New Developments in Cancer Vaccines

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



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)



Research Institute

Immunodeficiency Predisposes to Cancer

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



Research Institute

5

Immunosurveillance

Malignant Clone

CD20+

CD8+

NK

Fc γ Receptors

Antigen Receptors

CD4+ DC

Cytokines

Mф



Research Institute




Research Institute

7

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



Research Institute

Role of Immune System in Promoting

Cancer Growth



Research Institute

9

Mechanism of Immune Suppression –

Tumor Escape

Loss of tumor antigens

Regulatory

T-cells


Intrinsic

Loss of complement sensitivity

Loss of human leukocyte antigens

Expression of

Immunesuppressive factors

Extrinsic

Tumor

Associated

Macrophages

Myeloid

Derived

Suppressor

Cells



Research Institute

10

Regulatory T-Cells Suppress Cytotoxic

Immunity

CD4+

CD25+

FoxP3+

T reg

Secretes Inhibitory cytokines

IL-10

TGF β

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



Research Institute

11

MDSC Expansion in Cancer

Hematopoietic

Stem Cell

IL-3 c-kit, SCF, FLT3

G-CSF, GM-

CSR

IL1β, IL-6, IL-10

PGE, GM-CSF, G-CSF, M-CSF

VEGF, CXCL5, CXCL12

Partial Block of

Differentiation

(STAT3)

Immature Myeloid Cell

Tumor Cells

Tumor Associated

Macrophages

CD68+, F4/80+

CD11+, CD33+, HLA DR-,

Lin lo/(Gr1+ in Mice)

Myeloid Derived Suppressor Cells



Research Institute

Myeloid Derived

Suppressor Cells

DC

NK

Dendritic cells

Maturation

T reg

NK cells

NKG2D

IFNγ

Cytotoxicity

CD4+

T cells

Cysteine

Arginine (ARG1)

Nitration (iNOS)

CD8+

MDSC

Suppressor cells

IL-10

TGF-β

TAM

MAC

Macrophages

Drives M2

IL-12

Borrowed from Dr. William Carson



Research Institute

MDSC Are Elevated in Spleens of

Tumor- Bearing Mice

12

10

8

6

4

2

0

18

16

14

*

Normal n=19

C26 n=21 * p<0.05

Borrowed from Dr. William Carson



Research Institute

MDSC in a Breast Cancer Patient

Normal

Volunteer

Adjuvant

Chemotherapy

Metastatic

Cancer

HLA-DR

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

CD11b



Research Institute

Prognostic value of MDSC In Breast Cancer

N=25

First Visit

MDSC ≥3.17%

MDSC <3.17%

Median Overall Survival

19.32 months

6.78 months

Last Visit

MDSC ≥3.04%

MDSC <3.04%

Median Overall Survival

N/A

7.7 months

Cole at al. SABC 2009 Abstract 4135



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)



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.



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.



Research Institute

Tumor Associated Macrophages



Research Institute

20

N=179

Immune Signatures

N=498

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



Research Institute

CD68 and CD8a expression is prognostic in

Human Breast Cancer

N=311

N=3,872




Research Institute

Re-programming Immune System in Cancer

Patients



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



Research Institute

24

Immune Checkpoint Inhibitors



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



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



Research Institute

CTLA-4

 anti-CTLA-4 MoAb

 humanized IgG1k

 T

1/2

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

TGF β)



Research Institute

Phase III MDX010-20 – 2

nd

Line Tx

Open 9/2004 – 8/2008

Double blind

(3:1:1; for ipi & gp100, ipi and gp100 alone)

676 pts with prior treated metastatic melanoma

70% had

M1c poor risk visceral disease

O

M

I

Z

E

R

A

N

D

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.



Research Institute

Phase III MDX010-20 – 2 nd Line Tx

Overall Survival

Ipi. Alone

Progression Free Survival




Research Institute

Phase III MDX010-20 – 2

nd

Line Tx

 Results

PFS ipi and gp 100

2.8 mos med OS 10.1 mos ipi

2.8 mos

10 mos gp100

2.8 mos

6.4 mos

12 mos 46%

24 mos 24%

RR 11%

44%

22%

6%

25%

14%

2%

CBR* 29% 22% 11%

*

CBR = Clinical Benefit Rate (CR, + PR, + SD)

* CR, + PR, + SD


Hodi, NEJM 363:711, 2010



Research Institute

MDX010-20 Ipilimumab – 2 nd 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



Research Institute

Phase III Ipilimumab

+/- Dacarbazine – 1 st Line

Open 8/2006 to 1/2008

Stratification:

Metastases stage

Study site

ECOG PS

502 pt with untreated metastatic melanoma

O

M

I

Z

E

R

A

N

D

1:1

Ipilimumab 10 mg/kg IV + DTIC

All drugs  q 3 wks x 4

DTIC 850 mg/m 2 252 pts

250 pts

Maintenance given in pts with stable to responding dis.

