immuno-oncology: an evolving approach to cancer care

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product information, and comparison with recommendations of other authorities.

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Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestThomas F. Gajewski, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Consultant, Amgen, Bristol-Myers Squibb Company, GlaxoSmithKline plc, Merck & Co., Inc., Roche Pharmaceuticals, Inc.; Contracted Research, Bristol-Myers Squibb Company, CureTech Ltd., GlaxoSmithKline plc, Morphotek, Inc., Roche-Genentech.

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, Amplimmune, Inc., Bristol-Myers Squibb Company, Dendreon Corporation, ImmuneXcite, 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, Inc.; Consulting Fees, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech BioOncology; Speakers Bureau, Bristol-Myers Squibb Company; Contracted Research, Amplimmune, Inc., Bristol-Myers Squibb Company, Genentech BioOncology; Company Ownership Interest, BioCytics, Inc.

Michael B. Atkins, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, AstraZeneca Pharmaceuticals LP, AVEO Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Genentech BioOncology, Prometheus.

Welcome and Activity Welcome and Activity OverviewOverview

Thomas F. Gajewski, MD, PhDThe University of Chicago Medicine

Learning ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants

should be better able to:should be better able to:

Enhance knowledge on the biological foundations of immuno-oncology approaches to the treatment of cancer

Describe the roles, targets, and mechanisms of action of novel and emerging immuno-oncologic agents

Evaluate new safety and efficacy data on recently approved and emerging immuno-oncologic agents across tumor types

Identify unique patterns of clinical response in patients treated with immuno-oncologic agents

Monitor and manage immune-related adverse effects associated with immuno-oncologic agents

Describe how new immuno-oncologic agents are being integrated into existing treatment evidence-based guidelines

Activity AgendaActivity Agenda

7:30 – 7:35 pm Welcome and Activity Overview

7:35 – 7:50 pm Immuno-Oncology: Understanding the Biological Foundations of the Immune System in Cancer

7:50 – 8:10 pm Melanoma: A Classic Tumor Model for Immunotherapy

8:10 – 8:25 pm The Evolving Role of Immunotherapy for Prostate Cancer

8:25 – 8:40 pm The Emerging Role of Immunotherapy for Lung Cancer

8:40 – 8:55 pm Emerging Immunotherapies for Renal Cell Carcinoma

8:55 – 9:15 pm Interactive Case Studies: Applying Current Immunotherapies Into Practice

9:15 – 9:25 pm Expert Panel Perspectives: Placing Current and Emerging Immunotherapies in Clinical Context

9:25 – 9:30 pm Questions & Answers and Activity Conclusion

Immuno-Oncology: Immuno-Oncology: Understanding Biological Understanding Biological

Foundations of the Immune Foundations of the Immune System in CancerSystem in Cancer


The Genetic Instability of Cancer Cells Creates The Genetic Instability of Cancer Cells Creates Antigens That Can Be Recognized by the Antigens That Can Be Recognized by the

Immune SystemImmune System

MHC = major histocompatibility complex.www.immunoweb.com/tu10.htm

Normal cell presents self peptides bound to MHC molecules

Normal cell

A point mutation in a self protein allows binding of a new peptide to MHC molecules

Tumor cell

A point mutation in a self peptide createsa new epitope for recognition by T cells

Tumor cell

New peptidescreated by mutation

or increased expression

Generation of Tumor AntigensGeneration of Tumor Antigens

Point mutations in normal genes

Overexpressed normal genes

Molecular mishaps (reverse strand, intron sequences, alternative splicing)

Embryonic genes

Tissue-restricted differentiation antigens

Translocation fusion proteins

Viral genes

Alternative glycosylation

Two Principal Means to Promote Two Principal Means to Promote Immune-Mediated Tumor Destruction: Immune-Mediated Tumor Destruction:

Cytolytic T Lymphocytes and AntibodiesCytolytic T Lymphocytes and Antibodies

NK = natural killer.

CD8+ Cytotoxic T Lymphocyte Killing CD8+ Cytotoxic T Lymphocyte Killing an Antigen-Expressing Tumor Cellan Antigen-Expressing Tumor Cell

How Do These CD8+ T Cells Initially Become Activated to Fight Tumors?

TCR = T-cell receptor.Boissonnas et al, 2007.

T Cells Traffic Between the Tissues, T Cells Traffic Between the Tissues, Lymphatics, and the Blood in Two Major Lymphatics, and the Blood in Two Major

Differentiation StatesDifferentiation States

Tumor

Janeway et al, 2001.

Lymphocytes and lymph return to blood

via thoracic duct

Naïve lymphocytes enter lymph nodes

from blood

Antigens from sites of infection reach lymph nodes via lymphatics

Infected peripheral tissue

Lymph node

heart

Dendritic Cells (DCs) Pick Up Antigens From Dendritic Cells (DCs) Pick Up Antigens From Infected Tissues and Migrate to Lymph NodesInfected Tissues and Migrate to Lymph Nodes

Discovery of dendritic cells by Ralph Steinman earned Nobel Prize in 2011

Banchereau et al, 1998.

Antigen uptake by Langerhans’ cells in the skin

Langerhans’ cells leave the skin and enter the lymphatic system

Langerhans’ cells enter the lymph node to become dendritic

cells expressing B7

B7-positive dendritic cells stimulate naïve T cells

The Main Costimulatory Receptor on The Main Costimulatory Receptor on T Cells is CD28, Which Binds to B7-1/B7-T Cells is CD28, Which Binds to B7-1/B7-

2 on Activated Dendritic Cells2 on Activated Dendritic Cells

APC = antigen presenting cell.Janeway et al, 1996; Topalian et al, 2011.

T cell

CD4

TCR/CD3complex

CD28

APC MHC class II

B7.1 or

B7.2

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2

nCD8 Migration FromLymph Node

Migration toLymph Node

Migration FromTumor

granzymes

Model for CD8+ T-Cell-Mediated Anti-Tumor Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response Immune Response In VivoIn Vivo

Harlin et al, 2009; Gajewski et al, 2006.

Theoretical Reasons for Failure of Immune Theoretical Reasons for Failure of Immune System to Prevent Cancer OutgrowthSystem to Prevent Cancer Outgrowth

Failure to activate specific T cells

– Inadequate antigen processing/presentation

– Insufficient T-cell repertoire

– Available T cells below activation threshold setpoint

Ineffective T-cell differentiation into effector cells

Inadequate expansion of T cells to needed frequency

Lack of homing of primed T cells to tumor sites

Immunosuppression in tumor microenvironment

– CTLA-4 on T cells (inhibitory receptor)

– PD-1 on T cells (binds PD-L1 on tumor cells)

– T-cell anergy (deficient B7 costimulation)

– CD4+CD25+FoxP3+ Tregs (extrinsic suppression)

– Indoleamine-2,3-dioxygenase (IDO tryptophan catabolism)

Gajewski et al, 2007; Zou, 2005.

