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Targeting the Immune System in Cancer

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Title: Targeting the Immune System in Cancer


1
Targeting the Immune System in Cancer
Transforming Failure into Success
  • Robert Wesolowski, MD

Stefanie Spielman Comprehensive Breast Center
2
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

3
Immune System and Cancer
4
Cancer Development Depends on Immunity/Inflammatio
n
  • Cancer Immuno-surveillance Theory (Burnett and
    Thomas in 1950s)
  • 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)

5
Immunodeficiency Predisposes to Cancer
Schreiber et al. Science 2011331, 1565-1570
6
Immunosurveillance
NK
Fc? Receptors Antigen Receptors
Malignant Clone
M?
DC
CD4
Cytokines
CD20
CD8
7
Schreiber et al. Science 2011331, 1565-1570
8
Vesely, et al. Annual Review of Immunology, 2011
29 235-71.
9
Role of Immune System in Promoting Cancer Growth
10
Mechanism of Immune Suppression Tumor Escape
Expression of Immune-suppressive factors
Schreiber et al. Science 2011331, 1565-1570
11
Regulatory T-Cells Suppress Cytotoxic Immunity
Secretes Inhibitory cytokines IL-10 TGFß
CD4 CD25 FoxP3
Expresses Immune checkpoint signals CTLA-4 PD-1 PD
-L1
Treg
Sequesters IL-2
  • Normal Function
  • Stop immune response when it is no longer needed
  • Thought to be involved in prevention of
    auto-immunity

12
MDSC Expansion in Cancer
Hematopoietic Stem Cell
IL-3 c-kit, SCF, FLT3 G-CSF, GM-CSR
Bone Marrow
IL1ß, IL-6, IL-10 PGE, GM-CSF, G-CSF, M-CSF VEGF,
CXCL5, CXCL12
Partial Block of Differentiation (STAT3)
Immature Myeloid Cell
CD68, F4/80
CD11, CD33, HLA DR-, Linlo/- (Gr1 in Mice)
Tumor Associated Macrophages
Myeloid Derived Suppressor Cells
Tumor Cells
13
Myeloid Derived Suppressor Cells
Borrowed from Dr. William Carson
14
MDSC Are Elevated in Spleens of Tumor- Bearing
Mice

plt0.05
Borrowed from Dr. William Carson
15
MDSC in a Breast Cancer Patient
Normal Volunteer
Adjuvant Chemotherapy
Metastatic Cancer
Lin
CD33
HLA-DR
CD11b
Diaz-Montero et al. Cancer Immunol Immunother
2009 584959
16
Prognostic value of MDSC In Breast Cancer
N25
Median Overall Survival
MDSC 3.17 19.32 months
MDSC lt3.17 6.78 months
First Visit
Median Overall Survival
MDSC 3.04 N/A
MDSC lt3.04 7.7 months
Last Visit
Cole at al. SABC 2009 Abstract 4135
17
MDSCs and Survival of Patients with GI Cancers
N131
  • Adjustments
  • Cancer Type
  • Stage
  • Treatment
  • Performance Status

Gabitass et al Cancer Immunol Immunother 2011
(published online ahead of print)
18
MDSC Pilot - Neo-adjuvant Cohort (N24)
  • Primary Objectives
  • Baseline levels of circulating MDSCs and
    determine their association with pathologic
    response at the time of surgery.
  • Levels of MDSCs in the peripheral blood during
    the course of neoadjuvant chemotherapy.
  • Determine whether these changes could be
    predictive of response.

19
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.

20
Tumor Associated Macrophages
21
Immune Signatures
N498
N179
DeNardo et al. Cancer Discov. 2011 1 5467.
22
CD68 and CD8a expression is prognostic in Human
Breast Cancer
N311
N3,872
DeNardo et al. Cancer Discov. 2011 1 5467.
23
Re-programming Immune System in Cancer Patients
24
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

25
Immune Checkpoint Inhibitors
26
Cytotoxic T Lymphocyte Assoc Protein-4 (CTLA-4)
Ag presenting Dendritic cell
Activated T Cell
MHC II Ag
TCR
CD 28 T cell stimulation (with IL-2 production)
CD 80 B 7.1 CD 86 B 7.2
CTLA-4 T cell inhibition (induction of
tolerance) - CD152
27
CTLA-4
Ag presenting Dendritic cell
Activated T Cell
MHC II Ag
TCR
CD 28 Unopposed T cell stimulation
CD 80 B 7.1 CD 86 B 7.2
Unopposed autoimmune effects - uveitis - rash
and vitiligo - pan hypo-pituitarism - diarrhea
and colitis - hepatitis
28
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
    TGFß)

