Case Study (cont.)Course of TreatmentCourse of Treatment

Post RT PSA continues to rise

3 mos post RT = 2.3

6 mos = 7.0

9 mos = 16.5

Asymptomatic

– CT scan = negative for recurrent or progressive disease

– Bone scan = negative for evidence of metastases

NCCN, 2012a.


What would you recommend at this time?

1. Continued observation

2. Initiate intermittent androgen ablation

3. Initiate continuous androgen ablation

4. Refer for Sipuleucel-T

5. Refer for clinical trial

NCCN, 2012a.

Case Study (cont.) Case Study (cont.) Course of TreatmentCourse of Treatment

Based on rapidly rising PSA (doubling time < 12 mos), patient starts continuous androgen-ablation

3 mos later PSA nadirs at 0.4

– Stable x 2 yrs

– 2 yrs 3 mos 1.2

– 2 yrs 6 mos 3.5

– 2 yrs 9 mos 11.2

Bone scan + (3 small rib lesions, R femur)

NCCN, 2012a.


Current recommendation?

Asymptomatic, mCRPC

1. Switch bicalutamide to nilutamide

2. DC bicalutamide (antiandrogen withdrawal)

3. Ketoconazole + hydrocortisone

4. Abiraterone acetate

5. Sipuleucel-T

6. Docetaxel chemotherapy

NCCN, 2012a.

Case Study (cont.) Case Study (cont.) Course of TreatmentCourse of Treatment

Patient choses Rx with Sipuleucel-T

PSA continues to rise

What is next treatment modality?

– Abiraterone acetate + prednisone

– Enzalutamide (MDV3100)

– Docetaxel + prednisone

– Cabazitaxel

NCCN, 2012a.

Clinical States ModelClinical States Model

Rising PSA

Hormone

Naive

Non-Metastatic CastrateResistant

Metastatic CastrateResistant

Asymptomatic

MetastaticCastrateResistant

SymptomaticPrimary

Disease

Metastatic

Disease

(de novo)

MetastaticCastrateResistant

Post Docetaxel

Sipuleucel-T

Abiraterone

Cabazitaxel

Enzalutamide (MDV3100)

DocetaxelADT

Modified from Scher et al, 2008.

Immuno-Oncology: MelanomaImmuno-Oncology: Melanoma

Jedd D. Wolchok, MD, PhDMemorial Sloan-Kettering Cancer Center

Agents Used for Cancer Agents Used for Cancer ImmunotherapyImmunotherapy

Immune modulators

– BCG (bladder cancer)

– Alpha interferon (melanoma, kidney, leukemia)

– IL-2 (melanoma, kidney cancer)

– CTLA-4 blockade

Monoclonal antibodies

– Anti-CD20, CD19 (lymphoma)

– Anti-HER2 (breast cancer)

– Anti-EGF receptor (colorectal cancer)

Vaccines

– Hepatitis vaccine

– HPV vaccine

– BCG?

Adoptive cellular therapy

– Allogeneic bone marrow transplant

BCG = Bacillus Calmette-Guerin; HPV = human papillomavirus.

CR (n = 17)

PR (n = 26)

CR + PR (n = 43)

High-Dose IL-2 TherapyHigh-Dose IL-2 Therapy

RR: 16% (43/270)

Durable responses

– Median 8.9 mos

– CR: not reached

Atkins et al, 1999.

0 10 20 30 40 50 60 70 80 90 130

0.8

0.6

0.4

0.2

0.0

1.0

100 110 120Pro

bab

ility

of

Co

nti

nu

ing

Res

po

nse

(%

)

Duration of Response (mos)

T-Cell Remains Active

Korman et al, 2006.

T-Cell

Inactivation

T-Cell Activation

Ipilimumab

APC

CTLA-4

T Cell

APC

T CellResting

T Cell

APC

B7

CD28TCR

HLA

CTLA-4

CTLA-4

Ipilimumab, A CTLA-4 Blocking MoAB, Ipilimumab, A CTLA-4 Blocking MoAB, Augments T-Cell Activation Augments T-Cell Activation

Experienced complete resolution of 2 subcutaneous nodules, 31 lung metastases and 0.5 cm brain metastasis

Clinical Response in Melanoma: NCI Clinical Response in Melanoma: NCI

Phan et al, 2003.

Immune-Related Adverse EventsImmune-Related Adverse Events

Rash (20%)

Colitis/Enteritis (15%)

Elevated AST/ALT (10%)

Thyroiditis (3%–5%)

Adrenal Insufficiency (< 1%)

Hypophysitis (3%–5%)

Severity is inversely related to vigilance of surveillance.If detected early, most are easily treated and reversible.

Wolchok, 2010.

MDX010-20 Study SchemaMDX010-20 Study Schema

Screening

Induction: Ipilimumab at 3 mg/kg, with or without gp100, q3wks for 4 treatments

Reinduction: Patients with SD for 3 mos’ duration from Wk 12, or a confirmed CR or PR, could receive additional therapy with their assigned treatment regimen upon PD

Ipilimumab + gp100

(n = 403)

Ipilimumab alone

(n = 137)

gp100 alone

(n = 136)

≥ 1 Re-Induction

(eligible patients)Induction

Previously treated,

HLA-A2*0201+ patients with

advanced melanoma(N = 676)

R

A

N

D

O

M

I

Z

E

Follow-Up

PD

PD

PD

3:1:1

Hodi et al, 2010.

Ipilimumab + gp100

Ipilimumab alone

gp100 alone

Years

Ipilimumab + gp100 (A)Ipilimumab + gp100 (A)Ipilimumab alone (B)Ipilimumab alone (B)gp100 alone (C)gp100 alone (C)

1 2 3 4

Comparison HR Comparison HR PP-value-value Arm A vs CArm A vs C 0.680.68 0.00040.0004 Arm B vs CArm B vs C 0.660.66 0.00260.0026 Arm A vs BArm A vs B 1.041.04 0.75750.7575

Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone

1-yr 44% 46% 25%

2-yr 22% 24% 14%

Kaplan-Meier Analysis of SurvivalKaplan-Meier Analysis of Survival

Hodi et al, 2010.

Estimated Survival Rate 1 Yr 2 Yr 3 Yr*

Ipilimumab + DTICN = 250

47.3 28.5 20.8

Placebo + DTICN = 252

36.3 17.9 12.2

Study 024: Overall Survival Study 024: Overall Survival

*3-yr survival was a post-hoc analysis.Wolchok et al, 2011.

11/28/06 1/9/0711/28/06 1/9/07

Wolchok , 2010.

Ipilimumab Pattern of Response:Ipilimumab Pattern of Response:Responses After the Appearance and Responses After the Appearance and

Subsequent Disappearance of New LesionsSubsequent Disappearance of New Lesions

3 mg/kg Ipilimumab q3wks X 4

Pre-Treatment

Wk 36: Still Regressing

Wk 12: Progression

Wk 20: Regression

New lesions

Wolchok et al, 2008a.

July 2006

Four Patterns of Response to Four Patterns of Response to Ipilimumab Therapy Were ObservedIpilimumab Therapy Were Observed 2 conventional

– Response in baseline lesions

– SD with slow, steady decline in total tumor volume

2 novel

– Response after initial increase in total tumor volume

– Response in index plus new lesions at or after the appearance of new lesions

Wolchok et al, 2009.

