More information about this activity can be found here: http://bit.ly/ST0uRp Chairperson Jedd D. Wolchok, MD, PhD Memorial Sloan-Kettering Cancer Center Faculty Antoni Ribas, MD, PhD University of California, Los Angeles Mary L. Disis, MD University of Washington School of Medicine Charles G. Drake, MD, PhD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John Powderly II, MD, CPI Carolina BioOncology Institute, PLLC Cancer Therapy & Research Center Activity Overview Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumors, generating renewed interest in novel immunologic approaches to the treatment of cancer. Indeed, there have been multiple FDA approvals of immunologic agents in recent years and there are many ongoing trials of novel immunotherapies in lung cancer, colorectal cancer, and other tumor types. In this series of half-day conferences, leading oncologists will provide an overview of immune system–cancer interactions, the safety and efficacy of recently approved immunologic agents for the treatment of melanoma and prostate cancer, the latest data from ongoing trials in non-small cell lung cancer, colorectal cancer, and others, and the management of immune-related adverse events (IRAEs). These sessions will include case studies to stimulate interactive discussion of real-world treatment scenarios. Learning Objectives Upon completion of this activity, participants should be better able to: • Describe the biological foundations of immunotherapy approaches to the treatment of cancer • Identify the mechanisms of action of immuno-oncologic agents such as vaccines and immune system-modulating antibodies • Evaluate new safety and efficacy data on recently approved and emerging immunotherapies across tumor types • Describe how new immunotherapies are integrated into existing treatment evidence-based guidelines • Identify ongoing research efforts in immuno-oncology including how to appropriately select patients who would be candidates for clinical trials More information about this activity can be found here: http://bit.ly/ST0uRp

2. DISCLAIMER
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3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
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This activity may contain discussion of published and/or investigational uses of
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The opinions expressed in the activity are those of the faculty and do not
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4. Disclosure 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®.

5. 5
Disclosure 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.

6. Welcome and Introduction
Jedd D. Wolchok, MD, PhD
Memorial Sloan-Kettering Cancer Center

7. Immuno-Oncology:
The Biological Foundations
Mary L. Disis, MD
University of Washington School of Medicine

8. Immuno-Oncology:
The Biological Foundations
 The immune system
 Cancer and the immune system
 The basics of immune therapy

9. The Immune System
T cell (orange) killing a cancer
cell (magenta)
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, T Cells, B Cells
Neutrophil
First Line of Defense Effectors
Immune Sensors
MØ = macrophages; DC = dendritic cell; NK = natural killer cell.
Alberts et al, 2002; Murphy et al, 2008.

10. Cells of the Innate Immune System
Neutrophil
Phagocytosis and debris clean up
Secrete chemokines that call in other innate
immune cells
Dendritic Cell
Potent antigen presenting cells (APC)
Uptake and process antigen
Both “class I” and “class II” pathways
Will stimulate both CTL and T helper (Th) cells
Macrophage
Phagocytosis and cleaning up debris,
secrete cytokines
Type 1 can turn on adaptive immunity
Type 2 will limit adaptive immunity
Natural Killer Cell
Can directly kill tumor without docking to MHC
Secrete high levels of IFN-gamma (critical cytokine)
Antibodies can activate them via FC receptor
(ADCC)
ADCC = antibody-dependent cell-mediated cytotoxicity; MHC = major histocompatibility center; IFN = interferon; CTL = cytotoxic T lymphocytes.
Alberts et al, 2002; Murphy et al, 2008.

11. Cells of the Adaptive Immune System
Humoral Immunity Cellular Immunity
Extracellular microbes (e.g., bacteria)
Intracellular microbes (e.g., viruses)
B lymphocytes
Processed and
B Antigen-presenting
B presented antigen
cell
Helper
Secreted T-cell
antibody T
T-cell
receptor
Cytokines
Cytokine
Proliferation and receptor
Neutralization activation of
effector cells
Lysis (complement)
(cytotoxic T-cells,
Phagocytosis natural killer cells,
(PMN, macrophage) macrophages)
Lysis of
infected cell
PMN = polymorphonuclear leukocyt.
Kumar, et al 2007.

