Targeting the Immune System in Cancer – Transforming Failure into Success Robert Wesolowski, MD Stefanie Spielman Comprehensive Breast Center

Targeting the Immune System in Cancer Targeting the Immune System in Cancer – Transforming Failure into Success– Transforming Failure into Success

Robert Wesolowski, MD

Stefanie Spielman Comprehensive Breast Center

The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

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



Immune System and Cancer

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)



Immunodeficiency Predisposes to Cancer

5

Schreiber et al. Science 2011;331, 1565-1570



Immunosurveillance

Malignant Clone

Fcγ ReceptorsAntigen Receptors

NK

DC Mф

CD8+

CD4+

CytokinesCD20+



7




Vesely, et al. Annual Review of Immunology, 2011; 29: 235-71.



Role of Immune System in Promoting Cancer Growth

9



Mechanism of Immune Suppression – Tumor Escape

10

Expression of Immune-

suppressive factors




Regulatory T-Cells Suppress Cytotoxic Immunity

11

Treg

CD4+CD25+FoxP3+

Secretes Inhibitory cytokinesIL-10TGFβ

Expresses Immune checkpoint signalsCTLA-4PD-1PD-L1

Sequesters IL-2

Normal Function:•Stop immune response when it is no longer needed•Thought to be involved in prevention of auto-immunity



MDSC Expansion in Cancer

Hematopoietic Stem Cell

IL-3c-kit, SCF, FLT3

G-CSF, GM-CSR

Immature Myeloid Cell

Bone M

arrow

Tumor Cells

IL1β, IL-6, IL-10PGE, GM-CSF, G-CSF, M-CSFVEGF, CXCL5, CXCL12 Partial Block of

Differentiation(STAT3)

Tumor Associated Macrophages

Myeloid Derived Suppressor Cells

CD11+, CD33+, HLA DR-, Linlo/- (Gr1+ in Mice)

CD68+, F4/80+



CD8+

CD4+

NK

DC

Treg

TAM

MAC

MDSC

T cellsCysteine

Arginine (ARG1)Nitration (iNOS)

MacrophagesDrives M2

IL-12

Suppressor cells

IL-10TGF-β

NK cellsNKG2D

IFNγCytotoxicity

Dendritic cellsMaturation

Borrowed from Dr. William Carson

Myeloid Derived Suppressor Cells



MDSC Are Elevated in Spleens of Tumor- Bearing Mice

CD11b-APC

GR

-1-F

ITC

MDSC

CD11b-APC

GR

-1-F

ITC

MDSC

Sid

e S

catt

er

Forward Scatter

Normal C26-Bearing

Sid

e S

catt

er

Forward Scatter

Normal C26-Bearing

CD11b-APC

GR

-1-F

ITC

MDSC

CD11b-APC

GR

-1-F

ITC

MDSC

CD11b-APC

GR

-1-F

ITC

MDSC

CD11b-APC

GR

-1-F

ITC

MDSC

Sid

e S

catt

er

Forward Scatter

Normal C26-Bearing

Sid

e S

catt

er

Forward Scatter

Normal C26-Bearing

Sid

e S

catt

er

Forward Scatter

Normal C26-Bearing

Sid

e S

catt

er

Forward Scatter

Normal C26-Bearing

0

2

4

6

8

10

12

14

16

18

Normal C26

Mea

n P

erce

nt

Po

siti

ve M

DS

C

n=19 n=21 * p<0.05

*

Borrowed from Dr. William Carson



MDSC in a Breast Cancer Patient

Normal Volunteer

Adjuvant Chemotherapy

Metastatic Cancer

Lin

HLA-DR

CD33

CD11bDiaz-Montero et al. Cancer Immunol Immunother 2009; 58:49–59



Prognostic value of MDSC In Breast Cancer

Median Overall Survival

MDSC ≥3.17% 19.32 months

MDSC <3.17% 6.78 months

Cole at al. SABC 2009 Abstract 4135

N=25

Median Overall Survival

MDSC ≥3.04% N/A

MDSC <3.04% 7.7 months

First Visit

Last Visit



MDSCs and Survival of Patients with GI Cancers

N=131

Gabitass et al Cancer Immunol Immunother 2011 (published online ahead of print)

Adjustments:•Cancer Type•Stage•Treatment•Performance Status



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.