CTLA-4 Blockade: A Case Study for CTLA-4 Blockade: A Case Study for Immunotherapy in Need of BiomarkersImmunotherapy in Need of Biomarkers

Knowns

Clinical benefit for a subset of patients with refractory melanoma

Reversible mechanism-based side effects

Tumor responses tend to be durable

Kinetics of response unlike cytotoxics

Unknowns

Biomarkers for response

Biomarkers for toxicities

Effect on effector vs regulatory T cells in humans

Antigens recognized after infusion

Importance of vaccination before treatment

Relevance of PBMC vs. tumor site findingsPBMC = peripheral blood mononuclear cell.

Wolchok, 2010.

This patient population comprises all patients (N = 73) available at the Immune Monitoring Facility of Memorial Sloan-Kettering Cancer Center, New York

Mean longterm ALC

1

2

3

4clinicalbenefit

no clinicalbenefit

-4 m

on

ths

-3 m

on

ths

-2 m

on

ths

-1 m

on

th

week 1

week 4

week 7

week 1

0w

eek 1

2

week 2

4

week 3

6

AL

C [

K/m

cl]

ALC = absolute lymphocyte count.Ku et al, 2010.

ALC Correlates With Clinical BenefitALC Correlates With Clinical Benefit

AMP-224, CT-011, MDX-1106, MK-3475

BMS-663513PF-05082566

Ipilimumab, Tremelimumab

Anti-OX40

Positive and Negative Signals Regulate Positive and Negative Signals Regulate T-Cell ActivationT-Cell Activation

Wolchok et al, 2008b, 2010.

PD-1: Role in T-Cell ActivationPD-1: Role in T-Cell Activation

Member of CD28 family involved in T-cell regulation

Expressed by activated T cells, memory T cells, and regulatory T cells

Down regulates T-cell activity upon binding to PD-L1/L2

Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self defense

What is PD-1?

T CellDendritic Cell, Parenchymal Cell, Tumor Cell

Sznol et al, 2010.

MDX-1106 (BMS-936558/ONO-4538) MDX-1106 (BMS-936558/ONO-4538) Human Anti-PD-1 Antibody Human Anti-PD-1 Antibody

IgG4 (S228P) – no ADCC/CDCC activity

High affinity binding to human and cynomolgus PD-1

Blocks binding of PD-1 to PD-L1 and PD-L2

In vitro, BMS-936558

– Promotes cytokine production/proliferation

• Human allogeneic MLR

• Antigen reactive T cells in response to CMV or tumor antigen

– Reverses T reg-mediated suppression of allogeneic MLR

CDCC = complement-dependent cellular cytotoxicity; MLR = mixed lymphocyte reaction; CMV = cytomegalovirus. Sznol et al, 2010.

Change in Tumor BurdenChange in Tumor Burden 296 patients with advanced solid tumors, including 104 melanoma patients

– 26 objective responses observed at doses ranging from 0.1–10.0 mg/kg

– 3.0 mg per kilogram: Objective responses noted in 41%

– SD lasting 24 wks or more was observed in 6 patients (6%)

Topalian et al, 2012.

Preclinical DataPreclinical Data

PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors

Curran et al, 2010.

Time (days)

Ipilimumab

MDX-1106

Induction Maintenance

Dosing/Evaluation Schedule

Imaging Studies

Cohort MDX-1106 Ipilimumab

1 0.3 mg/kg 3 mg/kg

2 1 mg/kg 3 mg/kg

3 3 mg/kg 3 mg/kg

4 3 mg/kg 10 mg/kg

5 10 mg/kg 10 mg/kg

Dose Escalation

09-155 – Study Design 09-155 – Study Design


PET Scans at Baseline and Day 15 PET Scans at Baseline and Day 15 After PLX4032After PLX4032

#63 MSKCC#69 MDA

#59 Peter MacCallum#56 Vanderbilt

PET = positron emission tomography; MDA = The University of Texas M. D. Anderson Cancer Center; MSKCC = Memorial Sloan-Kettering Cancer Center.Chapman, 2009.

Decreased immune suppressive factor

release

Activation of T cells and increased homing

DC

Increased antigen Cross-presentation

Increased direct antigen presentation

How Can BRAF Targeted Therapy Increase the How Can BRAF Targeted Therapy Increase the Activity of Tumor Immunotherapy?Activity of Tumor Immunotherapy?

BRAF BRAFi

DC = dendritic cell

Pre-clinical Evidence Supporting the Feasibility Pre-clinical Evidence Supporting the Feasibility of Combinations of BRAFi + Immunotherapyof Combinations of BRAFi + Immunotherapy

Oncogenic BRAF-induced production of immune suppressive factors (IL-6, IL-10, VEGF) is inhibited with a MEK inhibitor (Sumimoto et al, 2006)

Vemurafenib increases melanosomal antigen expression and T cell recognition (Boni et al, 2010)

Human T cells exposed to vemurafenib are fully functional (Comin-Anduix et al, 2010)

Goel, Haluska et al. Oncogene. 2009

BRAFV600E mutation

Days

0 5 10 15 20 25

% T

umor

-Fre

e A

nim

als

0

20

40

60

80

100

Vehicle Control (n = 14)

PLX4032 (n = 14)

pmel-1 ACT (n = 19)

pmel-1 ACT+PLX4032 (n = 19)

3 replicated experiments, p < 0.0001 by log rank test

pERK

ERK

VC 1 155

Tubulin

PLX4032 (µM)

CRAF

MEK1/2

ERK

P

P

BRAF

PLX4032

MAPK signaling

Koya et al, 2012.

Pre-clinical Evidence Supporting the Feasibility of Pre-clinical Evidence Supporting the Feasibility of Combinations of BRAFi + Immunotherapy (cont.)Combinations of BRAFi + Immunotherapy (cont.)

PLX4720 treatment leads to a decreased frequency of immune cells in BRAFV600E/PTEN-/- melanomas and this cannot be restored by CTLA-4 blockade

Addition of anti-CTLA-4 mAb treatment to PLX4720 treatment does not further improve tumor growth control

Pre-clinical Evidence Against the Feasibility of Pre-clinical Evidence Against the Feasibility of Combinations of BRAFi + ImmunotherapyCombinations of BRAFi + Immunotherapy

Hooijkaas et al, 2012.

Clinical Evidence Supporting the Feasibility of Clinical Evidence Supporting the Feasibility of Combinations of BRAFi + ImmunotherapyCombinations of BRAFi + Immunotherapy

CD8+ T cell infiltration in regressing melanoma lesions after BRAFi therapy

T cells from patients treated with dabrafenib are fully functional

Wilmott et al, 2012; Hong et al, 2012.

Results of Diagnostic and Radiotherapy Simulation Results of Diagnostic and Radiotherapy Simulation Imaging Throughout the Disease CourseImaging Throughout the Disease Course

Postow et al, 2012.

Postow et al, 2012.

NY-ESO-1 Expression and Antibody Response NY-ESO-1 Expression and Antibody Response to Ipilimumab and Radiotherapyto Ipilimumab and Radiotherapy

Results of Flow Cytometry of Results of Flow Cytometry of Peripheral Blood Mononuclear CellsPeripheral Blood Mononuclear Cells

Postow et al, 2012.


Checkpoint blockade is an effective treatment with durable responses

New and promising immune modulators are in clinical development

Combination therapy will be necessary for immunotherapy to achieve full potential (other immune modulators, vaccines, radiation, chemotherapy, targeted therapy, antiangiogenic therapy)

Case Study: MelanomaCase Study: Melanoma

Antoni Ribas, MD, PhDUniversity of California, Los Angeles

Case Study 1Case Study 1

A 55-yr-old man is diagnosed with melanoma, and further examination reveals metastatic disease

Discussion

– What factors should be considered when selecting frontline therapy for this patient?

– What indications would lead to your recommendation of a specific treatment?