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor

granzymesVaccinesVaccines

CytokinesCytokines

ChemokinesChemokines

Blockade of suppressionBlockade of suppression

CostimulationCostimulation

Model for CD8+ T-Cell-Mediated Anti-Tumor Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response Immune Response In VivoIn Vivo: Interventions: Interventions


TLR ligandsTLR ligands

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor


CytokinesCytokines




Model for CD8+ T-Cell-Mediated Anti-Tumor Model for CD8+ T-Cell-Mediated Anti-Tumor Immune Response Immune Response In VivoIn Vivo: Interventions (cont.): Interventions (cont.)


TLR ligandsTLR ligands

Toll-Like Receptors (TLRs)Toll-Like Receptors (TLRs)

First identified in Drosophila as receptor recognizing pathogens for innate immunity

At least 11 mammalian homologues identified

Expressed on DCs and other APCs

Mediate activation and maturation of APCs to render them optimal for T-cell activation

Ligands should be excellent vaccine adjuvants

Discovery of Innate Immune Sensing Systems by Bruce Beutler and Jules Hoffmann Earned Nobel Prize in 2011

Takeda et al, 2004.

TLR PathwayTLR Pathway

Triggers activation of dendritic cells and other APCs

Medzhitov et al, 2001.

Plants Drosophila Mammals

Extracellular

Cytoplasm

RPP5, N, L6

Pathogen or PAMP

Immune response Immune response Immune response

PAMP

Protease

Spätzle

Toll

MyD88 MyD88 MyD88

TLR4

TIRAP

IL-1R

IL-1PAMP

Imiquimod for Basal Cell Carcinoma (BCC)Imiquimod for Basal Cell Carcinoma (BCC)

Imiquimod is a TLR7 agonist that activates DCs Randomized clinical trial done in patients with BCC 100% RR with BID dosing compared to 19% with vehicle

alone! Also active on warts and cutaneous metastases of

melanoma Other TLR ligands are in clinical trials, including CpG 7909

(TLR9 agonist) TLR agonists being combined with tumor antigens in

cancer vaccines (eg, GSK-Bio MAGE3 vaccine)

RR = response rate.Sapijaszko, 2005; Goldman et al, 2009.

Key TakeawaysKey Takeaways

CD8+ T cells can recognize neoantigens expressed by tumor cells

In order for antigen-specific T cells to become activated to differentiate into cytolytic effector cells, they need to be stimulated by activated DCs in lymph nodes

DCs must be activated via innate immune sensing pathways (TLRs)

Activated CTL recirculate and traffic tumor tumors where they have a chance to destroy cancer cells

In cancer, failure can occur at various stages of this process, which generates multiple opportunities for therapeutic intervention

CTL = cytotoxic T lymphocyte.

Melanoma: A Classic Tumor Melanoma: A Classic Tumor Model for ImmunotherapyModel for Immunotherapy


eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor


CytokinesCytokines






Immunization ModalitiesImmunization Modalities Antigen delivery strategy

– Targeting endogenous APCs

• Synthetic peptides or protein in adjuvant

• Recombinant viruses, bacteria

• Irradiated tumor transfectants

• Antigen/antibody complexes

• Antigen/TLR ligand fusions

• Plasmids (CpG oligonucleotides)

– Ex vivo loaded APCs

• Peptide, protein, tumor lysates, etc.

Additional modulators

– Cytokines, adjuvants, modulatory antibodies

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor


CytokinesCytokines






CTLA-4 Blockade for CTLA-4 Blockade for ImmunopotentiationImmunopotentiation

CTLA-4 is receptor induced on activated T cells

Ligation inhibits T cell activation

CTLA-4 deficient mice develop autoimmunity dominant role is negative

Two defined ligands expressed largely on APC populations: B7-1 and B7-2

Neutralizing mAbs against CTLA-4 augment T-cell activation and promote tumor rejection in several mouse models

Two anti-CTLA-4 mAbs explored in clinical trials

Ipilimumab approved by FDA in 2011

CTLA-4 = cytotoxic T lymphocyte antigen-4; mAbs = monoclonal antibodies. Pardoll, 2012; YervoyTM prescribing information, 2012.

CTLA-4 Is a Negative Regulator CTLA-4 Is a Negative Regulator of T-Cell Activationof T-Cell Activation

TCR

CD28B7

T Cell APC TCR

CD28 B7

B7CTLA4

T Cell APC

Resting T Cell Activated T Cell

Pardoll, 2012; Korman et al, 2006.

Randomized Study of Vaccine Vs. Ipilimumab Randomized Study of Vaccine Vs. Ipilimumab Vs. Combination in Advanced MelanomVs. Combination in Advanced Melanomaa

Ipi = ipilimumab.Hodi et al, 2010.

Clinical Response in Melanoma With Clinical Response in Melanoma With Single Agent Anti-CTLA-4 mAbSingle Agent Anti-CTLA-4 mAb

Week 20: Regression Week 36: Still Regressing

Screening Week 12: Progression

Wolchok et al, 2008.

T-Cell Infiltration in Skin and Gut T-Cell Infiltration in Skin and Gut Following Anti-CTLA-4 mAb TreatmentFollowing Anti-CTLA-4 mAb Treatment

Sarnaik et al, 2009.

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor


CytokinesCytokines






IL-2 in Melanoma: RR 16%IL-2 in Melanoma: RR 16%

Atkins et al, 1999.

Modified gp100 Peptide in Montanide Modified gp100 Peptide in Montanide +/- Exogenous IL-2+/- Exogenous IL-2

Additional 19 patients treated with high-dose IL-2 after gp100 209M vaccination

In this study, 8 patients (42%) showed objective tumor regression

Suggests IL-2 may help expand relevant T cells or support their trafficking

Caveat: Effect of IL-2 alone?

Rosenberg et al, 1998.

High-Dose IL-2 ± Peptide Vaccine Phase IIIHigh-Dose IL-2 ± Peptide Vaccine Phase III

Schwartzentruber et al, 2011.