29
Phase III MDX010-20 2nd Line Tx
Open 9/2004 8/2008 Double blind
(311 for ipi gp100, ipi and gp100 alone)
Ipilimumab 3 mg/kg IV gp 100
N403
R A N D O M I Z E
676 pts with prior treated metastatic melanoma
All drugs ? q 3 wks x 4 doses
Ipilimumab 3 mg/kg IV
N137
70 had M1c poor risk visceral disease
gp 100 vaccine
N136
Hodi et al. N Engl J Med 2010363711-23.
30
Phase III MDX010-20 2nd Line Tx

Overall Survival
Progression Free Survival
Hodi et al. N Engl J Med 2010363711-23.
31
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 363711, 2010
Hodi et al. N Engl J Med 2010363711-23.
32
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
    re-challenged and still have a chance of response

Hodi, NEJM 363711, 2010
33
Phase III Ipilimumab /- Dacarbazine 1st Line
Stratification Metastases stage Study site ECOG
PS
Open 8/2006 to 1/2008
R A N D O M I Z E
250 pts
Ipilimumab 10 mg/kg IV DTIC
502 pt with untreated metastatic melanoma
All drugs ? q 3 wks x 4
11
DTIC 850 mg/m2
252 pts
Maintenance given in pts with stable to
responding dis.
Robert et al. N Engl J Med 20113642517-26.
34
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 33 30

CR, PR, SD
Robert, NEJM 3642517, 2011
Robert et al. N Engl J Med 20113642517-26.
35
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

36
PD-1 / PDL-1 Interaction
MDX-1105 (MoAb to PDL-1)
MDX-1106 (MoAb to PD-1)
Activated T Cell
B7-H1 (PD-L1) B7-DC (PD-L2)
PD-1 - T cell inhibition (induction of tolerance)
MHC II Ag
TCR
Tumor
Brahmer at al. J Clin Oncol. 2010283167-75.
37
BMS-936558 (MDX-1106) Phase I Study
  • Eligibility
  • Melanoma (N104)
  • Nonsmall cell lung Ca (N122)
  • Renal-cell Ca (N34)
  • Castration Resistant Prostate Ca (N17)
  • Colorectal Cancer (N19)
  • EGOG PS 0-2
  • Life Expectancy 12 wks
  • Measurable Disease
  • 1-5 prior treatments
  • No prior CTLA-4/PD-1 inhibitors

Dose Escalationa
Expansion Cohortb
  • aDose 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
  • 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 20123662443-54.
38
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 20123662443-54.
39
Immune Related Adverse Events
Topolian et al. N Engl J Med 20123662443-54.
40
Patient with Non-Small Cell Lung Cancer
41
Response Based on PD-L1 Expression in Tumors
42
Myeloid Derived Suppressor Cell Inhibitors
Inhibition of NOS, ROS or Arginase
Differentiating Agents
Blocking Recruitment or activation
Tyrosine Kinase Inhibition
Chemotherapy
  • Nitro-Aspirins
  • (NCX 4016)
  • NOHA
  • PDE-5 Inhibitors
  • (sildenafil )
  • Synthetic Triterpenoids
  • (CDDO-Me)
  • COX-2 Inhibitors
  • (mAbGB3.1)

ATRA Vitamin A Vitamin D3
  • Gemcitabine
  • Cisplatin
  • Paclitaxel
  • CSF-1R Inhibitors
  • (GW2580)
  • Anti-glycan antibodies
  • (mAbGB3.1)
  • MMP-9 Inhibitors
  • (Zoledronic Acid)
  • C-Kit and VEGF Inhibitors
  • (Sunitinib)

43
Balb-neuT Mice Treated with Zoledronic Acid
MDSC Levels
Serum
Bone Marrow
Melani et al. Cancer Res. 20076711438-46.
44
Balb neu-T Mice
Melani et al. Cancer Res. 20076711438-46.
45
Pilot Study
10 Patients Skeletal Mets ER and/or PR Endocrine
Tx
Endocrine Therapy
Zoledronic Acid 4 mg IV every 4 weeks
0
1
4
8
12
16
20
-2
Weeks
?9d2 T-cells MDSC
Myeloid Derived Suppressor Cells CD33 CD11b
and HLA-DR-
Dieli F et al. J. Exp. Med. 2003, 198 391397
46
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 IFN? response
Gemcitabineb Survivin () Panc02 tumors in C57BL/6 mice Attenuated vaccina virus (MVA) expressing murine survivin protein Improved Survival Improved IFN? production Presence of survivin specific T-cells
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 antir-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 IL-13Rachain 5-fold decrease in tumor size Decreased MDSC and Tregs Enhanced T-cell responses Increased survival by 50
  1. Kusmartsev et al. Cancer Res. 200363 44414449.
  2. Ishizaki et al. Cancer Immunol. Immunother
    20116099-109.
  3. 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.
20076711438-46. f. Nakashima et al. J.
Immunol. 2011 187 4935-4946.
47
Inhibition of Tumor Associated Macrophages
48
Combination Therapy
DeNardo et al. Cancer Discov. 2011 1 5467.
49
Levels of CD8 T-lymphocytes
DeNardo et al. Cancer Discov. 2011 1 5467.
50
(No Transcript)
51
Appearance of Metastases
52
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

