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Targeting the Immune System in Cancer
– Transforming Failure into Success
Robert Wesolowski, MD
Stefanie Spielman Comprehensive Breast Center
Overview
 Cancer Immunity – Emerging Hallmark of Cancer
 New Concept - Immune-editing and development of cancer
 Process of cancer induced reprogramming of the immune
system
 Role of Immune System in Promoting Cancer Growth




Myeloid Derived Suppressor Cells
T-regulatory Cells
Cytokines
Immune Checkpoints
 Introduction to Immunotherapies for Cancer
 Inhibitors of myeloid cells
 Immune Checkpoint inhibitors
 Cancer Vaccines
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
2
Immune System and Cancer
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
3
Cancer Development Depends on Immunity/Inflammation
 Cancer Immuno-surveillance Theory (Burnett and
Thomas in 1950’s)
 Cancer can be recognized then stopped or controlled by the host
adoptive immunity
 Higher cancer rates in immune compromised people
 Malignant cells express antigens that can be recognized
by the immune system
 Protein products from mutated genes
 Normal Proteins only expressed in malignant cells (MAGE-1,
NY-ESO-1)
 Protein expressed at excessive levels
 Viral proteins
 Inflammation likely plays a role in cancer development
 Immune infiltrate within tumor stroma
 Inflammation promotes angiogenesis and cell growth (wound
healing)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Immunodeficiency Predisposes to Cancer
Schreiber et al. Science 2011;331, 1565-1570
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
5
Immunosurveillance
NK
Fcγ Receptors
Antigen Receptors
Malignant Clone
CD4+
Mф
DC
Cytokines
CD20+
CD8+
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Schreiber et al. Science 2011;331, 1565-1570
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
7
Vesely, et al. Annual Review of Immunology, 2011; 29: 235-71.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Role of Immune System in Promoting
Cancer Growth
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
9
Mechanism of Immune Suppression –
Tumor Escape
Intrinsic
Loss of
tumor
antigens
Loss of
complement
sensitivity
Loss of
human
leukocyte
antigens
Expression of
Immunesuppressive
factors
Extrinsic
Regulatory
T-cells
Tumor
Associated
Macrophages
Myeloid
Derived
Suppressor
Cells
Schreiber et al. Science 2011;331, 1565-1570
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
10
Regulatory T-Cells Suppress Cytotoxic
Immunity
Secretes Inhibitory cytokines
IL-10
TGFβ
CD4+
CD25+
FoxP3+
Treg
Expresses Immune checkpoint signals
CTLA-4
PD-1
PD-L1
Sequesters IL-2
Normal Function:
•Stop immune response when it is no longer needed
•Thought to be involved in prevention of auto-immunity
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
11
MDSC Expansion in Cancer
Hematopoietic
Stem Cell
Differentiation
(STAT3)
Bone Marrow
IL1β, IL-6, IL-10
PGE, GM-CSF, G-CSF, M-CSF
VEGF, CXCL5, CXCL12
Partial Block of
IL-3
c-kit, SCF, FLT3
G-CSF, GMCSR
Immature Myeloid Cell
CD68+, F4/80+
Tumor Cells
Tumor Associated
Macrophages
CD11+, CD33+, HLA DR-,
Linlo/- (Gr1+ in Mice)
Myeloid Derived Suppressor Cells
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Myeloid Derived
Suppressor Cells
DC
Dendritic cells
Maturation
NK
Treg
NK cells
NKG2D
IFNγ
Cytotoxicity
Suppressor
cells
IL-10
TGF-β
MDSC
CD4+
T cells
Cysteine
Arginine (ARG1)
Nitration (iNOS)
TAM
Macrophages
Drives M2
IL-12
CD8+
Borrowed from Dr. William Carson
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
MAC
Normal
C26-Bearing
18
*
16
Mean Percent Positive MDSC
Side Scatter
MDSC Are Elevated in Spleens of
Tumor- Bearing Mice
GR-1-FITC
Forward Scatter
MDSC
14
12
10
8
6
4
2
0
CD11b-APC
Normal
n=19
Borrowed from Dr. William Carson
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
C26
n=21
* p<0.05
MDSC in a Breast Cancer Patient
Normal
Volunteer
Adjuvant
Chemotherapy
Lin
CD33
Metastatic
Cancer
HLA-DR
CD11b
Diaz-Montero et al. Cancer Immunol Immunother 2009; 58:49–59
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Prognostic value of MDSC In Breast Cancer
N=25
First Visit
Median Overall Survival
MDSC ≥3.17%
19.32 months
MDSC <3.17%
6.78 months
Last Visit
Median Overall Survival
MDSC ≥3.04%
N/A
MDSC <3.04%
7.7 months
Cole at al. SABC 2009 Abstract 4135
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
MDSCs and Survival of Patients with GI
Cancers
Adjustments:
•Cancer Type
•Stage
•Treatment
•Performance Status
N=131
Gabitass et al Cancer Immunol Immunother 2011 (published online ahead of print)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
MDSC Pilot - Neo-adjuvant Cohort (N=24)
Primary Objectives:
1. Baseline levels of circulating MDSCs and determine their association with
pathologic response at the time of surgery.