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

eCD8

CD28IL-2



Migration FromTumor

granzymes

Adoptive T-cellAdoptive T-celltherapytherapy

Model for CD8+ T-Cell Mediated Anti-Model for CD8+ T-Cell Mediated Anti-Tumor Immune Response Tumor Immune Response In Vivo In Vivo (cont.)(cont.)


Adoptive T-Cell TherapyAdoptive T-Cell Therapy

T cells are isolated, from tumor site or generated in vitro

Ex vivo enrichment and expansion of antigen-specific effector T cells

T cells are reintroduced back to the patient

Usually the patient is “conditioned” first with lympho depleting chemotherapy or other agents

Yee, 2009.

T cells isolated

from patient

In vitro expansion

and activation

Adoptive transfer

into patient

TIL Therapy for Melanoma: TIL Therapy for Melanoma: Rosenberg ApproachRosenberg Approach

Tumor harvested, TILs collected and expanded for infusion

In interim, patients receive lymphoablative chemotherapy to “make space”

T cells are transferred and patients are given IL-2

Results: 6 of 13 patients responded

TILs = tumor-infiltrating lymphocytes. Dudley et al, 2003.

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor


CytokinesCytokines






Expression of a Subset of Chemokine Genes Is Expression of a Subset of Chemokine Genes Is Associated With Presence of CD8 TranscriptsAssociated With Presence of CD8 Transcripts

CD8bCCL2CCL4CCL5CXCL9CXCL10CCL19CCL21

Harlin et al, 2009.

‘‘‘‘Inflamed’’ Gene Expression Signature Is Inflamed’’ Gene Expression Signature Is Associated With Survival Following GSK MAGE3 Associated With Survival Following GSK MAGE3

Protein VaccineProtein Vaccine%

P

ati

en

ts

Time (mos)

AS15 GS+AS02B GS+

AS15 GS-AS02B GS-AS15: HR (GS+ vs. GS-) = 0.268 (95%CI [0.08;0.90])

AS02B: HR (GS+ vs. GS-) = 0.433 (95%CI [0.17;1.14])

100

90

80

70

60

50

40

30

20

10

HR = hazard ratio; CI = confidence interval.Louahed et al, 2009.

Ipilimumab (anti-CTLA4 mAb) Clinical Responders Ipilimumab (anti-CTLA4 mAb) Clinical Responders Also Appear to Show an Also Appear to Show an ““InflamedInflamed”” Tumor Gene Tumor Gene

Expression ProfileExpression Profile

Ji et al, 2011.

CXCL9, 10, 11 CCL4, CCL5 Granzyme B Perforin CD8a

No Benefit Benefit

eCD8

APC

Tumor

Immature DC

Mature DC

MHC I MHC II

B7

TCR

Lymph Node

eCD8

CD28IL-2



Migration FromTumor


CytokinesCytokines






Why Are Melanomas That Attract CD8+ Why Are Melanomas That Attract CD8+ T Cells Not Rejected Spontaneously?T Cells Not Rejected Spontaneously?

Presence of Inhibitory PathwaysPresence of Inhibitory Pathways

IDO (indoleamine-2,3-dioxygenase: metabolizes tryptophan)

PD-L1 (engages PD-1: inhibitor receptor)

CD4+CD25+FoxP3+Tregs (extrinsic suppression)

T-cell anergy (B7-poor: T cell-intrinsic desensitization)

FoxP3 = forkhead box P3; PD-1 = Programmed death-1; PD-L1 = PD ligand 1.Gajewski et al, 2006; Gajewski, 2007.

A: IDO B: FoxP3

C: PD-L1

IHC for IDO, FoxP3, and PD-L1 Shows IHC for IDO, FoxP3, and PD-L1 Shows Expression in Distinct Cell Subsets in Expression in Distinct Cell Subsets in

Melanoma MetastasesMelanoma Metastases

Munn et al, 2007; Blank et al, 2004; Quaglino et al, 2011.

-100

-80.0

-60.0

-40.0

-20.0

0.00

20.00

40.00

60.00

Patients

Anti-PD-1 mAb Phase I (MDX-1106; Anti-PD-1 mAb Phase I (MDX-1106; BMS 936558): Tumor ResponseBMS 936558): Tumor Response

Melanoma

Responses Also Seen in NSCLC and RCC

NSCLC = non-small cell lung cancer; RCC = renal cell carcinoma.Sznol et al, 2010.

Clinical Trials Ongoing to Block Negative Clinical Trials Ongoing to Block Negative Regulatory Pathways Acting in the Regulatory Pathways Acting in the

Tumor MicroenvironmentTumor Microenvironment Depletion of Tregs

– Denileukin diftitox (DT; IL-2: DT fusion protein)

– Anti-CD25 mAbs (Basilixumab)

Blockade of PD-1/PD-L1 interactions

– Anti-PD-1 mAb

– Anti-PD-L1 mAb

Inhibition of IDO

– 1-methyltryptophan

– Incyte compound INCB24360

Reversal of anergy

– Adoptive transfer into lymphopenic host

– Exogenous IL-7, IL-15

Soon: Combinations to block two pathways synergistically

clinicaltrials.gov, 2012.

Key TakeawaysKey Takeaways New strategies for the immunotherapy of melanoma are

emerging through a careful dissection of the mechanisms of anti-tumor immune responses

New approaches include more potent vaccines, agents to block immune inhibitory pathways like CTLA-4, and adoptive T-cell therapy

The next wave of new agents are targeting immune suppressive mechanisms within the tumor microenvironment

Predictive biomarkers are being evaluated to better select patients with tumors amenable to the benefit of immunotherapies (HER2 expression and trastuzumab)

Translational Research Is Like Scuba DivingTranslational Research Is Like Scuba Diving

Hawaii, 2011.

The Evolving RoleThe Evolving Roleof Immunotherapy for of Immunotherapy for

Prostate CancerProstate Cancer

Charles G. Drake, MD, PhDThe Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

OutlineOutline

Prostate Cancer Vaccines

– Sipuleucel-T

– ProstVac VF

Immune Checkpoint Blockade in Prostate Cancer

– Anti-CTLA-4, Ipilimumab

– Anti-PD-1, BMS-936558

Combining Immunotherapy With Conventional Therapy

– Radiation Therapy

– Androgen-Ablation

The Evolving Landscape of Prostate Cancer Treatments

Patient WBC harvested

Short-term culture with protein “cassette”

Shipping

Cells infused BACK into patient (IV)

q2wks x 3

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.