– Under what circumstances might you suggest this patient participate in a clinical trial?

Case Study 1: Follow-UpCase Study 1: Follow-Up The patient is treated with ipilimumab; after 12 wks

of therapy, he has not responded and new hepatic lesions are observed

– How might this patient’s progression affect your recommended treatment strategy?

– At what point might you consider alternative therapeutic approaches?

– What factors might affect your treatment decisions?

NCCN, 2013.

Case Study 1: Follow-Up (cont.)Case Study 1: Follow-Up (cont.)

The patient has remained on ipilimumab and has begun to suffer from a grade 2 rash and diarrhea

– What concomitant medications can be used to reduce the severity of this AE?

– Can dose reductions/omissions be used for these AEs?

– How might this affect your recommended treatment strategy?

NCCN, 2013.

Case Study 2Case Study 2 A 61-yr-old woman is diagnosed with metastatic

melanoma and receives alkylating agents as frontline therapy. After 20 wks, there has been no measurable response. Testing of the tumor tissue reveals a V600E mutation. The patient wishes to discuss treatment options for refractory disease, including the possibility of clinical trial enrollment.

– What factors might help to determine an alternative treatment strategy?

– Which late-stage trials might be most promising for patients with this mutation?

– What other molecular approaches might help to direct potential therapies?

NCCN, 2013.

Immuno-Oncology: Immuno-Oncology: Non-Small Cell Lung CancerNon-Small Cell Lung Cancer

John Powderly II, MD, CPICarolina BioOncology Institute, PLLCCancer Therapy & Research Center

BackgroundBackground

NSCLC remains the leading cause of cancer-related mortality in the US and worldwide

NSCLC long considered non-immunogenic, that is, unable to induce immune destruction

However, there is evidence to suggest that the immune system can recognize NSCLC:

– Tumor-infiltrating lymphocytes have been identified in NSCLC patients, and correlates with survival

– T cells reactive to tumor associated antigens can be found in patients with NSCLC

NSCLC = non-small cell lung cancer.

Background (cont.)Background (cont.)

Why have prior attempts to modulate the immune system in NSCLC patients failed to show consistent benefit?

– Not the right immunotherapy

– Need for combination therapy to fully enable immune attack- e.g. immunotherapy with other immunotherapy, chemotherapy and/or radiation

Problem of immune tolerance- lack of immune attack despite recognition (e.g. immune checkpoints)

Newer therapies, including immune checkpoint inhibitors and novel vaccines are beginning to show promise in NSCLC

Clinical Significance of Tumor-Infiltrating Clinical Significance of Tumor-Infiltrating Lymphocytes in Lung Neoplasms Lymphocytes in Lung Neoplasms

Resected Squamous CellLung Cancer, Stage I–IIIap = .03

Ruffini et al, 2009.

Time (yrs)

Cancer Self-Tolerance BlockadeCancer Self-Tolerance Blockade Endogenous immune response to cancer is observed in patients,

however it is ineffective

– Tolerance: Cancer is viewed as self

– Tumors exploit mechanisms to suppress the host immune response

• Immune checkpoints (CTLA-4, PD-1) abort immune responses

– Co-opted by tumors to evade immune destruction

– “Tumor adaptive immune resistance”

• Immune checkpoint inhibitors may block self-tolerance of cancer, and enable antitumor immune destruction


Normal T Cell Activation and AttackNormal T Cell Activation and Attack

Dendritic cell

MHC

B7

TCR

CD28

T cell

Ribas, 2012.

T cell

MHCTCR

Cancer Cell

Effector phasePriming phase

Lymph node

Peripheral tissue

Release of :

- Perforin/ granzyme

- Cytokines

T cell proliferation

PD-L1

Immune Checkpoints – CTLA4 & PD1Immune Checkpoints – CTLA4 & PD1

Dendritic cell

MHC

B7

TCR

CD28

CTLA4

T cell

Ribas, 2012.

T cell

MHCTCR

PD-1

Cancer Cell

Antibody Antibody Antibody

B7

Effector phasePriming phase

Lymph node

Peripheral tissue

Inhibitory signals

Negative regulation

Self-Tolerance BlockadeSelf-Tolerance BlockadeDrugs in DevelopmentDrugs in Development

Anti-CTLA-4

– Ipilimumab (fully human IgG1, Medarex/BMS)

– Tremelimumab (fully human IgG2, Pfizer/Medimmune)

Anti-PD-1

– MDX-1106/BMS-936558 (fully human IgG4, Medarex/BMS)

– CT-011 (humanized IgG1, Curetech/Teva)

– MK-3475 (humanized IgG4, Merck)

– AMP-224 (B7-DC/IgG1fusion protein, Amplimmune/GSK)

Anti-PD-L1

– MDX-1105/BMS-936559 (fully human IgG4, Medarex/BMS)

– MPDL3280A (Genentech/Roche)

Pierard et al, 2012; Brahmer et al, 2010; Topalian et al, 2012; Paradoll et al, 2012b.

Ipilimumab in Combination With Paclitaxel Ipilimumab in Combination With Paclitaxel and Carboplatin as First-Line Treatment and Carboplatin as First-Line Treatment in Lung Cancer: Phase II Trial CA184-041in Lung Cancer: Phase II Trial CA184-041

Ipilimumab 10 mg/kg, Paclitaxel 175 mg/m2, Carboplatin AUC = 6

– Randomized 3 Arms 1:1:1

• Concurrent Ipilimumab + Paclitaxel/Carboplatin

• Phased Ipilimumab + Paclitaxel/Carboplatin

• Placebo Control + Paclitaxel/Carboplatin

Stratified by 2 Cohorts

– Stage IIIB/IV NSCLC, n = 203

– Extensive Disease SCLC (ED-SCLC), n = 128

Eligibility: ECOG 0–1; ECOG 0–2; at least 1 measurable lesion, no prior lung cancer therapy, no prior auto-immune disease, no active brain mets

ECOG = European Cooperative Oncology Group.Lynch et al, 2011; Reck et al, 2011.

CA184-041: Study SchemaCA184-041: Study SchemaStage IIIB/IV NSCLC CohortStage IIIB/IV NSCLC Cohort

p = placebo; c = chemotherapy (Pac/Carbo) Ipi (10 mg IV).Lynch et al, 2011.

CA184-041: Stage IIIB/IV NSCLung irPFSCA184-041: Stage IIIB/IV NSCLung irPFS

Lynch et al, 2012.

Time (mos)

CA184-041: Stage IIIB/IV NSCLungCA184-041: Stage IIIB/IV NSCLung Overall Survival Overall Survival

Lynch et al, 2012.

Time (mos)

CA184-041: Stage IIIB/IV NSCLungCA184-041: Stage IIIB/IV NSCLungSummary ConclusionsSummary Conclusions

Phased Concurrent Control

Median irPFS 5.7 mos 5.5 mos 4.6 mos

Median PFS 5.1 mos 4.1 mos 4.2 mos

irBORR 32% 21% 18%

BORR 32% 21% 14%

Median OS 12.2 mos 9.7 mos 8.3 mos

Grade 3/4 irAEs 15% 20% 6%

Any Grade 4 AEs 12% 27% 11%

Treatment-Related Deaths 0 1 patient 1 patient

Lynch et al, 2012.

CA184-041: Stage IIIB/IV NSCLC CohortCA184-041: Stage IIIB/IV NSCLC CohortActivity of Phased-IPI by Baseline HistologyActivity of Phased-IPI by Baseline Histology

Lynch et al, 2011.