2. Levels of MDSCs in the peripheral blood during the course of neoadjuvant
chemotherapy.
3. Determine whether these changes could be predictive of response.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
OSU 09142 – Other explorative Objectives
• Tumor and blood samples will be retrieved and
stored.
• Development of fluorescent based IHC method
for identification of MDSCs
• Study ability of MDSCs to suppress NK-killer
cells mediated antibody dependent cell
cytotoxicity (NK-ADCC) and T-cell function
• Measurement of cytokine production.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Tumor Associated Macrophages
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
20
Immune Signatures
N=179
N=498
DeNardo et al. Cancer Discov. 2011; 1: 54–67.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
CD68 and CD8a expression is prognostic in
Human Breast Cancer
N=311
N=3,872
DeNardo et al. Cancer Discov. 2011; 1: 54–67.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Re-programming Immune System in Cancer
Patients
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
23
Types of Immune Therapies
 Passive (Adoptive Cell Transfer)
 NK Cells
 Antibodies
 T-cell therapy
 Active
 Cancer Vaccines
 Antigen presenting cells loaded with tumor antigen
 Other immune-modulating drugs




Cytokines (Interferon alpha, IL-2)
MDSC inhibitors
CSF-1R inhibitors
Immune checkpoint inhibitors
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
24
Immune Checkpoint Inhibitors
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
25
Cytotoxic T Lymphocyte Assoc Protein-4 (CTLA-4)
Ag presenting
Dendritic cell
MHC II Ag
CD 80 B 7.1
CD 86 B 7.2
Activated T Cell
TCR
CD 28 – T cell stimulation (with IL-2
production)
CTLA-4 – T cell inhibition (induction of tolerance)
− CD152
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
CTLA-4
Ag presenting
Dendritic cell
MHC II Ag
CD 80 B 7.1
CD 86 B 7.2
Activated T Cell
TCR
CD 28 – Unopposed T cell stimulation
Unopposed autoimmune effects:
- uveitis
- rash and vitiligo
- pan hypo-pituitarism
- diarrhea and colitis
- hepatitis
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
CTLA-4
 anti-CTLA-4 MoAb
 humanized IgG1k
 T1/2 20 - 30 days
 BMS/ Medarex - MDX 010 - ipilimumab
 Breaks tolerance – removes the “brake “ on T
cells
 decreases T reg number and function (↓ IL-10 and
TGFβ)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Phase III MDX010-20 – 2nd Line Tx
Open 9/2004 – 8/2008
Double blind
676 pts with
prior treated
metastatic
melanoma
70% had
M1c poor risk
visceral disease
R
A
N
D
O
M
I
Z
E
(3:1:1; for ipi & gp100, ipi and gp100 alone)
Ipilimumab 3 mg/kg IV & gp 100 N=403
All drugs  q 3 wks x 4 doses
Ipilimumab 3 mg/kg IV N=137
gp 100 vaccine N=136
Hodi et al. N Engl J Med 2010;363:711-23.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Phase III MDX010-20 – 2nd Line Tx
Overall Survival
Ipi. Alone
Progression Free Survival
Hodi et al. N Engl J Med 2010;363:711-23.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Phase III MDX010-20 – 2nd Line Tx
 Results