Cancer Vaccines:Cancer Vaccines:Immunological MOAImmunological MOA

CD4 T Cell

TCR

CD8 T Cell

TCRCytokines = HELP

Activated CD8 T Cells Traffic to Tumor and Lysis 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.

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 = 0.032 (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

OS = overall survival; ITT = intent-to-treat.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; Drake, 2010.

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: Metastatic CRPC 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)

Study is currently recruiting.SPA = special protocol assessment.US NIH, 2012a.

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) TRICOM

Adjuvant placebo

PROSTVAC-(V)(F) TRICOM

Adjuvant placebo

Non/Minimally Symptomatic

MetastaticCRPC

Non/Minimally Symptomatic

MetastaticCRPC

Standard of Care

Primary end point: OS

T Cell

HLA

TCR

AntigenSignal 1

B7.1/2

CD28

Antigen Presenting Cell

Signal 2

CTLA-4

CTLA-4

CTLA-4 Blockade in Prostate CancerCTLA-4 Blockade in Prostate Cancer

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

CTLA-4 Blockade in Prostate Cancer Anecdotal CTLA-4 Blockade in Prostate Cancer Anecdotal Response: Subject 3020, 10 mg/kg MonotherapyResponse: Subject 3020, 10 mg/kg Monotherapy

uCR = unconfirmed complete response; TFTs = thyroid function tests; irAEs = immune-related adverse events.Beer et al, 2008.

Ipilimumab: Ipilimumab: Pre-Chemotherapy Pre-Chemotherapy PhasePhase III Trial III Trial

InductionRandomization – Wk 24

Ipilimumab 10 mg/kg

Ipilimumab 10 mg/kg

PlaceboPlacebo ObservationObservation

ObservationObservation

DosingWk 1, 4, 7, 10

Ipilimumab 10 mg/kg

Ipilimumab 10 mg/kg

PlaceboPlacebo

Dosingq12wks

MaintenanceWk 24 – 48+

ScreeningDay -28 to Rand

Randomization2:1

N = 600

After treatment is discontinued subjects enter F/U phaseAfter treatment is discontinued subjects enter F/U phase

Survival

Tox & PD

F/U q12wks for toxicity and/or PD

F/U q12wks for toxicity and/or PD

F/U q12wks for survival

F/U q12wks for survival

OS: Primary End Point

PD = progressive disease.US NIH, 2012b.

CTLA-4 and an Immune-Mediated Abscopal EffectCTLA-4 and an Immune-Mediated Abscopal Effect

33-yr-old with metastaticmelanoma

– Enrolled on ipilimumab trial

– SD x 1 yr

– Enlarging paraspinal mass, newsplenic lesions

RX 2850 cGy to mass(3 fxn, 7 days)

1-month post RT

– No response primary site

– Responding lesions in spleen

Immunological correlates

– 30x increase in anti-NY-ESO-1 titer

– Increase in NY-ESO-1 reactive T cells

RT = radiotherapy.Postow et al, 2012.

Ipilimumab: Post-Chemotherapy Ipilimumab: Post-Chemotherapy Phase III TrialPhase III Trial

ICF, Baseline Assessments

RT (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 Day -2 Day -2 to Wk 24 Wk 24 to Wk 48+

SCREENING

TA: q12wksPSA: q6wksOA: q12wks

CRPCPriorDocetaxel

N = 800

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

Effect of Androgen-Ablation Effect of Androgen-Ablation on T-Cell Response on T-Cell Response

Drake et al, 2005.

A Randomized, Open-Label, Phase II Trial A Randomized, Open-Label, Phase II Trial Examining the Sequencing of Sipuleucel-T Examining the Sequencing of Sipuleucel-T

and Androgen Deprivation Therapy and Androgen Deprivation Therapy

Eligibility• 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 1Sipuleucel-T ADTN = 30

Treatment Arm 2ADT Sipuleucel-TN = 30

RESPONSEImmune, PSA

SAFETY

24 mos visit

Stu

dy

Pa

rtic

ipa

tio

n C

on

clu

de

s

ADT = androgen deprivation therapy; RP = radical prostatectomy; XRT = radiation therapy; CT = computed tomography.Antonarakis et al, 2011; US NIH, 2012d.

RESPONSEImmune, PSA

SAFETY

27 mos visit

Exploratory end point: PSA Progression post RX

Sequencing Therapy in Prostate Cancer: 2012Sequencing Therapy in Prostate Cancer: 2012

AndrogenAblation

Sipuleucel-T*Cabazitaxel*

Abiraterone*Abiraterone**

Ipilimumab***

ProstVac VF***

Docetaxel Chemotherapy*

MDV3100**

Alpharadin**

* FDA approved.** Announced positive.*** In progress.

Ipilimumab***

Key TakeawaysKey Takeaways

Prostate Cancer Is Immunologically Responsive

– Sipuleucel-T FDA Approved

– ProstVac VF in Phase III

Immune Checkpoint Blockade in Prostate Cancer

– Objective Response(s) With CTLA-4 Blockade

– Phase III Trials in Progress

– Good Evidence for PD-1 Expression on TIL

Combining Immunotherapy With Conventional Therapy

– Radiation Therapy + CTLA-4 Blockade

– Androgen-Ablation + Sipuleucel-T

The Emerging Role of The Emerging Role of Immunotherapy for Lung CancerImmunotherapy for Lung Cancer

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

BackgroundBackground

NSCLC remains the leading cause of cancer-related mortality worldwide

Increased tumor-infiltrating lymphocytes in lung cancer are prognostic for improved survival

Any tumor may be antigenic (induce immune recognition)

– Rarely, tumors are immunogenic (induce immune destruction)

Lung cancers are highly mutated, therefore express large repertoire of “neoantigens” as targets of immune recognition

– Lung cancers are tolerogenic (induce immune tolerance)

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)

Long-Term Survival for Patients With Long-Term Survival for Patients With NSCLC With Intratumoral Lymphoid NSCLC With Intratumoral Lymphoid

StructuresStructures 74 patients resected

NSCLC tertiary lymphoid structures “tumor-induced bronchus-associated lymphoid tissue”Ti-BALT follicle density of mature DCs correlated with survival

Better predictor than all other clinical-pathologic parameters

DFS = disease-free survival; Ti-BALT = tumor-induced bronchus-associated lymphoid tissue.Dieu-Nosjean et al, 2008.

Time (mos)

Prognostic Value of Stromal Innate Prognostic Value of Stromal Innate Immune Cells in NSCLCImmune Cells in NSCLC

335 patients resected stage I–IIIa NSCLC

Stromal CD56+ NK cells were independent prognostic factor for disease-specific survival

Al-Shibli et al, 2009.