12. Critical Link Between Innate and
Adaptive Immunity
MHC II TCR
CD4
CD4+
Activation T-cell
Apoptotic cell
CD40L
CD40
Immature MHC I
dendritic cell
Necrotic cell
• Activation
TLR
• Proliferation
• CTL generation
Activation
Mature CD8
dendritic cell
Immature
CD8+
dendritic cell
Pathogen T-cell
TCR = T cell receptor; TLR = Toll-like receptors.
Bevan, 2004.

13. The Immune System Is All About
“Checks and Balances”
Tumor Regression Regulatory loops Tumor Progression
NK/NKT T H1 TH17 TH17 B cell T H2 TREG
DC1 N1 N2 DC2
M1 M2
Myeloid Phenotype
Angiostatic Pro-
angiogenic
Direct Tissue
cytotoxicity remodeling
Immune Immune
surveillance suppression
IL-12, IL-2, IFN-g, TNF-a IL-4, IL-5, IL-10, TGF-b
IL = Interleukin; TNF = tumor necrosis factor; TGF = transforming growth factor.
DeNardo et al, 2010.

14. Immuno-Oncology:
The Biological Foundations
 The immune system
 Cancer and the immune system
 The basics of immune therapy

15. Steps in Stimulating Cancer Specific Immunity
Melanoma
“Danger”
e.g. HSP
IFN-α
CD28
MAGE I B7 CD8
MARTI CTL Help
(TAAs) APC
e.g.
CD40
CD40
IL-2
CD4
Immature DC
CD40L TH
Activated mature DC
Lymph node
B7
CD40L
CD40 CD8 CD28 CD40
CD4
TCR Migration from
TCR
lymph node
MHC I MHC II
DC
Migration to lymph node

16. Epitope Spreading Is the Endpoint of an
Effective Immune Response in Cancer
MIP-1α= macrophage inflammatory protein 1α.
Vanderlught et al, 2002.

17. What Is Needed for Clinical Effective
Antitumor Immunity?
High Density of T Cells Modulation of
Type I Inflammation
Penetrating Tumor Self-Regulation
0 .1 6 10
105
Murine TNBC
4
10
< F IT C - A > : F O X P 3
3
10
2
10
Murine TNBC
0
43 46
FOXP3
2 3 4 5
0 10 10 10 10
< P e rC P -C y 5 -5 -A > : C D 4
0 .8 8 1 .1
105
4
10
< F IT C -A > : F O X P 3
Murine ER+BC
3
10
2
10
Murine breast tumor Murine ER+ BC
0
after activating the 46 52
2 3 4 5
Immune system 0 10 10 1 0 10
< P e rC P -C y 5 -5 -A > : C D 4
 75 colorectal cancers
 7 gene classifier  186 advanced ovarian cancers CD4
 Inverse correlation of gene  MVA: Intratumoral T cells  237 breast cancers
expression and relapse independent predictor survival  MVA: Density of Treg+ in ER+
tumors predictor of survival
MVA = multivariate regression analysis; ER+ = estrogen receptor positive; Treg = regulatory T cells.
Galon et al, 2006; Zhang et al, 2003; Bates et al, 2006.

18. Optimal Immune Reaction
Many cancer
patients have
demonstrated an
“optimal immune
reaction”
VEGF = vascular endothelial growth factor; CT = center; IM = invasive margin.
Bindea et al, 2010.

19. What Does the Immune System
See in Cancer?
Cell and Cell and Tumor Cell and Self
Virus Antigen Protein Only
Antigens Associated With
Clinical Response
Foreign Self Antigens
Antigens
LMP2 HER2 GD2
HPV WT1 CEA
HepB MUC1 MART-1
Dangerous Weak Tolerizing
• Cell damage • None of
MAGE A2 gp100
• No danger
(uric acid) signals these NY-ESO-1 PR1
• Innate • No CD40 signals
immunity signals PSMA Tyrosinase
activated • Pro-
• TLRs
PSA PAP
inflammatory
triggered cytokines PSCA NA17
• Inflammation
• Cytokines
• CD40 signals
• Others
Lake et al, 2005; Cheever et al, 2009.