ipi and gp 100
ipi
gp100
PFS
2.8 mos
2.8 mos
2.8 mos
med OS
10.1 mos
10 mos
6.4 mos
12 mos
46%
44%
25%
24 mos
24%
22%
14%
RR
11%
6%
2%
CBR*
29%
22%
11%
* CBR = Clinical Benefit Rate (CR, + PR, + SD)
* CR, + PR, + SD
Hodi, NEJM 363:711, 2010
Hodi et al. N Engl J Med 2010;363:711-23.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
MDX010-20 Ipilimumab – 2nd Line Tx
 Toxicity
 60% had immune related adverse events
 30% diarrhea/colitis (any grade) lasting a median
of 2.3 wks (after steroids begun)
 10-15% of pts have severe immune toxicity
 cutaneous – maculopapular rash and vitiligo
 Deaths – 14 pts (2%) of drug side effects
 Unique feature – pts who progress may be rechallenged and still have a chance of response
Hodi, NEJM 363:711, 2010
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Phase III Ipilimumab
+/- Dacarbazine – 1st Line
Stratification:
Metastases stage
Study site
ECOG PS
Open 8/2006 to 1/2008
502 pt with
untreated
metastatic
melanoma
R
A
N
D
O
M
I
Z
E
Ipilimumab 10 mg/kg IV + DTIC
1:1
250 pts
All drugs  q 3 wks x 4
DTIC 850 mg/m2
252 pts
Maintenance given in pts
with stable to responding dis.
Robert et al. N Engl J Med 2011;364:2517-26.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Phase III MDX 010-24 – 1st Line Tx
Results
ipi and DTIC
DTIC
PFS (stat significant)
2.8 mos
2.6 mos
med OS
11 mos
9 mos
12 mos OS
47%
36%
24 mos OS
29%
18%
RR (duration)
15% (19 mos)
10% (8 mos)
Clinical benefit*
* CR, + PR, + SD
33%
30%
Robert, NEJM 364:2517, 2011
Robert et al. N Engl J Med 2011;364:2517-26.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Conclusions
 Uncertainty remains
 re the effect of dacarbazine given in combination
with ipi
 whether ipi should be given 1st or 2 nd line
 whether ipi should be given in combination or
sequentially with other drugs
 As optimal therapy remains lacking, pts should be
treated on clinical trials as much as possible
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
PD-1 / PDL-1 Interaction
MDX-1105
(MoAb to PDL-1)
B7-H1 (PD-L1)
B7-DC (PD-L2)
MHC II Ag
MDX-1106
(MoAb to PD-1)
Activated T Cell
PD-1 - T cell inhibition (induction of tolerance)
TCR
Tumor
Brahmer at al. J Clin Oncol. 2010;28:3167-75.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
BMS-936558 (MDX-1106) – Phase I Study
Eligibility:
•
•
•
•
•
Melanoma (N=104)
Non–small cell lung Ca (N=122)
Renal-cell Ca (N=34)
Castration Resistant Prostate Ca (N=17)
Colorectal Cancer (N=19)
•
•
•
•
•
EGOG PS 0-2
Life Expectancy ≥12 wks
Measurable Disease
1-5 prior treatments
No prior CTLA-4/PD-1 inhibitors
aDose
Dose
Escalationa
Escalation Cohort
3-6 patients in dose levels:
• 1.0 mg/kg q2w
• 3.0 mg/kg q2w
• 10 mg/kg q2w
Dose limiting toxicities assess for 56 days
Expansion
Cohortb
bExpension
Cohort
Patients with following Cancers:
• Melanoma (1mg/kg; 3mg/kg; 10 mg/kg)
• NSCLCa (1mg/kg; 3mg/kg; 10 mg/kg)
• Renal Cell Carcinoma (1mg/kg)
Topolian et al. N Engl J Med 2012;366:2443-54.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
37
Results – Toxicity
 MTD was not defined in this study.