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.



Tumor Associated Macrophages

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Immune Signatures

N=179 N=498

DeNardo et al. Cancer Discov. 2011; 1: 54–67.



CD68 and CD8a expression is prognostic in Human Breast Cancer

N=311N=3,872




Re-programming Immune System in Cancer Patients

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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

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Immune Checkpoint Inhibitors

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Cytotoxic T Lymphocyte Assoc Protein-4 (CTLA-4)

Ag presentingDendritic cell

MHC II Ag TCR

CD 28 – T cell stimulation (with IL-2 production)

CD 80 B 7.1CD 86 B 7.2

Activated T Cell

CTLA-4 – T cell inhibition (induction of tolerance)− CD152



CTLA-4

Ag presentingDendritic cell

MHC II Ag TCR

CD 28 – Unopposed T cell stimulationCD 80 B 7.1CD 86 B 7.2

Activated T Cell

Unopposed autoimmune effects: - uveitis - rash and vitiligo - pan hypo-pituitarism - diarrhea and colitis - hepatitis



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)



Phase III MDX010-20 – 2nd Line Tx

RANDOMIZE

Ipilimumab 3 mg/kg IV

Ipilimumab 3 mg/kg IV & gp 100

Open 9/2004 – 8/2008Double blind (3:1:1; for ipi & gp100, ipi and gp100 alone)

Hodi et al. N Engl J Med 2010;363:711-23.

676 pts with prior treatedmetastatic melanoma

70% hadM1c poor risk

visceral disease

gp 100 vaccine

All drugs q 3 wks x 4 doses

N=403

N=137

N=136



Ipi. Alone

V



Overall Survival

Progression Free Survival




* CR, + PR, + SD Hodi, NEJM 363:711, 2010

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)




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 363:711, 2010



Phase III Ipilimumab +/- Dacarbazine – 1st Line

RANDOMIZE

Ipilimumab 10 mg/kg IV + DTIC

DTIC 850 mg/m2

250 pts

252 pts

Open 8/2006 to 1/2008

All drugs q 3 wks x 4502 pt with untreated

metastatic melanoma

Maintenance given in ptswith stable to responding dis.

Robert et al. N Engl J Med 2011;364:2517-26.

1:1

Stratification:Metastases stageStudy siteECOG PS



Phase III MDX 010-24 – 1st Line Tx

* CR, + PR, + SDRobert, NEJM 364:2517, 2011

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%

Robert et al. N Engl J Med 2011;364:2517-26.



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



PD-1 / PDL-1 Interaction

Tumor

MHC II Ag TCR

Activated T Cell

PD-1 - T cell inhibition (induction of tolerance)

MDX-1106 (MoAb to PD-1)

MDX-1105 (MoAb to PDL-1)

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

B7-H1 (PD-L1)B7-DC (PD-L2)



BMS-936558 (MDX-1106) – Phase I Study

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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

Dose Escalationa

aDose Escalation Cohort3-6 patients in dose levels:•1.0 mg/kg q2w•3.0 mg/kg q2w•10 mg/kg q2wDose limiting toxicities assess for 56 days

Expansion Cohortb

bExpension CohortPatients 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.



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%).

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Immune Related Adverse Events

39




Patient with Non-Small Cell Lung Cancer

40



Response Based on PD-L1 Expression in Tumors

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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)

ATRAVitamin AVitamin D3

•CSF-1R Inhibitors(GW2580)•Anti-glycan antibodies(mAbGB3.1)•MMP-9 Inhibitors(Zoledronic Acid)

•C-Kit and VEGF Inhibitors(Sunitinib)

•Gemcitabine•Cisplatin•Paclitaxel



Balb-neuT Mice Treated with Zoledronic Acid

Melani et al. Cancer Res. 2007;67:11438-46.

Serum

Bone Marrow

MDSC Levels:



Balb neu-T Mice

Melani et al. Cancer Res. 2007;67:11438-46.