Time (mos)

Cancer Self-Tolerance BlockadeCancer Self-Tolerance Blockade

Human cancers harbor genetic alterations, generating neo-antigens

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, PD-1L) abort immune responses

– Co-opted by tumors to evade immune destruction

– “Tumor adaptive immune resistance”

• Immune checkpoint inhibitors can block self-tolerance of cancer, and enable anti-tumor immune destruction

PD-1 = programmed cell death protein-1.Topalian et al, 2011.

Immunological SynapseImmunological Synapse

4-1BBL = 4-1BB ligand; BTLA = B- and T-lymphocyte attenuator; ICOS = inducible T-cell costimulator.Topalian et al, 2011.

Targeting the PD-1/B7-H1 (PD-1L) Pathway Targeting the PD-1/B7-H1 (PD-1L) Pathway to Anti-Tumor Activate Immunityto Anti-Tumor Activate Immunity

DC = dendritic cell.Topalian et al, 2012.

B7.1/2

DC DCSignal 1 Signal 1

CTLA-4 tocell surface

CD28

Naïve/resting T cell CTLA-4

Costim. lignad Costim. receptor

DCSignal 1

Traffic to periphery

T cell priming Inflammation

Signal 1

Tissue

B7-H1

PD-1

Antigen experienced T cell

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 (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-1L

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

– MPDL3280A (Genentech/Roche)

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

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

P = placebo; C = chemotherapy (Pac/Carbo); Pac = paclitaxel; Carbo = carboplatin; Ipi = ipilimumab (10 mg IV).Lynch et al, 2011.

CA184-041: Stage IIIB/IV NSCLC CA184-041: Stage IIIB/IV NSCLC Cohort OSCohort OS

Lynch et al, 2011.

CA184-041: Stage IIIB/IV NSCLC CA184-041: Stage IIIB/IV NSCLC Cohort mWHO PFSCohort mWHO PFS

PFS = progression-free survival.Lynch et al, 2011.

CA184-041: Stage IIIB/IV NSCLC Cohort OS CA184-041: Stage IIIB/IV NSCLC Cohort OS Squamous SubsetSquamous Subset

Lynch et al, 2011.

Ongoing Lung Cancer Ipilimumab TrialsOngoing Lung Cancer Ipilimumab Trials

NSCLC

– CA184-104: Randomized, Multicenter, 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 Ipilumumab 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

Small Cell Lung Cancer (SCLC)

– CA184-156: Trial in 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


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 regions p = .02

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

Konishi et al, 2004.

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

Activity, Pharmacodynamics, and Immunologic CorrelatesActivity, Pharmacodynamics, and Immunologic Correlates

39 patients

– Dose escalation 6 patient cohorts (0.3, 1, 3, 10 mg/kg)

– 1 CR (colon cancer), 2 PR (melanoma, renal), 12 SD > 3 mos, including 2 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 steroids)

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

MTD = maximum-tolerated dose; DLT = dose-limiting toxicity.Brahmer et al, 2010.

May 2007 July 2007

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

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

Rechallenged MDX-1106, progressed

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

Clinical Activity and Safety of Anti-PD-1 (BMS-Clinical Activity and Safety of Anti-PD-1 (BMS-936558, MDX-1106) in Patients936558, MDX-1106) in Patients

With Advanced NSCLCWith Advanced NSCLC Phase Ib, 240 patients solid tumors stage IV

– 75 NSCLC, failed prior chemo (60% > 3 regimens)

– RX monotherapy mAb up to 12 cycles (4 doses/cycle) until PD or CR (RECIST criteria)

– Grade 3/4 toxicity 8%, including 1 death from pulmonary toxicity

aResponse evaluable patientsbCR or PRcUnconfirmed PRdRR [(OR + uPR) ÷ n]Brahmer et al, 2012.

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

60-yr-old male patient

– 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.

Anti-PD-1 mAb ResponderAnti-PD-1 mAb Responder 69-yr-old white male recurrent stage IV NSCLC, progressed after

carboplatin/paclitaxel/bevacizumab. Started on MDX-1106.

February 2009 September 2009

Courtesy of John Powderly II, MD, CPI.

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 With 3 Platinum-Based Doublet Chemotherapy Regimens in Subjects With Treatment-Naive Stage IIIB/IV NSCLC (NCT01454102) North America, 60 Patients

PCD4989g: Study of the Safety and Pharmacokinetics of MPDL3280A (anti-PD-1 mAb) Administered Intravenously As a Single Agent to Patients With Locally Advanced or Metastatic Solid Tumors (NCT01375842) US 88 Patients


Vaccines in NSCLC: Rational, Combination Vaccines in NSCLC: Rational, Combination Strategies, and Update on Clinical TrialsStrategies, and Update on Clinical Trials

Stage IIIB/IV Setting

– L-BLP25 (Liposomal MUC1 core peptide, 25 AA, Oncothyreon/Merck)

• Phase III 1,300 patients stage IIIB START trial, Global

• Phase III 420 patients stage IIIB INSPIRE trial, Asia

– TG4010 (Modified vaccinia virus Ankara expressing MUC, IL-2, Transgene/Novartis)

• Phase IIB/III

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

• Phase III

– GVAX (Autologous NSCLC cells, Adenoviral Vector modified GM-CSF) Cell Genesys-BioSante Pharma

• Phase II broncho-alveolar

– Belagenpumatucel-1 (4 allogeneic NSCLung lines transfected TGF-B2 antisense, irradiated) NovaRX

• Phase III 700 patients, Stage IIIA, B, IV, STOP trial, maintenance therapy after chemo

Adjuvant Stage I–IIIA Setting

– GSK1572932A MAGE-A3 liposomal AS15 adjuvant system GSK

• Phase III, 2,270 patients, MAGRIT trial, stage IB–IIIA

MAGE-A3 = melanoma-associated antigen-A3; AA = amino acid; START = Stimulating Targeted Antigenic Responses To NSCLC; INSPIRE = Stimuvax trial In Asian NSCLC Patients: Stimulating Immune Response; MAGRIT = MAGE-A3 as Adjuvant NSCLC Immunotherapy.DePas et al, 2012.