 A relative dose intensity (the proportion of administered
doses relative to planned doses) of 90% or more was
achieved in 86% of patients
 The most common treatment related adverse events:






Fatigue
Rash
Diarrhea
Pruritus
Decreased appetite
Nausea
 Grade 3 or 4 treatment-related adverse events were
observed in 41 of 296 patients (14%).
Topolian et al. N Engl J Med 2012;366:2443-54.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
38
Immune Related Adverse Events
Topolian et al. N Engl J Med 2012;366:2443-54.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
39
Patient with Non-Small Cell Lung Cancer
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
40
Response Based on PD-L1 Expression in Tumors
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
41
Myeloid Derived Suppressor Cell Inhibitors
Inhibition of NOS,
ROS or Arginase
Differentiating
Agents
Blocking Recruitment
or activation
•Nitro-Aspirins
(NCX 4016)
•NOHA
•PDE-5 Inhibitors
(sildenafil )
•Synthetic
Triterpenoids
(CDDO-Me)
•COX-2 Inhibitors
(mAbGB3.1)
ATRA
Vitamin A
Vitamin D3
•CSF-1R Inhibitors
(GW2580)
•Anti-glycan
antibodies
(mAbGB3.1)
•MMP-9 Inhibitors
(Zoledronic Acid)
Tyrosine Kinase
Inhibition
•C-Kit and
VEGF
Inhibitors
(Sunitinib)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Chemotherapy
•Gemcitabine
•Cisplatin
•Paclitaxel
Balb-neuT Mice Treated with Zoledronic Acid
MDSC Levels:
Serum
Bone Marrow
Melani et al. Cancer Res. 2007;67:11438-46.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Balb neu-T Mice
Melani et al. Cancer Res. 2007;67:11438-46.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Pilot Study
Endocrine Therapy
10 Patients
Skeletal Mets
ER and/or PR+
Endocrine Tx
Zoledronic Acid 4 mg IV every 4 weeks
-2 0 1
4
8
12
16
20…
γ9δ2 T-cells & MDSC
Myeloid Derived Suppressor Cells:
CD33+ CD11b+ and HLA-DR-
Dieli F et al. J. Exp. Med. 2003, 198; 391–397
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Weeks
MDSC Inhibitors and Cancer Vaccines – Pre-clinical Studies
MDSC Inhibitor
Tumor Model
Vaccine
End Result
ATRAa
3-methycholantrene-induced
sarcoma containing mutant p53
gene in BALB/c mice
Wild type p53 DC vaccine
•5-fold decreased tumor size
•Improved Tcell IFNγ response
Gemcitabineb
Survivin (+) Panc02 tumors in
C57BL/6 mice
Attenuated vaccina virus
(MVA) expressing murine
survivin protein
•Improved Survival
•Improved IFNγ production
•Presence of survivin specific Tcells
Nitroaspirin Derrivative
(NCX 4016)c
HER-2/neu + N2C tumors in
Balb/c mice
Plasmid DNA vaccine
encoding extracellular and
trans-membrane domains of
p185 peptide
•Increased median survival
•56% cure rate
CDDO-Med
EL-4 thymoma tumor cells
DC transduced with murine
survivin
•2-fold decreased tumor size
•Improved antigen specific
immune response
Zoledronic Acide
Balb T-neu mice that develop
HER-2 positive mammary
carcinomas
Plasmid DNA encoding
portion of HER-2 gene
•Delayed tumor onset
•Reduced tumor size
•Increased anti–r-p185/HER-2
Ab titer
IL-13-PE (immuno-toxin
composed of IL-13 and
pseudomonas exotoxin)f
Murine 4T1 breast carcinoma
and MCA304 sracoma tumors
DNA vaccine encoding IL13Rαchain
•5-fold decrease in tumor size
•Decreased MDSC and Tregs
•Enhanced T-cell responses
•Increased survival by 50%
a. Kusmartsev et al. Cancer Res. 2003;63: 4441–4449.
b. Ishizaki et al. Cancer Immunol. Immunother 2011;60:99-109.
c. DeSanto et al. Proc. Natl. Acad. Sci. USA 2005; 102: 4185-4190
d. Nagaraj et al. Clin Cancer Res 2010; 16: 1812-1823.
e. Melani et al. Cancer Res. 2007;67:11438-46.