20. Why Do Most Tumors Evade
Immune Recognition?
Murphy et al, 2008.

21. Multiple Factors Impact the
Tumor Immune Microenvironment
Pro-Tumorigenic Anticancer
Inflamation Immunosurveillance
Cell Types M2 macrophages Dendritic cells
Myeloid-derived suppressor M1 macrophages
cells cytotoxic CD8+ T cells with a
Neutrophils memory effector phenotype
Foxp3+ T reg. Th17 cells
Cytokine Th2, Th17 Th1
Profiles CX3CL1
CXCL9, CXCL10
Distribution Peritumoral Intratumoral, close to cancer
cells, as well as in the invasive
front
Associated Stat3 phosphorylation High endothelial venules
Features
Functional Negative prognostic impact Positive prognostic and
Impact predictive impact
Foxp3 = forkhead box P3.
Fridman et al, 2011; Disis, 2010a.

22. Immuno-Oncology:
The Biological Foundations
 The immune system
 Cancer and the immune system
 The basics of immune therapy

23. Types of Immune Therapy
PASSIVE ACTIVE
Transferred Generated
Ready Made Must Be Developed
Immediate Protection Takes Time
No Memory Long Lived
Immune System May Requires Functional Immune
Function Poorly System
Ig Infusions, Some MoAB Vaccines, Anti-CTLA-4
Therapy, T-Cell Transfer
Ig = immunoglobulins; MoAB = monoclonal antibody; CTLA-4 = cytotoxic T-lymphocyte antigen-4.
Murphy et al, 2008.

24. Monoclonal Antibody Therapy: Trastuzumab
HER-2/neu = human epidermal growth factor receptor 2. Time (Weeks)
Ferris et al, 2010; Taylor et al, 2007; Ladoire et al, 2011.

25. Adoptive T Cell Therapy
Factors Associated With Clinical Response
Diversity Objective Response
 Unfractionated TIL
34%-50%
polyclonal
 Selected tumor- reactive TIL
49%-72%
TCR gene transfer
(MART-1/Melan-A, 13%-30%
gp100,NY-ESO-1) 50% response rate
20/93 complete responders
monoclonal
 Individual T cell clones
(MART-1/Melan-A, 0%-11%
gp100,NY-ESO-1)
Specificity
TIL = tumor-infiltrating lymphocytes; CR = complete response; PR = partial response; NR = no response; MART-1/ Melan-A = melanoma
antigen 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.

26. Immuno-Oncology:
The Biological Foundations
T1
T2
Tx = treatment.
Disis, 2010b.

27. Key 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

28. Audience Q&A:
The Biological Foundations
of Immunotherapy
Mary L. Disis, MD
University of Washington School of Medicine

29. Immuno-Oncology:
Genitourinary Cancers
Charles G. Drake, MD, PhD
The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins

30. Outline
 Cancer “Vaccines”  Combination
– Sipuleucel-T Immunotherapy
– ProstVac VF – With androgen-ablation
– Argos AGS-003 – With TKIs
 Immune Checkpoint  Integrating immunotherapy
Blockade into the current (and
future) prostate cancer
– Anti-CTLA-4, ipilimumab
treatment paradigm
– Anti-PD-1, BMS-936558
(MDX-1106)
– Phase III trial design
PD-1 = programmed cell death protein-1; TKIs = tyrosine kinase inhibitors.

31. Cancer Vaccines:
An Immunological MOA
CD4 T Cell
Activated TCR
Dendritic Cell
Class II MHC
TCR Cytokines = HELP
Tumor Antigen
Class I MHC
CD8 T Cell
Activated CD8 T Cells Traffic to
Tumor and Lyse Tumor Cells
MOA = mechanism of action.
Burch et al, 2000; Small et al 2000; Fong et al, 1997.

32. Active Cellular Immunotherapy
Sipuleucel-T
Patient WBC Harvested
GM-CSF
Short-Term Culture With Protein
“Cassette”
PAP
Shipping
Cells Infused BACK
Into Patient (IV)
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.

33. D9902B – IMPACT
Immunotherapy Prostate
Adenocarcinoma Treatment
P
R
R
A Placebo q2wks Eligible for
x3
O Sipuleucel-Ta
N
 mCRPC G
D
 No Visceral R
O
Mets E
 N = 512 M
S
I Sipuleucel-T Physician’s
S
Z q2wks x 3 Discretion
I
E
O
N
 Patients: Asymptomatic or minimally symptomatic mCRPC
 Primary end point: OS
 Secondary end point: TTP
a
Prepared from cryo-preserved lymphocytes.
mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; TTP = time to progression.
Kantoff et al, 2010a.