53
Promising Cancer Vaccines
54
Tumor Antigens
  • Normal Proteins
  • Only Expressed in transforrmed cells (MAGE-1,
    NY-ESO-1)
  • Increased expression
  • Post-translational modification
  • Mutated Proteins
  • Viral Antigens
  • Human Papilloma Virus
  • Hepatitis B virus

55
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 155323-5337.
56
Sipuleucel-T
  • Antigen presenting cells from patients
    peripheral blood.
  • Process in vitro by activation with recombinant
    fusion protein PA2024
  • Prostate antigen - prostatic acid phosphatase,
  • Immune activator - granulocytemacrophage
    colony-stimulating factor (GM-CSF).

Defrancesco Nature Biotechnol. 201028 531-532
57
IMPACT TRIAL
322 centers
Stage IV Prostate Cancer Castration
Resistant ECOG PS 0-1 N512
Sipuleucel-T N341
  • The primary end point
  • Overall Survival
  • Secondary end points
  • Time to Objective Disease Progression
  • Exploratory end points
  • PSA and Lactate Dehydrogenase levels
  • Antibody Titers

R
21
Placebo N171
  • Stratification
  • Gleason grade 3 or 4
  • Number of bone metastases (5, 6 to 10, or gt10)
  • Bisphosphonate use (yes or no)

Kantoff et al. N Engl J Med. 2010363411-22.
58
Efficacy Results
Sipuleucel-T Placebo
Overall Survival (months) 25.8 21.7
Hazard Ratio 0.78 (95 CI 0.61 0.98, p0.032) Hazard Ratio 0.78 (95 CI 0.61 0.98, p0.032)
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) Hazard Ratio, 0.95 (95 CI, 0.77 - 1.17, p 0.63)
PSA reduction of gt50 2.6 1.6
59
Overall Survival Kaplan Maier Curves
60
Toxicities That were different btw 2 groups
Advers Event Sipuleucel-T () Sipuleucel-T () Placebo () Placebo ()
Advers Event 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
61
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 HLAA2A4.
  • 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

62
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 N185
  • The primary end point
  • Clinical Response (assessed q6weeks)
  • Secondary end points
  • Safety
  • Progression Free Survival
  • Immunologic Response
  • Quality of Life
  • Correlative Studies
  • Levels of peptide specific T-cells
  • Levels of CD4CD25FoxP3 cells
  • (before tx and after 4 cycles)

IL-2 720,000 IU/kg q8h
R
11
Vaccination with gp100 peptide followed by IL-2
720,000 IU/kg q8h
gp100 - 209-217(210M) (IMDQVPFSV) plus
incomplete Freunds 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
3642119-27
63
Response
The difference between the two groups was
greatest among patients with M1b disease (lung
involvement) - 0 vs. 25, P 0.005
64
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
65
Safety
66
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

67
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)

68
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 multiple HER-mediated signaling pathways
  • Activates ADCC
  • Inhibits HER-mediated signaling pathways
  • Prevents HER2 domain cleavage

Hubbard SR. Cancer Cell. 20057287-288.
69
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 275270-5277.
70
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 275270-5277.
71
Study Population
Kaumaya et al. J Clin Oncol 2009 275270-5277.
72
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
73
The Vaccine Induces IgG Response
Kaumaya et al. J Clin Oncol 2009 275270-5277.
74
Antibodies Induce NK Cell Mediated Antibody
dependent cell cytotoxicity (NK-ADCC)
75
The Antibodies Inhibit Growth of BT474 Breast
Cancer Cells
Kaumaya et al. J Clin Oncol 2009 275270-5277.
76
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
77
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 199842669-2676
78
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 61693-1701
79
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 61693-1701
80
Pilot Study
  • High Risk Breast Cancer Patients (N9)
  • 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 61693-1701
81
Study Population
Gilewski et al. Clin Can Res 2000 61693-1701
82
Toxicity
Gilewski et al. Clin Can Res 2000 61693-1701
83
Immune Reaction
Gilewski et al. Clin Can Res 2000 61693-1701
84
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.

85
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

86
Thank You For Your Attention
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