f. Nakashima et al. J. Immunol. 2011; 187: 4935-4946.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
46
Inhibition of Tumor Associated Macrophages
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
47
Combination Therapy
DeNardo et al. Cancer Discov. 2011; 1: 54–67.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Levels of CD8+ T-lymphocytes
DeNardo et al. Cancer Discov. 2011; 1: 54–67.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Appearance of Metastases
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
CSF-1R – Future Directions
 Two phase I studies are open at OSU that use
inhibition of CSF-1R as therapeutic strategy
 Phase I study with monoclonal antibody IMC-CS4 that
is IgG Molecule that binds to CSF-1R
 Phase I study with PLX 3397 in combination with
paclitaxel
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
52
Promising Cancer Vaccines
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
53
Tumor Antigens
 Normal Proteins
 Only Expressed in transforrmed cells (MAGE-1, NYESO-1)
 Increased expression
 Post-translational modification
 Mutated Proteins
 Viral Antigens
 Human Papilloma Virus
 Hepatitis B virus
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
54
NCI pilot project to
prioritize cancer antigens
Well-vetted, priority-ranked list of
cancer vaccine target antigens
Predefined and pre-weighted
objective criteria:
1. Therapeutic Function
2. Immunogenicity
3. Specificity
4. Oncogenicity
5. Expression Level & % (+) cells
6. Stem Cell Expression
7. # of Pts with Antigen (+)
Cancers
8. # of Epitopes
9. Cellular Location of Expresssion
Cheever et al. Clin Cancer Res 2009; 15:5323-5337.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
55
Sipuleucel-T
 Antigen presenting cells from patient’s
peripheral blood.
 Process in vitro by activation with recombinant
fusion protein PA2024:
 Prostate antigen - prostatic acid phosphatase,
 Immune activator - granulocyte–macrophage colonystimulating factor (GM-CSF).
Defrancesco Nature Biotechnol. 2010;28: 531-532
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
56
IMPACT TRIAL
Stage IV
Prostate
Cancer
322 centers
Sipuleucel-T
N=341
The primary end point:
•Overall Survival
Castration
Resistant
R
ECOG PS 0-1
N=512
Secondary end points:
2:1
•Time to Objective Disease Progression
Placebo
N=171
Exploratory end points:
•PSA and Lactate Dehydrogenase levels
•Antibody Titers
Stratification:
•Gleason grade ≤3 or ≥4
•Number of bone metastases (≤5, 6 to 10, or >10)
•Bisphosphonate use (yes or no)
Kantoff et al. N Engl J Med. 2010;363:411-22.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
57
Efficacy Results
Sipuleucel-T
Overall Survival (months)
25.8
Placebo
21.7
Hazard Ratio 0.78 (95% CI 0.61 – 0.98, p=0.032)
Median Survival (months)
25.8
21.7
3-Year Survival
37.1%
23%
Time to Disease Progression
3.7
3.6 months
Hazard Ratio, 0.95 (95% CI, 0.77 - 1.17, p = 0.63)
PSA reduction of >50%
2.6%
1.6%
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
58
Overall Survival – Kaplan Maier Curves
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
59
Toxicities That were different btw 2 groups
Advers Event
Sipuleucel-T (%)
Placebo (%)
All Grades
Grade 3-5
All Grades
Grade 3-5
Chills
54.1
1.2
12.5
0
Fever
29.3
0.3
13.7
1.8
Headache
16
0.3
4.8
0
Flu-Like
Symptoms
9.8
0
3.6
0
Myalgia
9.8
0.6
4.8
0
HTN
7.4
0.6
3.0
0
Hyperhydrosis
5.3
0
0.6
0
Groin Pain
5.0
0
2.4
0
Anorexia
7.1
0.3
16.1
1.8
Depression
2.4
0.3
6.5
0
Flank Pain
2.7
0
6.0
0
Hydronephrosis
3.8
7.1
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
60
gp100 - Melanoma Vaccine
 Modified peptide vaccine derived from screening
target antigens to T-cells that produced
responses in adoptive transfer experiments in
humans with metastatic melanoma
 Gp 100 epitope has been modified for better
binding to HLA*A2A4.