34. IMPACT OS: Primary End Point
ITT Population
100
p = .032 (Cox model)
HR = 0.775 [95% CI 0.614, 0.979]
75
Percent Survival
Median Survival Benefit = 4.1 mos
50 Sipuleucel-T (n = 341)
Median Survival = 25.8 mos
Placebo (n = 171)
25 Median Survival = 21.7 mos
0
0 6 12 18 24 30 36 42 48 54 60 66
ITT = intent-to-treat; HR = hazard ratio; CI = confidence interval.
Kantoff et al, 2010a.

35. Madan et al, 2009; Sonpavde et al, 2011.
DNA = deoxyribonucleic acid; PSA = prostate-specific antigen.
Co-Stimulatory
Molecules
PSA
B7-1 ICAM-1 LFA-3
Target Antigen
Vaccinia Virus
Fowlpox Virus
Plasmid DNA
Packaging Cell
Line
rV-PSA-
TRICOM
rF-PSA-
TRICOM
Vaccine
A Viral Vaccine Approach: ProstVac VF

36. Viral Vaccines – Same Idea:
But Starting At A Different Step
ProstVac VF
CD4 T Cell
TCR
Class II MHC
TCR
Class I MHC
Epithelial Cells CD8 T Cell
ACTIVATED
Cell Death - Necrosis CD8 T Cell
Madan et al, 2009; Sonpavde et al, 2011.

37. TBC-PRO-002 Survival Data
Time (mos)
Design: Nearly identical to IMPACT but NO crossover
Patients: mCRPC with either no or minimal
symptoms
Primary end point: TTP
CRPC = castration-resistant prostate cancer; TTP = time to progression.
Kantoff et al, 2010b.

38. Prospect Trial: Design (SPA)
Phase III Global (US-CAN-AUS/WE/EE/Latin America)
PROSTVAC-(V)(F)
TRICOM + Low-Dose S
Adjuvant GM-CSF
Non/Minimally U
Symptomatic
R
mCRPC PROSTVAC-(V)(F) V
TRICOM Standard
Adjuvant Placebo of Care I
No Crossover
V
Vector Placebo A
Adjuvant Placebo L
Primary End Point: OS
SPA = special protocol assessment.
US NIH, NCT01322490.

39. Using RNA to Load Dendritic Cells
Argos AGS-003
Kidney Cancer
Sample Tumor Load DC With RNA
RNA Isolation And Activate
(AGS-003)
Cryopreserve
Leukapheresis
DC
Product
Manufacture
Intranodal Injection
RNA = ribonucleic acid.
Figlin et al, 2012.

40. ADAPT:
Autologous Dendritic Cell Immunotherapy With AGS-003
Plus Sunitinib for the Treatment of Advanced RCC
R AGS-003
A 1 Cycle Sunitinib AGS-003
5 doses q3mos
 Metastatic, N (6 wks)
q3wks
Unfavorable D
Risk Clear O
Cell RCC
M
 N = 450
I 1 Cycle Sunitinib Placebo
Z (6 wks) q3mos
E
Ongoing Sunitinib (4 wks on, 2 wks off)
 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
RCC = renal cell carcinoma; ORR = overall response rate; PFS = progression-free survival.
US NIH, NCT01582672.

41. Normal T-Cell Activation
T Cell
TCR CD28
Signal 1 Signal 2
antigen
HLA B7.1/2
Antigen Presenting Cell
HLA = human leukocyte antigen.
Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.

42. Immune Checkpoints (CTLA-4) Prevent Normal
T-Cell Activation
T Cell
CTLA-4
TCR CD28
Signal 1 Signal 2
antigen
HLA B7.1/2
Antigen Presenting Cell
Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.

43. Ipilimumab (Anti-CTLA-4) Blocks the CTLA-4
Checkpoint, Restoring T-Cell Activation
Antigen Presenting Cell
HLA B7.1/2 CTLA-4
antigen
Signal 1
Signal 1 Signal 2
Signal 2
TCR CD28
CTLA-4
T Cell
Kirkwood et al, 2008; Ribas et al, 2005; Attia et al, 2005.