CA184-041: Stage IIIB/IV NSCLC CohortCA184-041: Stage IIIB/IV NSCLC CohortOverall Survival Squamous SubsetOverall Survival Squamous Subset

Lynch et al, 2011.

CA184-041: Stage IIIB/IV NSCLC CohortCA184-041: Stage IIIB/IV NSCLC CohortMost Common (> 15% Any Arm) Adverse EventsMost Common (> 15% Any Arm) Adverse Events

Lynch et al, 2011.

Ongoing Lung Cancer Ipilimumab TrialsOngoing Lung Cancer Ipilimumab Trials

NSCLC

– CA184-104: Randomized, Multi-Center, Double-Blind, Phase III Trial Comparing Efficacy of Ipilimumab in Addition to Paclitaxel and Carboplatin in Subjects With Stage IV/Recurrent NSCLC (NCT01285609) Global 920 Patients

– CA184-124: Randomized, Open-Label, Phase II Safety and Efficacy Trial of Ipilimumab Vs. Pemetrexed in Subjects With Recurrent/Stage IV Non-Squamous, NSCLC Who Have Not Progressed After Four Cycles of Platinum-Based First-Line Chemotherapy (NCT01471197) Global 200 Patients

SCLC

– CA184-156: Extensive-Disease SCLC Subjects Comparing Ipilimumab Plus Etoposide and Platinum Therapy to Etoposide and Platinum Therapy Alone (NCT01450761) Global 912 Patients

– The Addition of Ipilimumab to Carboplatin and Etoposide Chemotherapy for Extensive Stage SCLC (NCT01331525) Europe

Clinicaltrials.gov, 2012.

Adaptive Immune Resistance

Tumor

OncogenicPathway

T Cell

TCR

PD-1

MHC + Peptide

PD-L1

Oncogene-Driven PD-L1Expression

Tumor

PD-L1

Adaptive Up-Regulation Of PD-L1 Turns T Cell OFF

Tumor

Interferon g

Immune Resistance: PD-1Immune Resistance: PD-1Innate Immune Resistance

Pardoll, 2012a; Slide from Immuno-Oncology GU presentation by Charles Drake.

T Cell T Cell

B7-H1 (PD-1L) on Cancer Cells In Vitro B7-H1 (PD-1L) on Cancer Cells In Vitro Is Inducible by Gamma InterferonIs Inducible by Gamma Interferon

Haile et al, 2011.

B7-H1 (PD-1L) Expression on NSCLC and B7-H1 (PD-1L) Expression on NSCLC and Relationship With TIL PD-1 ExpressionRelationship With TIL PD-1 Expression

52 resected lung cancers

Fewer TIL in B7-H1+ regionsp = .01

Fewer PD-1+ TIL in B7-H1 regionsp = .02

Concluded: Expression of B7-H1 on tumorcells in local areas reciprocally correlated With # TIL, and may contribute to negative regulation in antitumor immune response

Konishi et al, 2004.

Phase Ia Study of Single-Agent Phase Ia Study of Single-Agent Anti-PD-1 (MDX-1106/BMS-936558/ONO-4538) in Anti-PD-1 (MDX-1106/BMS-936558/ONO-4538) in

Refractory Solid TumorsRefractory Solid Tumors– Fully human IgG4 anti-human PD-1 blocking Ab - No ADCC/CD

– High affinity for PD-1 (KD ~ 3 nM)

– Blocks binding of both PD-L1 (B7-H1) and PD-L2 (B7-DC)

– Among 39 Patients:

• 1 CR (CRC), 2 PRs (Melanoma, RCC), 12 SD > 3 mos, including2 significant mixed responses (NSCLC, Melanoma)

• CR and PR were ongoing 3–21+ mos

– Toxicities: No DLT; MTD not reached

• Grade 3 colitis (1 melanoma patient, after 5 doses)

• Grade 2 hypothyroidism (1 patient)

• Grade 2 polyarticular arthropathies (2 patients, required oral steriods)

– Among 9 patients examined, tumor expression of B7-H1 (PD-1L) showed correlation with likelihood of response

DLT = dose-limiting toxicity.

Brahmer J, et al. J Clin Oncol 2010;28:3167-75

61-yr-old BF stage IV NSCLC (squamous) bilateral lung metastasis, bone mets. Prior treatment carboplatin/vinorelbine/bevacizumab.

May 2007, Rx single dose of MDX-1106, anti-PD-1 mAb (1 mg/kg IV)

8 wks 41% RECIST PR, but 12-wk scans showed new spine mets (mixed response)

Rechallenged MDX-1106, progressed

May 2007 July 2007

MDX-1106 001: Phase I Study of Single-Agent MDX-1106 001: Phase I Study of Single-Agent Anti-PD-1 (MDX-1106) in Refractory Solid Tumors Anti-PD-1 (MDX-1106) in Refractory Solid Tumors

(cont.)(cont.)

RECIST = Response Evaluation Criteria in Solid Tumors.Brahmer et al, 2010.

BMS-936558 (Anti-PD1) Study Design: BMS-936558 (Anti-PD1) Study Design: Phase Ib Multi-dose RegimenPhase Ib Multi-dose Regimen

Topalian et al, NEJM, 2012.

BMS-936558 (Anti-PD-1):BMS-936558 (Anti-PD-1): Expansion Cohorts for NSCLC Expansion Cohorts for NSCLC

Baseline Characteristics Baseline Characteristics

Summary of Key Safety ResultsSummary of Key Safety Results

MTD was not identified at doses up to 10 mg/kg

There was no apparent relationship between drug dose and AE frequency in all treated patients or NSCLC patients

In the total patient population across all tumor types:

Grade 3-4 drug-related AEs occurred in 14% of patients

Grade 1-2 pneumonitis was noted in 6 (2%) patients

Three drug-related deaths occurred in patients with pneumonitis (2 with NSCLC and 1 with CRC)

In NSCLC patients:

Grade 3-4 drug-related AEs occurred in 8% of patients

Grade 1-2 pneumonitis was noted in 4 (3%) patients

The most common grade 3-4 AEs were fatigue, pneumonitis, and elevated AST (2 pts each)

Clinical Activity of BMS-936558 in Clinical Activity of BMS-936558 in NSCLC PatientsNSCLC Patients

Clinical Activity by Histology, Clinical Activity by Histology, Efficacy PopulationEfficacy Population

Safety, Activity, and Immune Correlates Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody (BMS-936558, of Anti-PD-1 Antibody (BMS-936558,

MDX-1106) in Cancer (cont.)MDX-1106) in Cancer (cont.)

Baseline 2 Mos 4 Mos

NSCLC Patient With Immune-Related Pattern of Delayed Response


Pre/ Post BMS 936558 (Jun / Oct Pre/ Post BMS 936558 (Jun / Oct ’’11)11)

- 58 y/o ex smoker with squam NSCLC- 4 prior tx for Stage IV disease- Left flank pain resolved within 2 mos

Anti-PD-1 mAb Lung Cancer ResponseAnti-PD-1 mAb Lung Cancer Response

60-yr-old man

– Diagnosed in 2002

Intermittent responses but eventual progression on multiple prior combination chemotherapies and RT

RX MDX-1106 10 mg/kg

A: Baseline

B: Cycle 2 assessment

Courtesy of Dr. Brahmer and Dr. Topalian, John Hopkins.