 In pre-clinical models, immunization has been
associated with high levels of circulating T-cells
that were capable to kill melanoma cells
suggesting synergy with T-cell stimulating
agents
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
61
gp100 – Phase III Study
21 centers
Stage III-IV
Melanoma
Expression of
HLA-A0201+
No brain
mets
Stratification:
Site of disease
(sub) cutaneous
vs. other
N=185
The primary end point:
IL-2
720,000 IU/kg q8h**
•Clinical Response (assessed
q6weeks)
Secondary end points:
R
•Safety
•Progression Free Survival
•Immunologic Response
•Quality of Life
1:1
Vaccination with
gp100 peptide*
followed by IL-2
720,000 IU/kg q8h**
Correlative Studies:
•Levels of peptide specific T-cells
•Levels of CD4+CD25+FoxP3+ cells
(before tx and after 4 cycles)
*gp100 - 209-217(210M) (IMDQVPFSV) plus incomplete Freund’s adjuvant (Montanide ISA-51)
** High dose IL-2 was administered up to 12 times as tolerated per cycle. Each cycle was repeated every
21 days with 1 extra week added q2 cycles. Treatment until disease progression.
Schwartzentruber et al. N Engl J Med 2011; 364:2119-27
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Response
The difference between the two groups was greatest among patients with M1b
disease (lung involvement) - 0% vs. 25%, P = 0.005
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Progression and Overall Survival
IL-2
IL-2 + gp 100
P-value
Progression Free Survival
(95% Confidence Interval)
1.6 months
(1.5 – 1.8)
2.2 months
(1.7 – 3.9)
0.008
Overall Survival
(95% Confidence Interval)
11.1 months
(8.7 – 16.3)
17.8 months
(11.9 – 25.8)
0.06
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Safety
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Important Considerations
 Total doses of IL-2: 21.5 vs. 25.7 in IL-2 vs.
vaccine/IL2 groups respectively
 Lower dose of IL-2 could have been used (3
phase II studies with the vaccine and lower dose
interleuikin showed response rates of 13-24%)
 Phase III Study with ipilimumab + gp 100
showed no benefit from addition of the vaccine
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HER-2/neu vaccines
 Most research concentrated on T-cell epitopes
 Kaumaya at al. at OSU developed a novel
vaccine that induced B-cell response
(“endogenous Trastuzumab and Pertuzumab”)
 Amino-acid 628-647 (Trastuzumab binding site)
 Amino-acids 316-329 (Pertuzumab binding site)
 These sequences were fused via 4 residue
linger sequence (GPSL) to promiscuous T-cell
epitope
 Amino-acids 288-302
 Adjuvant: nor-Muramyl-dipeptide (n-MDP)
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Pertuzumab-HER2 Complex
Trastuzumab-HER2 Complex
Pertuzumab
I
I
II
II
III
III
Dimerization domain
IV
IV
Trastuzumab

Inhibits HER2 dimerization with other HER
family receptors (particularly HER3)

Activates ADCC

Inhibits HER-mediated signaling pathways

Activates ADCC

Prevents HER2 domain cleavage

Inhibits multiple HER-mediated signaling
pathways
Hubbard SR. Cancer Cell. 2005;7:287-288.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
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Phase I Study of the HER-2/neu vaccine
 Eligibility:
 All patients with incurable/metastatic treatment
refractory malignancy
 stable disease (including brain metastases) for at
least 3 months
 ECOG 0-2
 ≥ 4 weeks past any prior surgery, cytotoxic
chemotherapy, other immunotherapy, hormonal
therapy, or radiation therapy
 No intercurrent uncontrolled illness
Kaumaya et al. J Clin Oncol 2009; 27:5270-5277.
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Administration Schedule
Cohort
Dose
Schedule
# of
doses
1
0.25 mg
Every 3 weeks
3
2
0.5 mg
Every 3 weeks
3
3
1.0 mg
Every 3 weeks
3
4
1.5 mg
Every 3 weeks
3
Kaumaya et al. J Clin Oncol 2009; 27:5270-5277.
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Study Population
Kaumaya et al. J Clin Oncol 2009; 27:5270-5277.