Pilot Study

10 PatientsSkeletal Mets

ER and/or PR+Endocrine Tx

γ9δ2 T-cells & MDSC

Zoledronic Acid 4 mg IV every 4 weeks

0 Weeks1 4 8 12 16 20…

Myeloid Derived Suppressor Cells:CD33+ CD11b+ and HLA-DR-

Endocrine Therapy

-2

Dieli F et al. J. Exp. Med. 2003, 198; 391–397



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 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 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 IL-13Rαchain

•5-fold decrease in tumor size•Decreased MDSC and Tregs•Enhanced T-cell responses•Increased survival by 50%

46

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.



Inhibition of Tumor Associated Macrophages

47



Combination Therapy




Levels of CD8+ T-lymphocytes






Appearance of Metastases



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

52



Promising Cancer Vaccines

53



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

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NCI pilot project to prioritize cancer antigens

55

Cheever et al. Clin Cancer Res 2009; 15:5323-5337.

Well-vetted, priority-ranked list of cancer vaccine target antigens

Predefined and pre-weighted objective criteria:1. Therapeutic Function2. Immunogenicity3. Specificity4. Oncogenicity5. Expression Level & % (+) cells6. Stem Cell Expression7. # of Pts with Antigen (+) Cancers8. # of Epitopes9. Cellular Location of Expresssion



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 colony-

stimulating factor (GM-CSF).

56

Defrancesco Nature Biotechnol. 2010;28: 531-532



IMPACT TRIAL

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Stage IV Prostate Cancer

Castration Resistant

ECOG PS 0-1

N=512

322 centers

R

Sipuleucel-TN=341

PlaceboN=171

Stratification:

•Gleason grade ≤3 or ≥4•Number of bone metastases (≤5, 6 to 10, or >10)•Bisphosphonate use (yes or no)

The primary end point:•Overall Survival

Secondary end points:•Time to Objective Disease Progression

Exploratory end points:•PSA and Lactate Dehydrogenase levels•Antibody Titers

2:1

Kantoff et al. N Engl J Med. 2010;363:411-22.



Efficacy Results

Sipuleucel-T Placebo

Overall Survival (months) 25.8 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%

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Overall Survival – Kaplan Maier Curves

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

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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

61



gp100 – Phase III Study

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Stage III-IVMelanomaExpression of HLA-A0201+No brain mets

Stratification:Site of disease(sub) cutaneous vs. other

N=185

21 centers

R

IL-2720,000 IU/kg q8h**

Vaccination with gp100 peptide* followed by IL-2

720,000 IU/kg q8h**

*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.

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 CD4+CD25+FoxP3+ cells(before tx and after 4 cycles)

1:1

Schwartzentruber et al. N Engl J Med 2011; 364:2119-27



Response

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The difference between the two groups was greatest among patients with M1b disease (lung involvement) - 0% vs. 25%, P = 0.005



Progression and Overall Survival

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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



Safety

65



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)

67



Hubbard SR. Cancer Cell. 2005;7:287-288.

Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex

Pertuzumab

Dimerization domain

Trastuzumab

IIIII

I

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

IIIII

I

IV IV



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

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Kaumaya et al. J Clin Oncol 2009; 27:5270-5277.



Administration Schedule

70

Cohort Dose Schedule # of doses

1 0.25 mg Every 3 weeks 3







Study Population

71




Grade 3-4 Toxicity

72

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



The Vaccine Induces IgG Response

73




Antibodies Induce NK Cell Mediated Antibody dependent cell cytotoxicity (NK-ADCC)

74



The Antibodies Inhibit Growth of BT474 Breast Cancer Cells

75




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.

76

Kimura et al. Expert Opin Biol Ther. 2012 Sep 24. [Epub ahead of print]



MUC1 and Normal Tissues

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Tissue ExpressionSpleen -

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



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

78

Gilewski et al. Clin Can Res 2000; 6:1693-1701

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.



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)

79


MBS – a bifunctional linker that facilitates covalent binding of KLH to terminal cysteine on MUC 1 Peptide



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

80




Study Population

81




Toxicity

82




Immune Reaction

83




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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Targeting the Immune System in Cancer – Transforming Failure into Success Robert Wesolowski, MD Stefanie Spielman Comprehensive Breast Center