Ongoing Adjuvant MAGRIT StudyOngoing Adjuvant MAGRIT Study

GSK1572932A (MAGE-A3) vaccine

• Liposomal AS15 adjuvant, synthetic CpG motifs, purified monophosphoral lipid from salmonella, tree saponin

2,270 Resected Stage IB–IIIA NSCLC

– 4 cycles platinum-based chemotherapy

• Cohort without chemo due to low stage or contra-indications

– Randomized 2:1 vaccine or placebo

– 11,000 patients screened, 10,000 tumors tested, 3,235 tested + MAGE A3, just completed accrual May 2012 (largest lung cancer trial ever)

clinicaltrials.gov; NCT00480025.

Emerging Immunotherapies Emerging Immunotherapies for Renal Cell Carcinomafor Renal Cell Carcinoma

Michael B. Atkins, MDGeorgetown Lombardi Comprehensive

Cancer Center

Six Years of Impressive ProgressSix Years of Impressive Progress

Setting Phase III Alternative

First-Line Therapy

Good or Intermediate Risk*

Sunitinib

Pazopanib High-Dose IL-2

Bevacizumab + IFN

Poor Risk* Temsirolimus Sunitinib

Second-Line Therapy

Prior Cytokine SorafenibSunitinib or

Bevacizumab

Prior VEGFR Inhibitor

Everolimus

AxitinibClinical Trials

Prior mTOR Inhibitor

Clinical Trials

Does Immunotherapy Have Any Role?

*MSKCC risk status.VEGFR = vascular endothelial growth factor; mTOR = mammalian target of rapamycin; MSKCC = Memorial Sloan-Kettering Cancer Center. Atkins, 2006; Figlin, 2007; Escudier, 2007; Cho et al, 2007; Atkins et al, 2005.

Immunotherapy for RCCImmunotherapy for RCC

High-dose IL-2

– Contemporary clinical experience

– Patient selection opportunities

Checkpoint inhibitors

– Anti-CTLA4

– PD-1 pathway blockade

Vaccine approaches

Rosenblatt et al, 2011.

Activity of IL-2 Is > 20 Years Ago Activity of IL-2 Is > 20 Years Ago

Response* %

Historical Rate 14

IL-2 Select Trial (all patients n = 120)* 25

p = .0014

95% CI = 17.5%–33.7%

*Using WHO Criteria.

McDermott et al, 2010.

Likely explanations for improved RR include:

1) Improved screening • Smaller non-clear cell population

2) Fewer patients treated with original tumor in place3) Impact of new therapies on IL-2 referral patterns

Overall Survival EstimatesOverall Survival Estimates

IL-2 Select RCC Survival CurveIL-2 Select RCC Survival Curve


Combined UCLA/DFHCC ModelCombined UCLA/DFHCC Model

+

HighLow

CA-9 Staining

Poor

Intermed

Good

Pathology Risk Group

CA = carbonic anhydrase.Atkins et al, 2005.

Intermed

Poor

Good

24% (15%–35%)Intermediate (n = 83)

p Value*RR (95% CI)Tumor risk group

.8927% (6%–61%)Good (n = 11)

28% (12%–49%)Poor (n = 25)

.1922% (13%–33%)High (> 85% n = 77)

33% (19%–50%)Low (≤ 85% n = 39)

CA-9 Score

Combined Score

.3923% (14%–34%)Good (n = 74)

30% (17%–46%)Poor (n = 42)

Response by Tumor FeaturesResponse by Tumor Features

CA-9 = cancer antigen-9; RR = relative risk.


IL-2 Select Trial: CommentaryIL-2 Select Trial: Commentary

Potential explanations for this result:

– Tumor factors are important but markers other than CA-9 will be more predictive

– Samples analyzed are not “representative” given the lack of standards for tumor processing at community centers


Gerlinger et al, 2012.

IL-2 Select Trial: CommentaryIL-2 Select Trial: Commentary

Potential explanations for this result:

– Tumor factors are important but markers other than CA-9 will be more predictive

– Samples analyzed are not “representative” given the lack of standards for tumor processing at community centers

– Host factors (eg, patient immune response, tumor microenvironment) may play are larger role in determining response


Response to IL-2 May Be Associated Response to IL-2 May Be Associated With Tumor Expression of PD-L1/L3With Tumor Expression of PD-L1/L3

RR (%) p Value*PD-L1 Tumor

Negative (n = 95) 19 .012

Positive (n = 18) 50

PD-L3 Tumor

Negative (n = 28) 10.7 .075

Positive (n = 85) 29.4

IHC performed at Mayo Clinic by Kwon, Leibovich, et al.

Status of the Immunotherapy Status of the Immunotherapy Selection ProjectSelection Project

In this trial, analysis of tumor based predictive markers through central pathology review and staining for CA-9 was unable to improve the selection criteria for high-dose IL-2

Expression of B7-H1 and H3 by IHC associated with response to IL-2, requires confirmation in an independent dataset

Efforts to confirm other proposed biomarkers are ongoing to understand tumor and host factors that predict IL-2 response

– eg, KIR ligand mismatch, HLA-DQα expression, etc.

Lessons from this work may guide the development of “targeted immunotherapies” (eg, CTLA-4, PD-1 antibodies) in mRCC

CTLA-4 Blockade in mRCCCTLA-4 Blockade in mRCC

Ipilimumab phase II trial

– Single institution (NCI)

Major RR = 9%

Max dose tested 3 mg/kg (dose response in melanoma)

Survival effect in melanoma despite low response rate

Additional studies warranted

– CTLA-4 blockade + bevacizumab

Yang et al, 2007; Hodi et al, 2011.

127

PD-1/PD-L1 Pathway: The BasicsPD-1/PD-L1 Pathway: The Basics

Several tumor types, including RCC, have been shown to express PD-L1

Over expression of PD-L1 by RCC tumors has been shown to be associated with adverse clinical/pathologic features, including the following:

– More aggressive disease

– Shorter survival

– Also reported to impair antitumor immunity

Can PD-1 pathway blockade lead to clinical benefit?

Thompson et al, 2004.

1Beth Israel Deaconess Medical Center, Boston, MA; 2Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; 3Yale Cancer Center, New

Haven, CT; 4Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA; 5Carolina BioOncology Institute, Huntersville, NC; 6University of

Michigan, Ann Arbor, MI; 7Bristol-Myers Squibb, Princeton, NJ

Clinical Activity and Safety of Anti-PD1 Clinical Activity and Safety of Anti-PD1 (BMS-936558, MDX-1106) in Patients(BMS-936558, MDX-1106) in Patientswith Previously Treated Metastaticwith Previously Treated Metastatic

Renal-Cell CarcinomaRenal-Cell Carcinoma

D.F. McDermott,1 C.G. Drake,2 M. Sznol,3 T.K. Choueiri,4 J.D. Powderly,5 D.C. Smith,6 J.M. Wigginton,7

D. McDonald,7 G. Kollia,7 A. Gupta,7 M.B. Atkins1

129

MethodsMethods

wPD = worsening progressive disease.McDermott et al, 2011.