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Grade 3-4 Toxicity
Toxicity
Number
Diarrhea
1
Pain
1
Cardiac Toxicity
0
Deaths
1*
Hospitalization
2**
*1 death occurred on day 118 and was felt to be unrelated to therapy
**Hospitalization occurred for reasons felt to be unrelated to vaccine
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The Vaccine Induces IgG Response
Kaumaya et al. J Clin Oncol 2009; 27:5270-5277.
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Antibodies Induce NK Cell Mediated Antibody
dependent cell cytotoxicity (NK-ADCC)
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The Antibodies Inhibit Growth of BT474
Breast Cancer Cells
Kaumaya et al. J Clin Oncol 2009; 27:5270-5277.
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Vaccines to MUC1 Antigen
 Present on 75-90% of breast carcinomas and in
about 80% of all epihelial malignancies.
 Polypeptide core of tandem 20 amino-acid
repeats with numerous carbohydrate side chains
 The position and carbohydrate content is
different when expressed on normal vs.
malignant cells.
Kimura et al. Expert Opin Biol Ther. 2012 Sep 24. [Epub ahead of print]
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MUC1 and Normal Tissues
Tissue
Expression
Spleen
-
Smooth/Striated Muscle
-
Lung Epithelium
2+
Breast Epithelium
1+
Prostate Epithelium
+/-
Colon Epithelium
2+
Stomach Epithelium
1+
Pancreas Epithelium
2+
Uterus Epithelium
1+
Ovary Epithelium
1+
Liver Epithelium
-
Kidney Epithelium
2+
Testis Epithelium
-
Brain Epithelium
-
Connective Tissue
-
Zhang et al. Clin Cancer Res 1998;4:2669-2676
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MUC 1 on Normal vs. Malignant Cells
Feature
Malignant Cells
Normal Cells
Polarity
Diffuse expression
Apical surface only
Amount of Carbohydrate
Low
High
Type of Glycosylation
Simple
Complex
MUC1 on normal cells is different than on malignant cells resulting in higher
number of exposed epitopes on cancer expressed glycoprotein
MUC1 Vaccines are immunogenic producing both humoral and T-cell immune
responses.
Gilewski et al. Clin Can Res 2000; 6:1693-1701
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MUC1 Vaccine
 MUC 1 peptide conjugated with a Keyhole
Limpet Hemocyanin (KLH) and in combination
with a powerful adjuvant:
 QS-21 (Saponin derived from South American tree
Quillaja saponaria)
MBS – a bifunctional linker that facilitates covalent binding of KLH to terminal cysteine
on MUC 1 Peptide
Gilewski et al. Clin Can Res 2000; 6:1693-1701
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Pilot Study:
 High Risk Breast Cancer Patients (N=9)
 Stage I-III and rising tumor markers
 Stage III that was initially unresectable (within 12 months
of completing systemic therapy)
 Stage IV in complete remission
Gilewski et al. Clin Can Res 2000; 6:1693-1701
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Study Population
Gilewski et al. Clin Can Res 2000; 6:1693-1701
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Toxicity
Gilewski et al. Clin Can Res 2000; 6:1693-1701
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Immune Reaction
Gilewski et al. Clin Can Res 2000; 6:1693-1701
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Further Development of MUC1 vaccine
 Two decades of immunotherapy trials targeting
MUC1, focusing primarily on vaccines but also
adoptive antibody and T-cell therapies.
 More than 1200 patients in clinical trials.
 Encouraging results reported particularly for less
immuno-suppressed patients (adjuvant setting).
 Anti-MUC1 immune responses are associated
with better prognosis or with a reduced lifetime
risk of developing MUC1+ cancers.
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Future Directions
 Use of conventional therapies in combination with
vaccines +/- modulators of host immunity
 MDSC or T-reg inhibitors
 Cytokines
 T-cell stimulating antibodies (ipilomumab)
 Use of emerging technologies to identify important tumor
antigens
 Use of these therapies to prevent cancer in high risk
individuals
 Translational studies of immuno-editing and how it
affects healthy high risk individuals, dysplastic lesions,
early stage cancer, advanced cancer
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Thank You For Your Attention
Questions?
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