44. CTLA-4 Blockade:
(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.

45. Ipilimumab in Melanoma: The First “Drug” Ever to
Show a Survival Benefit in a Randomized Clinical Trial
Comparison HR P-value
Arm A vs C 0.68 0.0004
Arm B vs C 0.66 0.0026
Arm A vs B 1.04 0.7575
Ipilimumab + gp100 (A)
Ipilimumab alone (B)
gp100 alone (C)
1 2 3 4
Years
Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone
1-yr 44% 46% 25%
2-yr 22% 24% 14%
Hodi et al, 2010.

46. Randomized, Double-Blind, Phase III Trial Comparing
Ipilimumab Vs. Placebo Following Radiotherapy in Subjects
With CRPC That Have Received Prior Treatment With
Docetaxel (CA184-043)
SCREENING INDUCTION MAINTENANCE
Ipilimumab 10 mg/kg Ipilimumab 10 mg/kg
CRPC Wks 1, 4, 7, 10 q12wks
Radiotherapy (8 gy)
Prior to bone metastases
Docetaxel IVRS
Day -2 or -1 Placebo Placebo
N = 800 Wks 1, 4, 7, 10 q12wks
ICF, Baseline TA: Wks 12, 24 TA: q12wks
PSA: Wks 7, 12, 18, 24 PSA: q6wks
Assessments
OA: Wks 7, 10, 12, 18, 24 OA: q12wks
Day -28 to -2 Day -2 to Wk 24 Wk 24 to 48+
Completed Accrual 1/2012
TA = tumor assessment; OA = outcome assessment; ICF = informed consent form; IVRS = interactive voice response system.
US NIH, NCT00861614.

47. Immune Checkpoint Blockade 2: PD-1
Tumor Cell or
Antigen Presenting Cell T Cell
Signal 2
B7.1/2 CD28
Signal 1 CTLA-
4
HLA antigen TCR
Class II
LAG-3
MHC
B7-H1
PD-1
(PD-L1)
Others: ICOS, GITR, Tim-3
Weber, 2010; Pardoll, 2012a.

48. Immune Resistance: PD-1
Innate Immune Resistance
MHC +
Peptide TCR
Tumor T Cell
Oncogene-Driven PD-L1
Expression
Oncogenic
Pathway
PD-1
PD-L1
Adaptive Immune Resistance
Tumor T Cell
Tumor
T Cell
PD-L1
Adaptive Up-Regulation
Interferon g Of PD-L1 Turns T Cell OFF
Pardoll, 2012a.

49. First BMS-936558 (MDX-1106)
Phase I Trial
Follow Up or Additional
1st Treatment Cycle
Treatment Cycle(s)
Day 1 Day 29 Day 57 Day 85 2 years
60 minute IV Optional tumor bx Or until PD
Scans
infusion 10mg/kg
Optional tumor bx
2 doses 4 wks apart, follow
SD or mixed response 12 more weeks, can repeat
Follow up every month x 2
PR or CR then every 2 months,
Re-treat on progression
SD = stable disease; MR = mixed response; PD = progression disease.
Brahmer et al, 2010.

50. BMS-936558 (MDX-1106)
Phase 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.

51. PD-1 Blockade: Results in Increased
CD8 T Cells in Tumors
Pre-Rx c m 12-wk Post Dose 1cm 8-wk Post Dose 3 cm
3.9 2.6 2.4
Anti-CD8 Anti-CD8 Anti-CD8
Pre-Rx 4-wk Post Dose 1 4-wk Post Dose 3
Rx = treatment.
Brahmer et al, 2010.

52. Durable Responses to Anti-PD-1
OFF THERAPY
Pt 2-
2013 CR Stop Rx Latest Evaluation: CR
0 1 yr 2 yr 3 yr 4
yr
? new brain met on MRI
Pt 1- Stop Best resected: - no viable tumor
4033 Rx resp.(PR) Latest Evaluation: CR
Sustained PR
0 1 yr 2 yr 3 yr 4
yr
Pt 1- Stop Best New LN mets Restart a PD-1
3019 Rx resp.(PR)
Sustained PR
0 1 yr 2 yr 3 yr 4 yr
MRI = magnetic resonance imaging; LN = lymph node.
Brahmer et al, 2010.