McDermott et al, 2011

130

Safety Results: All PatientsSafety Results: All Patients

For the entire study group, MTD was not reached at Doses 1, 3, and 10 mg/kg

There was no apparent relationship between drug dose and AE frequency

Total with an SAE = 11%

SAE = serious adverse event.McDermott et al, 2011.

Baseline Characteristic n=34

Median age, years (range) 58 (35-74)

Male, no. (%) 26 (76)

ECOG PS, no. (%)

0 13 (38)

1 21 (62)

2 0

Number of prior therapies, no. (%)

1-2 19 (56)

3 15 (44)

Nature of prior therapy, no. (%)

Immunotherapy 20 (59)

Anti-angiogenic therapy 25 (74)

Lesions at baseline, no. (%)

Bone 10 (29)

Liver 9 (26)

Lung 30 (88)

Lymph node 28 (82)

Other 20 (59)

Baseline CharacteristicsBaseline Characteristics

PopulationDose

(mg/kg)Patients

(n)

ORRn (%)

[95% CI]

Duration of response

(months)**

SD 24 wkn (%)

[95% CI]

PFSR at 24 wksn (%)

[95% CI]

All RCC 1, 10 339 (27)

[13-46]As Below

9 (27)

[13-46]

56

[39-73]

RCC

1 174 (24)

[7-50]

17.5+, 9.2+,

9.2, 5.6+

4 (24)

[7-50]

47

[23-71]

10 165 (31)*

[11-59]

22.3+,

21.7+, 12.9,

12.0, 8.4

5 (31)

[11-59]

67

[43-91]

*One CR

**Time from first response to time of documented progression, death, or for censored data (denoted by “+”), time to last tumor assessment.

Clinical Activity of BMS-936558 inClinical Activity of BMS-936558 in mRCC Patients, Efficacy Population mRCC Patients, Efficacy Population

Changes in Tumor Burden Over Time for mRCC Changes in Tumor Burden Over Time for mRCC Patients Treated with 1 mg/kg BMS-936558 Patients Treated with 1 mg/kg BMS-936558

Changes in Tumor Burden Over Time for Changes in Tumor Burden Over Time for RCC Patients Treated with 10 mg/kg BMS-936558 RCC Patients Treated with 10 mg/kg BMS-936558

Of 8 patients with OR who were treated 1 year, 5 had a response of 1 year

5/24/10

12/9/09

10/2/09

Response to PD1 Ab in Young Response to PD1 Ab in Young Woman With Sarcomatoid RCCWoman With Sarcomatoid RCC

With Progression After Sunitinib With Progression After Sunitinib

*2 patients still under evaluation

PD-L1 expression by IHC in 61 pretreatment tumor biopsies across tumor types from 42 pts

Patient samples: 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, 2 CRPC

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

PD-1 Antibody SummaryPD-1 Antibody Summary

At this early point, BMS 936558 has displayed manageable side effects at all dose levels tested

Anti-tumor activity observed in a small number of patients with RCC

– Potential for selection

Subsequent trials launched in RCC:

– Dose finding phase II study in patients with prior therapy

– Biomarker trial

– Combination Rx + VEGF TKI (phase I)

PD-1/PD-L1 Pathway Agents PD-1/PD-L1 Pathway Agents in Developmentin Development

Future PD-1/PD-L1 Ab Future PD-1/PD-L1 Ab Development in RCCDevelopment in RCC

Trials worth considering

– First-Line

– Adjuvant

– Combinations

• PD-1 or PD-L1 Ab + bevacizumab or VEGFR TKI

• PD-1 Ab + T-cell agonist

– IL-2, IL-21, CD-137 Ab

• PD-1 Ab + vaccine

N = 10 N = 23N = 30N = 34 N = 20

b

ap = < .05 (compared to normal)bp = < .001 (compared to normal)

cp = < .05 (compared to pre-treatment)dp = < .001 (compared to pre-treatment)

b

cc

d

dd

Ko et al, 2009.

Myeloid Derived Suppressor Cells in RCC Patients on SunitinibMyeloid Derived Suppressor Cells in RCC Patients on Sunitinib

a

Phase II Trial of AGS-003 + SunitinibPhase II Trial of AGS-003 + SunitinibOS Results: 21 PatientsOS Results: 21 Patients

Estimated median OS = 29.3 mos per Kaplan Meier method Encouraging OS compared to expected sunitinib OS in similar risk

mRCC subjects

Figlin et al, ASCO GU 2012.

• Study PIs: Robert Figlin, MD (Cedars-Sinai); Christopher G. Wood, MD (MD Anderson Cancer Center)

• In collaboration with the SUO-CTC

Phase 3 ADAPT Survival Trial Initiate 2QPhase 3 ADAPT Survival Trial Initiate 2Q’’1212

Figlin et al, ASCO GU 2012.

N = 330– First-line metastatic and/or locally advanced RCC

– HLA-A*02-positive– Documented tumor lesions– Favorable or intermediate risk

Primary End Point: OS

Secondary End Points

– OS in biomarker-defined subgroup

– PFS

– Safety and tolerability

– Cellular immunomonitoring

IMA091 is a vaccine comprised of multiple RCC tumor-associated peptides.US NIH, 2012e.

IMA901 RCC Phase III Trial: StudyIMA901 RCC Phase III Trial: Study DesignDesign

Is There a Role for Immunotherapy Is There a Role for Immunotherapy for mRCC? for mRCC?

There has been progress in the field of immunology in the last 30 yrs

Immunotherapy can be “targeted”

Opportunities exist for selection (PD-L1 expression/ Inflamed phenotype)

Opportunities for exciting combinations exist

Immunotherapy is worth preserving

Immunotherapy Can Achieve the Immunotherapy Can Achieve the Patients GoalPatients Goal

Pro

bab

ilit

y (%

)

DOR (mos)

Median – 23.3 months

Durable Responders = 15 (13%)

McDermott et al, 2010 Targets trial.