Correlation of PD-L1 Expression in Pretreatment Correlation of PD-L1 Expression in Pretreatment Tumor Biopsies with Clinical OutcomesTumor Biopsies with Clinical Outcomes

Ongoing PD-1 Blockade Trials Ongoing PD-1 Blockade Trials That Include Lung CancerThat Include Lung Cancer

CA209-012: Multi-Arm Study of BMS-936558 (MDX-1106, anti-PD-1 mAb) in Combination With3 Platinum-Based Doublet Chemotherapy Regimens in Subjects With Treatment-Naive Stage IIIB/IV NSCLC (NCT01454102) North America, 60 Patients

Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma (NCT01295827)


Pending PD-1 Blockade Pending PD-1 Blockade Registration NSCLC Trials Registration NSCLC Trials

An Open-Label Randomized Phase III Trial of BMS-936558 Versus Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NCT01642004)

An Open-Label Randomized Phase III Trial of BMS-936558 Versus Docetaxel in Previously Treated Advanced or Metastatic Non-squamous Cell Non-small Cell Lung Cancer (NCT016738677)

Safety and Activity of Anti-PD-L1 Antibody Safety and Activity of Anti-PD-L1 Antibody in Patients With Advanced Cancerin Patients With Advanced Cancer

Phase Ia, 207 patients solid tumors stage IV– Rx monotherapy anti-PD-L1 antibody q2wks (3 doses over

6-wk cycles) up to 16 cycles until PD or CR

– Cumulative objective response• Melanoma 17%

• RCC 12%

• NSCLC 10% (75 patients with NSCLC)

– 50% of responders durable > 1 yr

– Immune-related events 39% (rash, hypothryoidism, hepatitis, myasthenia gravis)

– Drug related grade 3–4 AEs 9%

– NSCLC 12% SD; Clinical benefit (CR + PR + SD) = 22%






Lung Cancer VaccinesLung Cancer Vaccines

GSK1572932A (MAGE-A3) VaccineGSK1572932A (MAGE-A3) Vaccine

MAGE-A3 (melanoma associated antigen A3) genes constitute a family of ‘cancer-germline’ or ‘cancer testis’ genes (testes, placenta, cancers)

30-50% of NSCLCs express MAGE-A3 on their surface (higher expression in squamous cell NSCLC)

GSK1572932A (MAGE-A3) vaccine

• Recombinant protein vaccine combined with immunological adjuvant ASO2B

US NIH, NCT00480025

MAGRIT MAGRIT MMAGE-A3 as AGE-A3 as AAdjuvant Non-djuvant Non-Small Cell LunSmall Cell LunGG Cance CanceRR IImmunommunoTTherapyherapy

Primary endpt: DFS overall and DFS in a gene signature positive population

11,000 patients screened, 10,000 tumors tested, 3,235 tested + MAGE A3, 2270 randomized (Largest lung cancer trial ever)

L-BLP (Stimuvax)L-BLP (Stimuvax)

MUC-1 is a cell surface mucinous glycoprotein overexpressed or aberrantly glycosylated in a number of epithelial malignancies

Aberrant glycosylation appears to expose the core peptide of MUC-1 to immune effector cells

L-BLP-25: MUC-1 vaccine consisting of the BLP 25 peptide, monophosphoryl lipid A adjuvant and liposomal cholesterol, dimyristoyl phosphatidylglycerol (DMPG) and dipalmitoyl phosphatidylcholine (DPPC) to facilitate immune recognition

RPhII of Stimuvax in advanced NSCLC- Subgroup analysis suggested benefit in Stg IIIB (but not SS)

L-BLP25: A Peptide Vaccine Strategy L-BLP25: A Peptide Vaccine Strategy in NSCLCin NSCLC

Randomized Phase IIB 171 Patients Stage IIIB–IV Canada & UK

Post hoc subgroup Analysis IIIB(65 patients)

p Value non-significant But trend favorable. Led to phase III trial with stage III patients ongoing.

BSC = best supportive care.Sangha et al, 2007.

Survival Time (mos)

START Phase III Trial: L-BLP-25 inSTART Phase III Trial: L-BLP-25 inUn-resectable, Stage III NSCLCUn-resectable, Stage III NSCLC

•Unresectable, stage III

NSCLC

•Stable or responding

disease after chemoradio-

therapy

•PS 0-1

(Adjusted N=1476)

R

A

N

D

O

M

I

Z

E

L-BLP-25 930 μg

q7d x 8 cycles

Placebo

q7d x 8 cycles

• Primary endpoint: survival

• Secondary endpoints: TTP; TTSP; 1-, 2-, and 3-year survival; and safety

L-BLP-25 930 μg

q6w

Placebo

q6w

Maintenance until

progressionEligibility Criteria

TTSP=time to symptom progression.

US NIH, NCT01015443

Belagenpumatucel-L (Lucanix)Belagenpumatucel-L (Lucanix)

One mechanism used by tumors to escape immune surveillance is secretion of transforming growth factor beta (TGF-β) which:

– Inhibits T and B cell activation

– Inhibits dendritic cell maturation and antigen presentation

– Inhibits NK and lymphokine activated (LAK) cells

– Induces immunosuppressive FoxP3 Treg cells

Lucanix- allogeneic whole tumor vaccine consisting of four irradiated NSCLC tumor cell lines modified to block TGF- β2 secretion

PhII (primarily IIIb/IV), n=75, 3 doses tolerated well with encouraging survival

Lucanix Phase III NSCLC trialLucanix Phase III NSCLC trial

Stage III-IV NSCLC

without POD after

1-6 cycles of 1st line

platinum based chemo

(n=1322)

Lucanix

18 monthly inj

2 quarterly inj

+ BSC

Placebo

+ BSC

Survival

• Primary endpoint:

– Overall survival

• Secondary endpoints:

– Safety

– PFS

– OR

– QOL

Randomization

* 420/ 506 accrued as of 2-09-2012US NIH, NCT00676507.

Talactoferrin Alfa (TLF)Talactoferrin Alfa (TLF)

Recombinant human lactoferrin with immunomodulatory properties

After ingestion, TLF acts of GI epithelium to release chemokines which recruit immature dendritic cells to gut-associated lymphoid tissue where they undergo maturation/ activation

– Initiate both active immunity (via NK cells) and adaptive immunity by antigen presentation to CD8+ T cells that seek out tumor

Encouraging survival data in RPhII trials as monotherapy and with chemotherapy

Parikh et al, 2011; Digumarti, 2011

FORTIS-M (LF-0207)FORTIS-M (LF-0207)

742 patients

enrolled

Stage IIIB/IV

NSCLC who have

failed two or more

prior regimens

ECOG PS 0-2

R

A

N

D

O

M

I

Z

E

TLF 1.5 g BID

12 wks on, 2 wks off

up to 5 cycles

+ BSC

Placebo BID

12 wks on, 2 wks off

up to 5 cycles

+ BSC

2:1

Primary Endpoint: Overall Survival

Secondary Endpoints: 6-month & 1-year survival rate, PFS, ORR, Disease Stabilization Rate (PR+CR+SD), TLF

safety and tolerability

Stratifications: Prior regimens (2 vs ≥3), ECOG PS, Geographical region

US NIH, NCT00707304

FORTIS-C (LF-0208)FORTIS-C (LF-0208)

1,100 patients previously untreated

Stage IIIB/IV NSCLC

ECOG PS 0-1

TLF 1.5g BID+ Carboplatin (AUC 6) + Paclitaxel (200mg/m2)

q3 weeks for 6 cycles

Placebo BID+ Carboplatin (AUC 6) + Paclitaxel (200mg/m2)q3 weeks for 6 cycles

TLF until disease progression

(up to 18 months)

Placebo until disease progression (up to 18

months)

Co-Primary Endpoints: PFS & OSSecondary Endpoints: Objective Response Rate, Duration of Response, Safety