53. Multidose Phase Ib Trial of Anti-PD-1
(BMS-936558/MDX 1106)
cCR = confirmed complete response; uCR = unconfirmed complete response; uPD = unconfirmed progressive disease;
wPD = worsening progressive disease.
McDermott et al, 2011.

54. Efficacy Results: RCC Patients
Changes in Target Lesions Over Time in RCC Patients
McDermott et al, 2012.

55. Anti-PD-1 (BMS-936558) Dose
Finding Study CA209010
Arm 1 n = 50
Prior Anti-
BMS-936558 (0.3 mg/kg) IV q3wks
Angiogenic Tx
Arm 2 n = 50
(1:1:1
Randomization) BMS-936558 (2 mg/kg) IV q3wks
N = 150
Arm 3 n = 50
BMS-936558 (10 mg/kg) IV q3wks
1° end point: PFS as measured by TA
2° end points: PFS, ORR, OS
Completed Accrual 12/2011
US NIH, NCT01354431.

56. Anti-PD-1 (BMS-936558) Biomarker Study
CA209009
Arm 1 n = 20
Prior Anti- BMS-936558 (0.3 mg/kg) IV q3wks
Angiogenic Tx
(1:1:1 Arm 2 n = 20
Randomization) BMS-936558 (2 mg/kg) IV q3wks
N = 80
Arm 3 n = 20
BMS-936558 (10 mg/kg) IV q3wks
Treatment Arm 4 n = 20 (treatment naïve arm)
Naïve BMS-936558 (10 mg/kg) IV q3wks
1° end point: Measurement of immunomodulatory activity
2° end points: PFS, ORR, safety, and tolerability
Treatment Naïve
Cohort Closed 2/2012
Other Cohorts Open
US NIH, NCT01358721.

57. Why Has Immunotherapy Been
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.

58. Effect of Androgen-Ablation
on T-Cell Response
Drake et al, 2005.

59. Testing the Optimal Sequencing of
Androgen-Ablation and “Vaccination”
P10-2
Study Participation Concludes
Eligibility Treatment Arm 1
• Post Primary Rx (RP or XRT or RP + XRT)
• PSADT ≤ 12 mos Sipuleucel-T ADT
• Non-Metastatic (bone and CT scan) N = 30
Stratification Immune 18-mos
• PSADT ≤ 3 mos or > 3 mos and ≤ 12 mos Response, visit
• RP or XRT or RP + XRT Treatment Arm 2 Safety
ADT  Sipuleucel-T
N = 30
Primary Objective: To determine whether
ADT started before or after sipuleucel-T Primary End Point: Immune response,
leads to superior augmentation of immune which will be evaluated with an INF-γ
response ELISPOT specific for PA2024
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.

60. Combining PD-1 Blockade
With TKIs in RCC
Orthotopic RENCA Model
 Hypoxia Anti-PD-1
 High VEGF Levels 10 mg/kg
 Growth Inhibition With Sunitinib
Days -8 -3 0 3 6 9 Day 12
RENCA Treatment Ends
Orthotopic
(0.5M Cells)
Sunitinib
40 mg/kg daily
Courtesy of Hans Hammers, MD, PhD.

61. Tumor Response
Courtesy of Hans Hammers, MD, PhD.

62. Antibody Response
14x 49x
Courtesy of Hans Hammers, MD, PhD.

63. Phase I Study Combining Anti-PD-1
With Sunitinib or Pazopanib in Patients
With Metastatic RCC
Metastatic RCC Arm S Escalation Arm S Expansion
MTD
(Prior Pazopanib) Sunitinib + BMS-936558 Sunitinib + BMS-936558
Metastatic RCC Arm P Escalation Arm P Expansion
MTD
(Prior Sunitinib) Pazopanib + BMS-936558 Pazopanib + BMS-936558
Primary End Points: Safety, Tolerability, MTD
MTD = maximum tolerated dose.
US NIH, NCT01472081.