Treatment stops

Benefit continues

Interactive Case Studies: Interactive Case Studies: Applying Current Immunotherapies Applying Current Immunotherapies

Into PracticeInto Practice

Thomas F. Gajewski, MD, PhDCharles G. Drake, MD, PhD

Melanoma Case StudyMelanoma Case Study

Thomas F. Gajewski, MD, PhD

Melanoma Case Study Melanoma Case Study IntroductionIntroduction

57-yr-old male with metastatic melanoma, prior metastectomy of liver lesion, presented with single major lung metastasis. Asymptomatic, PS = 0, no autoimmunity. Normal LDH.

Biopsy confirmed melanoma. As part of a clinical trial had gene expression profiling: High expression of chemokines and inflamed signature present. HLA-A2+.

PS = performance status; LDH = lactate dehydrogenase; HLA = human leukocyte antigen.

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

Enrolled on multipeptide vaccine trial with IL-12

Completed 12 mos of immunization PR; lesion became PET-

3 yrs later recurred with pelvic mass—not resectable

Treated with dacarbazine PR

Enrolled on new vaccine trial combined with reagent for Treg depletion PR after 12 mos, now PET-

IL-12 = Interleukin-12; PET = positron emission tomography; Treg = regulatory T cells.

Question 1Question 1Did well for 2 yrs, when he recurred with a large pelvic mass and several additional sites of metastasis. Does have clinical symptoms now. Now in the contemporary era, mutation testing revealed B-Raf V600E. Which treatment option would you consider first?

1) Vemurafenib

2) Ipilimumab

3) Carboplatin/paclitaxel

4) Clinical trial of new anti-angiogenic agent

NCCN, 2012.

Melanoma Case Study (cont.)Melanoma Case Study (cont.) Given his clinical symptoms and exposure to prior

immunotherapies, he was treated with vemurafenib major PR

Complicated by multiple new SCCs of skin, resected by dermatology

Also significant sun sensitivity and sunburns, found to be better prevented by UVA+UVB sunscreen of SPF50

SCCs = squamous cell carcinoma; UVA = ultraviolet A; UVB = ultraviolet B; SPF = sun protection factor.

Question 2Question 2

Had disease control for 7 mos when he experienced regrowth of same metastatic sites. Started to become symptomatic again. Which treatment option would you consider next?

1) Ipilimumab

2) Clinical trial of a MEK inhibitor combined with vemurafenib


4) Clinical trial of a new antiangiogenic agent

MEK = MAPK/ERK kinase.NCCN, 2012.

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

Because of recent evidence that secondary resistance to B-Raf inhibitors frequently involves re-activation of the Ras/MAPK pathway, enrollment on a clinical trial combining a MEK inhibitor with vemurafenib was pursued

Experienced minor response that remained stable for 4 mos, then began to progress again

LDH now ~ 300

MAPK = mitogen-activated protein kinase; MEK = MAPK/ERK kinase; LDH = lactate dehydrogenase.


Which therapy would you consider next?

1) Ipilimumab


3) Surgical resection of the largest metastasis

4) Clinical trial of a new melanoma vaccine

NCCN, 2012.

Melanoma Case Study (cont.) Melanoma Case Study (cont.) ConclusionConclusion

Patient was treated with commercial ipilimumab at 3 mg/kg q3wks x 4 doses

Complicated by mild pruritic rash—treated with antihistamines only. Also fatigue—found to have elevated TSH, treated with levothyroxine with symptomatic improvement.

CT scan done at 12 wks major PR. Now asymptomatic. Being followed clinically with history, physical, labs, and periodic CT scanning. In durable PR for 6 mos currently.

TSH = thyroid-stimulating hormone; CT = computed tomography.YervoyTM prescribing information, 2012.

Prostate Cancer Case StudyProstate Cancer Case Study

Charles G. Drake, MD, PhD

Clinical States ModelClinical States Model

Rising PSAHormone Naive

Non-Metastatic CastrateResistant

Metastatic CastrateResistantAsymptomatic

MetastaticCastrateResistantSymptomatic

Primary

Disease

Metastatic Disease(De novo)

MetastaticCastrateResistantPost Docetaxel

Sipuleucel-T

Abiraterone

Cabazitaxel

MDV3100

DocetaxelADT

PSA = prostate-specific antigen; ADT = androgen deprivation therapy. Modified from Scher et al, 2008.

Prostate Cancer Case Study Prostate Cancer Case Study IntroductionIntroduction

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: Insignficant

PSA = prostate-specific antigen; DRE = digital rectal exam; Bx = biopsy; CT = computed tomography; PMH = past medical history; PSH = past surgical history.


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

NCCN, 2012.

Prostate Cancer Case Study (cont.)Prostate Cancer Case Study (cont.)

Patient undergoes radical retropubic prostatectomy

– Gleason 7 (3 + 4)

– Organ confined

– Negative margins

– 5/5 LNs negative

LNs = lymph nodes.


Which subsequent therapy would you choose?

1) Observation

2) Adjuvant RT

3) Adjuvant ADT

4) Clinical trial

NCCN, 2012.

Prostate Cancer Case Study (cont.)Prostate Cancer 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 (at 6-mos intervals)

Referred to radiation oncology

Salvage RT (66 Gy over 8 wks)

– Well tolerated

NCCN, 2012.


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 PD

– Bone scan = negative for evidence of metastases

NCCN, 2012.


What would you recommend at this time?

1) Continued observation

2) Intermittent androgen ablation

3) Continuous androgen ablation

4) Refer for Sipuleucel-T

5) Refer for clinical trial

NCCN, 2012.


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, 2012.


Current recommendation? (asymptomatic, metastatic CRPC)

1) Switch bicaluatmide to nilutamide

2) DC bicalutamide (anti-androgen withdrawal)

3) Ketoconazole + hydrocortisone

4) Abiraterone Acetate

5) Sipuleucel-T

6) Docetaxel chemotherapy

NCCN, 2012.

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

Patient choses RX with Sipuleucel-T

PSA continues to rise

What is next treatment modality?

1) Abiraterone acetate + prednisone

2) MDV3100

3) Docetaxel + prednisone

4) Cabazitaxel

NCCN, 2012.

Clinical States Model (cont.)Clinical States Model (cont.)

Rising PSAHormone Naive

Non-Metastatic CastrateResistant

Metastatic CastrateResistantAsymptomatic

MetastaticCastrateResistantSymptomatic

Primary

Disease

Metastatic Disease(De novo)

MetastaticCastrateResistantPost Docetaxel

Sipuleucel-T

Abiraterone

Cabazitaxel

MDV3100

DocetaxelADT

Modified from Scher et al, 2008.

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