Stratifications: gender; disease stage; geographical region

1:1

RANDOMIZE

US NIH, NCT00706862

Additional Immunotherapies Being Evaluated in Additional Immunotherapies Being Evaluated in NSCLC & SCLCNSCLC & SCLC

NSCLC

– TG4010 (modified vaccine virus Ankara expressing MUC, IL-2, Transgene/Novartis)

• Phase IIB/III (NCT01383148)

– EGF (conjugated to an immunoadjuvant, “Cuban Vaccine”)

• Phase III (NCT01444118)

– Reolysin (naturally occurring unmodified oncolytic virus)

• Phase I/II (NCT00861627; NCT00998192)

SCLC

– -SVV1 (Seneca Valley Virus; replication competent picovirus with selective tropism for tumors with neuroendocrine features)

• Phase II (NCT01017601)

– Autologous dendritic cell-adenovirus p53 vaccine +/- tretinoin

• Phase II (NCT00618891)


Tumor infiltrating lymphocytes in lung cancer predict improved survival

Lung cancer can be immunogenic, withself-tolerance blockade drugs

– Anti-CTLA4 (randomized phase II durable responses)

– Anti-PD1/PDL1 (early phase IB durable responses)

– Phase III trials launched

Phase III Vaccine trials close to completing accrual

Case Study: Case Study: Non-Small Cell Lung CancerNon-Small Cell Lung Cancer

John Powderly II, MD, CPICarolina BioOncology Institute, PLLCCancer Therapy & Research Center

Case Study: Diagnostic Work-UpCase Study: Diagnostic Work-Up

69-yr-old Caucasian man, prior smoker, presenting with cough and night sweats

– 1/06 CT Chest: RUL necrotic mass 5.7 x 5.9 cm (? abscess vs. cancer)

– 1/06 Bronchoscopy RUL lung biopsy (Bx): Poorly differentiated adenocarcinoma with extensive tumor necrosis

– PET: RUL mass SUV 14.7; precarinal LN SUV 4.0

– CT brain: Neg

RUL = right upper lobe; LN = lymph node; SUV = standardized uptake value.

Initial TreatmentInitial Treatment 1/06 bronchoscopy, R thoracotomy, RUL lobectomy,

mediastinal lymphadenectomy

Path:

– 5 cm SCC, high grade, 0 of 18 LNs

• Incidental lymphoid follicular hyperplasia in level 10 LNs

– pT3pN0, initial stage IIB

– Patient declined chemotherapy

ICU = intensive care unit.NCCN, 2012b.

Surveillance and RelapseSurveillance and Relapse Surveillance q6mos CT scan

• 9/07 CT scan: New R adrenal nodule 2.4 cm

• 1/08 PET/CT scan: R adrenal mass larger 5.4 x 3.8 cm, SUV 10

1/08 Bx R adrenal mass: Poorly differentiated, non-small cell, mixed adenocarcinomatous with squamoid features

Stage IV with solitary R adrenal mass (oligometastatic)

NCCN, 2012b.

Stage IV MetastectomyStage IV Metastectomy

4/08 R adrenalectomy, Path: 4.5 cm lung carcinoma poorly differentiated (EGFR PCR wild-type)

– Rendered surgical no evidence of disease

8/08 Started chemotherapy. Carboplatin/Paclitaxel/Bevacizumab x 4 cycles, with maintenance bevacizumab until progression.

PCR = polymerase chain reaction.NCCN, 2012b.

Second Recurrance Second Recurrance

2/09 CT scan: Enlarging contralateral L adrenal mass5.5 cm

2/09 Brain MRI: Negative

3/09 Informed consent for phase I clinical trial with MDX-1106 (anti-PD-1 mAb)

3/09 First dose MDX-1106 (3 mg/kg) IV q2wks

Baseline ANA 1:40, + Rheumatoid Factor = 19, CRP = 23

CTC = circulating tumor cell; CRP = C-reactive protein. NCCN, 2012b.

Immunotherapy ResponseImmunotherapy Response

5/09 CT scan: Decreased L adrenal mass 3.0 x 2.8 cm (PR)

5/09 Hospitalization COPD exacerbation, Rx azithromycin, methylprednisolone, then prednisone taper (MDX-1106 delayed until 2 wks after last dose of prednisone)

6/09 Resumed MDX-1106

7/09 CT scan: Further decrease L adrenal mass 2.7 x 2.9 cm

NCCN, 2011.

Durable Partial Response (cont.)Durable Partial Response (cont.)

February 2009 September 2009

Durable Partial ResponseDurable Partial Response

2/11 Completed 2 yrs of bi-wkly MDX-1106

8/12 Remains with durable PR, with only measurable disease at L adrenal nodule 2.0 cm

Circulating Tumor Cell Count Circulating Tumor Cell Count Correlated With Tumor ResponseCorrelated With Tumor Response

R adrenal metastectomy

Carbo/Paclitaxel/Bevacizumab

L adrenal metastasis

MDX-1106 Anti-PD-1 mAb durable response

ANA 1:40CRP 8.7RF 19

Pre-Immunotherapy baseline ANA 1:40, CRP 23, RF 19

RF = rheumatoid factor.

Evaluation and Prognostic Significance Evaluation and Prognostic Significance of CTCs in Patients With NSCLCof CTCs in Patients With NSCLC

101 patients Stage III–IV

Krebs et al, 2011.

Time From Baseline Blood Draw (months)

Ove

rall

Sur

viva

l (%

)

0 2 4 6 8 10 12 14 16 18 20

20

4

0

60

80

10

0

p < .001

CTC / 7.5 mL N (%) Median OS in at Baseline Mo. (95% CI) < 5 CTC 92 (91%) 8.1 (7.8 to 8.4)≥ 5 CTC 9 (9%) 4.3 (2.8 to 5.8)

B7-H1 (PDL1) Profiling ofB7-H1 (PDL1) Profiling ofCirculating Tumor CellsCirculating Tumor Cells

Carolina BioOncology Institute and BioCytics Inc.

Immuno-Oncology: Immuno-Oncology: Other Tumor TypesOther Tumor Types


Immune response detected?

Antigens identified?

Immunity associated with prognosis?

Spontaneous tumor regression?

TIL that can kill tumor?

There Is Evidence of Immunogenicity in Nearly

Every Tumor Type

What Defines anWhat Defines anImmunogenic Tumor?Immunogenic Tumor?

Finn, 2003

Therapeutic Adjuvant

Why Has it Been So Difficult to Develop Why Has it Been So Difficult to Develop Immune-Based Therapies That Work?Immune-Based Therapies That Work?

Successes with:– Combination therapy– Targeted populations– Low burden disease

EFS = event-free survival.Yu et al, 2010.

Anti-GD2 Antibody With GM-CSF, IL-2, Anti-GD2 Antibody With GM-CSF, IL-2, and Isotretinoin for Neuroblastoma, and Isotretinoin for Neuroblastoma,

Phase IIIPhase III

Monoclonal antibody targeting a tumor-associated ganglioside-GD2 with enhanced activity when administered with IL-2 (increases T cells) and GM-CSF (increases innate immune cells)

226 high risk neuroblastoma patients post induction and transplant, randomized 1:1, standard therapy (isoretinoin) or anti-GD2, IL-2, GM-CSF + isoretinoin

Immunotherapy superior for EFS: 67% vs. 46% at 2 yrs, p = .01

Immunotherapy superior for OS: 86% vs. 76% at 2 yrs, p = .02

52% with grade 3–5 toxicity about 25% with capillary leak syndrome

TLR-9 = toll-like receptor 9; PFS = progression-free survival, FOXP3 = forkhead box protein P3; T-reg = regulatory T cells. Brody et al, 2010.