64. Integrating Immunotherapy Into the
Prostate Cancer Treatment Paradigm
2004
Androgen Docetaxel
Ablation Chemotherapy
2010
Androgen Docetaxel
Ablation Sipuleucel-T Chemotherapy Sipuleucel-T

65. 2012
Androgen Sipuleucel-T Docetaxel
Ablation Chemotherapy Sipuleucel-T
Abiraterone
Cabazitaxel
Abiraterone
and beyond… Enzalutamide
(MDV3100)
Iplimumab?

66. Key Takeaways
 Sipuleucel-T  In development for kidney
– FDA approved in US for cancer
CRPC – AGS-003
– Precise MOA under • Randomized phase III
investigation ongoing
– T cell and antibody data – Anti-PD-1 (BMS-936558)
consistent with an adaptive • Phase II dose finding
immune response completed
 In development for prostate • Biomarker study ongoing
cancer • TKI combination trial ongoing
– ProstVac VF
• Phase III ongoing
– Anti-CTLA-4 (ipilimumab)
• Post-Tax phase III trials
ongoing

67. Case Study: Prostate Cancer
Charles G. Drake, MD, PhD
The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins

68. Clinical States Model
Sipuleucel-T
Metastatic
Disease Cabazitaxel
(de novo)
Metastatic Metastatic Metastatic
Castrate
Primary Rising PSA Resistant
Castrate Castrate
Resistant Resistant
Hormone Asymptomatic
Disease Symptomatic Post Docetaxel
Naive
Non-Metastatic
Castrate
Resistant
Docetaxel Abiraterone
ADT
Enzalutamide
(MDV3100)
Modified from Scher et al, 2008.

69. Case 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.

70. Question 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.

71. Case Study (cont.)
 Patient undergoes radical retropubic prostatectomy
– Gleason 7 (3+4)
– Organ Confined
– Negative Margins
– 5/5 LN negative

72. Question 2
Which subsequent therapy would you choose?
1. Observation
2. Adjuvant RT
3. Adjuvant ADT
4. Clinical Trial
NCCN, 2012a.

73. Case Study (cont.)
Course 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.

74. Case Study (cont.)
Course 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.

75. Question 3
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.

76. Case Study (cont.)
Course 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.

77. Question 4
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.

78. Case Study (cont.)
Course 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.

79. Clinical States Model
Sipuleucel-T
Metastatic
Disease
Cabazitaxel
(de novo)
Metastatic Metastatic Metastatic
Rising PSA Castrate Castrate Castrate
Primary Resistant Resistant Resistant
Hormone Asymptomatic Symptomatic Post Docetaxel
Disease
Naive
Non-Metastatic
Castrate
Resistant
Docetaxel Abiraterone
ADT
Enzalutamide
(MDV3100)
Modified from Scher et al, 2008.

80. Immuno-Oncology: Melanoma
Jedd D. Wolchok, MD, PhD
Memorial Sloan-Kettering Cancer Center

81. Agents Used for Cancer
Immunotherapy
 Immune modulators  Vaccines
– BCG (bladder cancer) – Hepatitis vaccine
– Alpha interferon (melanoma, – HPV vaccine
kidney, leukemia) – BCG?
– IL-2 (melanoma, kidney  Adoptive cellular therapy
cancer)
– Allogeneic bone marrow
– CTLA-4 blockade
transplant
 Monoclonal antibodies
– Anti-CD20, CD19 (lymphoma)
– Anti-HER2 (breast cancer)
– Anti-EGF receptor (colorectal
cancer)
BCG = Bacillus Calmette-Guerin; HPV = human papillomavirus.

83. High-Dose IL-2 Therapy
 RR: 16% (43/270)
Probability of Continuing Response (%)
1.0  Durable responses
CR (n = 17)
PR (n = 26) – Median 8.9 mos
0.8
CR + PR (n = 43) – CR: not reached
0.6
0.4
0.2
0.0
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (mos)
Atkins et al, 1999.

84. Ipilimumab, A CTLA-4 Blocking MoAB,
Augments T-Cell Activation
T-Cell Remains Active
T-Cell Activation T-Cell
Inactivation
CTLA-4
T Cell
Resting
T Cell
T Cell
TCR CD28 CTLA-4
CTLA-4
HLA B7 Ipilimumab
APC APC APC
Korman et al, 2006.

85. Anti-CTLA-4 and GM-CSF Tumor Cell
Vaccine Synergize to Eradicate
Established B16 Melanoma
van Elsas et al, 1999.

86. Clinical Response in Melanoma: NCI
 Experienced complete resolution of 2 subcutaneous nodules,
31 lung metastases and 0.5 cm brain metastasis
Phan et al, 2003.

87. Immune-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.

88. MDX010-20 Study Schema
≥ 1 Re-Induction
Screening Induction
(eligible patients)
3:1:1
R
A Ipilimumab + gp100 PD Ipilimumab + gp100
Previously N (n = 403)
treated,
HLA-A2*0201+ D
Follow-Up
patients with Ipilimumab alone PD Ipilimumab alone
O
advanced
(n = 137)
melanoma M
(N = 676)
I gp100 alone gp100 alone
PD
Z (n = 136)
E
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
Hodi et al, 2010.

89. Kaplan-Meier Analysis of Survival
Comparison HR P-value
Arm A vs C 0.68 0.0004
Arm B vs C 0.66 0.0026
Arm A vs B 1.04 0.7575
Ipilimumab + gp100 (A)
Ipilimumab alone (B)
gp100 alone (C)
1 2 Years 3 4
Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone
1-yr 44% 46% 25%
2-yr 22% 24% 14%
Hodi et al, 2010.

90. Study 024: Overall Survival
Estimated Survival 1 Yr 2 Yr 3 Yr*
Rate
Ipilimumab + DTIC 47.3 28.5 20.8
N = 250
Placebo + DTIC 36.3 17.9 12.2
N = 252
*3-yr survival was a post-hoc analysis.
Wolchok et al, 2011.

91. 11/28/06 1/9/07
Wolchok , 2010.

92. Ipilimumab Pattern of Response:
Responses After the Appearance and
Subsequent Disappearance of New Lesions
Pre-Treatment Wk 12: Progression
July 2006
3 mg/kg
Ipilimumab
q3wks X 4
New lesions
Wk 20: Regression Wk 36: Still Regressing
Wolchok et al, 2008a.

93. Four Patterns of Response to
Ipilimumab 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.

94. irRC Identifies Survivors in Patients
With Progressive Disease by mWHO
Pooled data from phase II studies CA184-008 and CA184-022: Ipilimumab monotherapy 10 mg/kg (N = 227)
mWHO = modified World Health Oncology criteria.
Wolchok et al, 2009.

95. CTLA-4 Blockade: A Case Study for
Immunotherapy in Need of Biomarkers
Knowns Unknowns
 Clinical benefit for a  Biomarkers for response
subset of patients with  Biomarkers for toxicities
refractory melanoma
 Effect on effector vs
 Reversible mechanism- regulatory T cells in
based side effects humans
 Tumor responses tend to  Antigens recognized after
be durable infusion
 Kinetics of response  Importance of vaccination
unlike cytotoxics before treatment
 Relevance of PBMC vs.
PBMC = peripheral blood mononuclear cell. tumor site findings
Wolchok, 2010.

96. ALC Correlates With Clinical Benefit
Mean longterm ALC
4
clinical
benefit
3
ALC [K/mcl]
no clinical
benefit
2
1
-4 months
-3 months
-2 months
-1 month
week 10
week 12
week 24
week 36
week 1
week 4
week 7
 This patient population comprises all patients (N = 73) available at the Immune Monitoring Facility
of Memorial Sloan-Kettering Cancer Center, New York
ALC = absolute lymphocyte count.
Ku et al, 2010.

97. NY-ESO-1 Antibody and CD4 TCR Were Detected
After Full-Length NY-ESO-1 Protein Vaccination
% IFNg+ CD4 T Cells
Reciprocal Titer
NY-ESO-1 recombinant protein
NY-ESO-1 peptide pool
Modified from Adams et al, 2008.

98. NY-ESO-1 CD4 and CD8 T-Cell Specific Response
After CTLA-4 Blockade (Patient IMF-11)
Percent of IFN-g+MIP-1b+ or IFN-
g+TNF-a+ T Cells
Reciprocal Titer
IMF-11 Experiencing CR CD8 T Cells CD4 T Cells
Yuan et al, 2011a.