In Situ TLR-9 With Radiotherapy inIn Situ TLR-9 With Radiotherapy inLow Grade B Cell Lymphoma, Phase IILow Grade B Cell Lymphoma, Phase II

Treg Fold Induction

5.5x 4.5x 5.0x 0.9x 1.5x 1.3xCD25

Patient 14 Patient 13 Patient 9 Patient 3 Patient 15 Patient 11

Treg inducers Treg noninducers

Time (weeks)Log (PFS or censored

follow-up [weeks])

Patient No.

Time of Best Response (weeks)

Radiation

PF-3512676

Clinical response assessment

p=0.041

p=0.001

p=0.03

Sampson et al, 2010; Camp et al, 2005.

EGFRvIII Vaccination in GlioblastomaEGFRvIII Vaccination in Glioblastoma

EGFRvIII = epidermal growth factor receptor variant III.

Before Vaccination At Recurrence

Positive Negative

Positive Negative

Positive Negative

Positive Positive (< 1%)

Positive Negative

Positive Negative

Positive Negative

Positive Negative

Positive Negative

Positive Positive

Positive Negative

EGFRvIII Immunohistochemistry Before and After Vaccination

Percent negative after vaccine is 82% (95% CI, 48%–97%) or nine of 11; binomial test p < .001

Inclusion Criteria• ≥ 18 yrs old• Newly diagnosed glioblastoma• Attempted surgical resection followed by conventional chemoradiation• Documented EGFRvIII positive tumor• No evidence of progressive disease from the post-operative period to the post-chemoradiation period• Candidate for, and agrees to receive, adjuvant (maintenance) temozolomide therapy

ESTIMATED ENROLLMENT: 440

Randomized Phase III Trial RecruitingRandomized Phase III Trial Recruiting

US NIH, NCT01480479. KLH = keyhole limpet hemocyanin.

LE = low expressor; OE = overexpressor; DTH = delayed-type hypersensitivity; HER2 = human epidermal growth factor receptor 2.Mittendorf et al, 2011; Benavides et al, 2009.

All Patients

HER2 Low Expressing

HER2 Vaccination in Early Stage HER2 Vaccination in Early Stage Breast Cancer (node +)Breast Cancer (node +)

Time (mos)

Time (mos)

Inclusion Criteria:• ≥ 18 yrs old• Pathological diagnosis of invasive adenocarcinoma of the breast• Breast cancer completely excised• Node + disease• Primary tumor stage T1–3• HER2- (HER2 1+ by IHC or HER2 2+ by IHC/FISH)• HLA-A2 or HLA-A3 haplotype• Completed NCCN approved neo-adjuvant/adjuvant chemotherapy or both• Completed radiation therapy• No evidence of disease


Randomized Phase III Trial RecruitingRandomized Phase III Trial Recruiting

WFI = water for injection; NCCN = National Comprehensive Cancer Network; IHC = immunohistochemistry;FISH = fluorescence in-situ hybridization; HLA = human leukocyte antigen. US NIH, NCT01479244.

Could generate vaccine in 91% Common solid metastatic tumors Majority vaccinated achieved SD Survival significantly associated with number of vaccines

Autologous Tumor Cell Vaccine With GM-CSF and Autologous Tumor Cell Vaccine With GM-CSF and bi-shRNA Downregulation TGF-Beta (FANG)bi-shRNA Downregulation TGF-Beta (FANG)

Senzer et al, 2012.

bi-shRNA = bifunctional short hairpin ribonucleic acid; TGF = transforming growth factor.

FANG mean TGFβ1 - ELISA (n = 42)

DaysPaired t-test*< .05, **< .01, ***≤ .001

FANG mean TGFβ2 - ELISA (n = 42)

DaysPaired t-test*< .05, **< .01, ***≤ .001

Days Since Procurement

Inclusion Criteria:• ≥ 18 yrs old• Histologically confirmed colorectal carcinoma with synchronous or metachronous liver metastases +/- pulmonary metastases• Maximum total number of metastatic lesions ≤ 6• Candidate for surgical excision +/= ablation with curative intent• Planned resected viable tumor in sufficient quantity ("golf ball size" estimated weight ~ 30 grams) for vaccine processing• ECOG performance status (PS) 0–2• Estimated > 4-mos survival probability


Randomized Phase II Trial RecruitingRandomized Phase II Trial Recruiting


….and multiple myeloma, renal, brain

355 Open Cancer Vaccine Trials180 Open Phase II and III Trials

Clinical TrialsClinical Trials Approximately 2,380 open cancer immune therapy trials

1,444 open phase II and III trials



Immunotherapy clinical trials integrate treatment into current standard of care regimens

– Recent studies suggest some of the most common chemotherapeutic agents we use have profound immunologic effects

There are immunotherapy approaches being studied in almost every common cancer, both hematopoietic and solid tumors

Both adults and children with cancer have shown benefit with immune-based therapies in published clinical trials

Most immune therapies are associated with tolerable toxicities (or even rare toxicity in the case of cancer vaccines)

There are numerous immune-based clinical trials, at all stages, open for enrollment in the US

Management of Immunotherapy-Management of Immunotherapy-Related Adverse EventsRelated Adverse Events


Disis, 2010a.

Successful Anti-Cancer Immunity Successful Anti-Cancer Immunity Is AutoimmunityIs Autoimmunity

Disis, 2011.

Autoimmunity Associated With Autoimmunity Associated With Clinical Response to Immune TherapyClinical Response to Immune Therapy Prospective observational study of 3,000 patients evaluated clinical factors

associated with favorable outcome

− Vitiligo predictive in multivariate analysis (p = .006 for OS)

Study evaluating the laboratory and clinical characteristics of 374 patients treated with IL-2 to determine biomarkers of response (NCI)

− Thyroid dysfunction (p = .01) and vitiligo (p < .01) were predictors of increased survival

Trial of 198 MM or RCC patients treated with ipilimumab suggested a higher response rate in patients who developed enterocolitis compared to those that did not (p = .0065) (NCI)

Evaluation of 200 stage II/III melanoma patients treated with interferon; development of autoimmunity correlated with longer relapse-free survival (p < .001) as well as OS (p < .001)

− Some immunity was sub-clinical (serologic only) and still demonstrated effect

Autoimmunity Associated With Improved Autoimmunity Associated With Improved Prognosis After IFN Therapy in Melanoma Prognosis After IFN Therapy in Melanoma

0.0 25.0 50.0 75.0 100.0 125.0

Patients with autoimmunity

Patients without autoimmunity

Months from start of treatment

Patients with autoimmunity

Patients without autoimmunity

0.0 20.0 40.0 60.0 80.0 100.0 120.0

Months from start of treatment

• 26% incidence• Clinical and serologic

Gogas et al, 2006; Dafni et al, 2008.

Mellman et al, 2011; Weber, 2008b.

Re

sp

on

se

ra

te t

o i

pil

imu

ma

b

Autoimmunity Associated With Autoimmunity Associated With Clinical Response After IpilimumabClinical Response After Ipilimumab

Attia Study2005

Beck Study2006

Maker Study2005

Patient number (n=)

Phase III Ipi and DTIC (Ipi at 10 mg/kg) 250

Phase-III Ipi monotherapy (3 mg/kg) 131

Phase-II Ipi monotherapy different doses 217 (71 each at 3 mg/kg and 10 mg/kg)

All grade irAE % [Grade 3, 4%]

77.7 [31.6, 10.1]

61.1 [12.2, 2.3]

65 at 3 mg/kg [7] 70 at 10 mg/kg [25]

Dermatologic % [Grade 3, 4%] Pruritus%

Rash

Vitiligo

26.7 [2.0, 0]

22.3 [1.2, 0]

43.5 [1.5, 0]24.4 [0, 0]

19.1 [0.8, 0]

2.3 [0, 0]

45 at 3 mg/kg [1.5]46 at 10 mg/kg [4.2] 21.3 at 3 mg/kg[1.4] 32.4 at 10 mg/kg [2.8] 23.9 at 3 mg/kg [1.4] 22.5 at 10 mg/kg [0]

Gastrointestinal % [Grade 3, 4%] Diarrhoea %

Colitis

32.8 [4.0, 0] 4.5 [1.6, 0.4]

29 [7.6, 0] 27.5 [4.6, 0]

7.6 [5.3, 0]

32 at 3 mg/kg [2.8] 39.4 at 10 mg/kg [15.5] 25.3 at 3 mg/kg [1.4] 39.4 at 10 mg/kg [14.0] 5.6 at 3 mg/kg [1.4]5.6 at 10 mg/kg [2.8]

Endocrine %[Grade 3, 4%] Hypothyroid % Hypopituitarism Hypophysitis Adrenal insufficiencyIncrease thyrotropin Decrease corticotrophin

7.6[2.3, 1.5] 1.5 [0, 0] 2.3 [0.8, 0.8] 1.5 [1.5, 0] 1.5 [0, 0]0.8 [0, 0] 1.5 [0, 0.8]

5.6 at 3 mg/kg [2.8]4.2 at 10 mg/kg [1.5]

Hepatic %[Grade 3, 4%] Increase ALT %Increase AST Hepatitis

29.1 [15.0, 5.7]26.7 [13.8, 3.6] 1.6 [1.2, 0]

3.8[0, 0] 1.5 [0, 0]0.8 [0, 0]0.8 [0, 0]

0 at 3 mg/kg 2.8 at 10 mg/kg [2.8]

MO

RE

CO

MM

ON

LE

SS

CO

MM

ON

DTIC = dacarbazine; Ipi = ipilimumab; ALT = alanine aminotransferase; AST = aspartate aminotransferase.Lemech et al, 2012.

irAE Associated With Ipilimumab: irAE Associated With Ipilimumab: Covers All BasesCovers All Bases

IRAEs From lpilimumab in Phase II and III Trials

Perivascular CD8

Hodi et al, 2008; Lemech et al, 2012.

Grade 1, 2:• Topical steroids or topical creams (urea based)• May require anti-pruritic management (diphenhydramine)• Avoid direct contact with sunlight, sunscreen (prophylactic)

Grade Persistent Grade 2 or Grade 3:• Withhold dose• Treat with 4-wk tapering oral steroid (1 mg/kg/day)

Grade 4:• Discontinue drug permanently• Consider IV steroids

Rash ~ 40%Grade 3–4 ~ 2%

irAE Management: Reticular irAE Management: Reticular Erythematous RashErythematous Rash

irAE Management: GI EffectsirAE Management: GI EffectsDiarrhea ~ 40%

Colitis ~ 5%

Grade 1, 2:

Loperamide and close follow-up

Small frequent meals

Bland diet

No lactose containing products

Electrolyte replacement (oral)

Grade Persistent Grade 2:

Treat with slow tapering oral steroid

(1 mg/kg/day)

Oral budesonide (9 mg daily) x8 wks

(last 2 taper)

Consider endoscopy (R/O colitis), rapidprogression can occur

Grade 3, 4:

Endoscopy

HD IV steroids, slow taper

No response to steroids: infliximab (5 mg/kg IV)

Rare case of perforation (1%)

Discontinue drug permanently

HD = high dose; R/O = rule out; GI = gastrointestinal.Lemech et al, 2012; Weber, 2007.

irAE Management: Hepatic EffectsirAE Management: Hepatic Effects

Hepatic ~ 5%

Grade 1: Monitor closely

Grade 2: Withhold drug, w/u non-immune causes LFTs daily x3 Initiate oral steroids if no improvement 48–72 hrs

Grade 3, 4: HD IV steroids, slow taper (over 1 mos) Daily LFTs No response to steroids at 48 hrs: consider mycophenolate mofetil Discontinue drug permanently

ANA = antinuclear antibody; creat = creatinine; LFTs = liver function tests; SMA = smooth muscle antibody; T Bili = total bilirubin.Lemech et al, 2012; Weber, 2007.

Determine baseline LFTs, T Bili at screening

Baseline LFTs. T Bili =

NORMAL

Baseline LFTs. T Bili= grade 1 or 2

Routine monitoring of

LFTs and T Bili

Routine monitoring of

LFTs and T Bili

LFTs and/or T Bili grade

≥2?

LFTs and/or T Bili grade ≥2x

baseline values ?

Trigger point #1 intensified monitoring

Workup for autoimmunity:1. Clinical signs

2. Labs: ANA, SMA, LFTs., T Bili, creat, other3. Check LFTs, T Bili q 3 days

Workup to do non-IRAE causes:1. Imaging to do mets

2. Consider liver biopsy if suggestion of autoimmune etiology

Monitor course:Check labs q 3

days until stable or decreasing, then once per week

Monitor course:Check labs q 3

days until stable or decreasing, then once per week

LFTs >8x ULN?And/or T Bili >5x

ULN?

Monitor course:1. Hold further Ipilimumab

2. Repeat LFTs within 24 hrs

LFTs still rising over 24-48 hrs?

and/or suspect IRAE

Trigger point #2 Therapeuticintervention

Therapeutic intervention(recommended

sequence):1. Admit to hospital2. Check labs daily

3. Steroids (IV)4. Mycophenolate mofetil

5. Tacrolimus6. Infliximab

Yes

Yes

No No

No No

NoNo

Yes

Yes

Endocrine ~ 7%Grade 3–4 < 2%

Symptoms: Headache, visual field changes, nausea, vomiting, hypotension, electrolyte abnormalities

Work-Up: TSH, free T4/T3, ADH, serum cortisol, LH, FSH, prolactin, MRI of the head

Treatment:• Hold drug• Stress does IV steroids• Gonadal and thyroid replacement, may need permanently• Ongoing monitoring• May consider restarting ipilimumab is grade 1–2 after symptoms resolved

ADH = adrenocorticotropic hormone; LH = luteinizing hormone; FSH = follicle stimulating hormone; TSH=thyroid-stimulating hormone; T4= thyroxine; T3= triiodothyronine ;MRI = magnetic resonance imaging.Lemech et al, 2012.

irAE Management: EndocrinopathiesirAE Management: Endocrinopathies

Weber, 2008b.

Treatment

Post-Treatment Initiation (wks)

= First efficacy assessmentSD

PR

CR

Ongoing 57 + wk no new lesions

• When toxicities occur is variable • Early and late

• Prolonged treatment

• May need to treat again

T Cells Continue to Evolve Even T Cells Continue to Evolve Even After Drug Is Cleared After Drug Is Cleared

Evolving Immune Response

Responses as late as 106 wks


The development of autoimmune phenomenon may be an expected toxicity associated with some immune-based therapies

Autoimmunity may demonstrate immune activation and has been associated with improved outcome in studies of some immune-based treatments

Autoimmunity induced by current immune-based therapies is self-limited once the treatment has been discontinued

• If toxicity not life-threatening, consideration may be given to reinstituting therapy once symptoms have resolved

If the autoimmune toxicities are mild, symptoms can be managed medically while the patients remain on treatment

Autoimmune adverse events may occur at anytime in the course of treatment

Health & Medicine

Immuno-Oncology: A Colloquium on the State of the Science for Oncology Clinicians