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



Research Institute

Phase III MDX 010-24 – 1st Line Tx

Results

PFS (stat significant) med OS

12 mos OS

24 mos OS

RR (duration)

Clinical benefit*

* CR, + PR, + SD ipi and DTIC

2.8 mos

11 mos

47%

DTIC

2.6 mos

9 mos

36%

29% 18%

15% (19 mos) 10% (8 mos)

33% 30%

Robert, NEJM 364:2517, 2011

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



Research Institute

Conclusions

 Uncertainty remains

 re the effect of dacarbazine given in combination with ipi

 whether ipi should be given 1 st 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



Research Institute

PD-1 / PDL-1 Interaction

MDX-1105

(MoAb to PDL-1)

MDX-1106

(MoAb to PD-1)

B7-H1 (PD-L1)

B7-DC (PD-L2)

MHC II Ag

Activated T Cell

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

TCR

Tumor

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



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

Dose

Escalation a

Expansion

Cohort b a Dose 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

Topolian et al. N Engl J Med 2012;366:2443-54.

b Expension 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)



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%).




Research Institute

38

Immune Related Adverse Events




Research Institute

39

Patient with Non-Small Cell Lung Cancer



Research Institute

40

Response Based on PD-L1 Expression in Tumors



Research Institute

41

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

• CSF-1R Inhibitors

(GW2580)

• Anti-glycan antibodies

(mAbGB3.1)

• MMP-9 Inhibitors

(Zoledronic Acid)

• C-Kit and

VEGF

Inhibitors

(Sunitinib)

•

•

•

Gemcitabine

Cisplatin

Paclitaxel



Research Institute

Balb-neuT Mice Treated with Zoledronic Acid

MDSC Levels:

Serum

Bone Marrow

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



Research Institute

Balb neu-T Mice

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



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…

Weeks

γ9δ2 T-cells & MDSC

Myeloid Derived Suppressor Cells:

CD33+ CD11b+ and HLA-DR-

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

–397



Research Institute

MDSC Inhibitors and Cancer Vaccines – Pre-clinical Studies

MDSC Inhibitor

ATRA a

Gemcitabine

Nitroaspirin Derrivative

(NCX 4016)

CDDO-Me d c b

Zoledronic Acid e

IL-13-PE (immuno-toxin composed of IL-13 and pseudomonas exotoxin) f

Tumor Model

3-methycholantrene-induced sarcoma containing mutant p53 gene in BALB/c mice

Survivin (+) Panc02 tumors in

C57BL/6 mice

HER-2/neu + N2C tumors in

Balb/c mice

EL-4 thymoma tumor cells

Balb T-neu mice that develop

HER-2 positive mammary carcinomas

Murine 4T1 breast carcinoma and MCA304 sracoma tumors

Vaccine

Wild type p53 DC vaccine

Attenuated vaccina virus

(MVA) expressing murine survivin protein

Plasmid DNA vaccine encoding extracellular and trans-membrane domains of p185 peptide

DC transduced with murine survivin

Plasmid DNA encoding portion of HER-2 gene

DNA vaccine encoding IL-

13R αchain

End Result

•5-fold decreased tumor size

•Improved Tcell IFNγ response

•Improved Survival

•Improved IFNγ production

•Presence of survivin specific Tcells

•Increased median survival

•56% cure rate

•2-fold decreased tumor size

•Improved antigen specific immune response

•Delayed tumor onset

•Reduced tumor size

•Increased anti–r-p185/HER-2

Ab titer

•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.



Research Institute

46

Inhibition of Tumor Associated Macrophages



Research Institute

47

Combination Therapy




Research Institute

Levels of CD8+ T-lymphocytes




Research Institute



Research Institute

Appearance of Metastases



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



Research Institute

52

Promising Cancer Vaccines



Research Institute

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



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.



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



Research Institute

56

IMPACT TRIAL

322 centers

Stage IV

Prostate

Cancer

Castration

Resistant

ECOG PS 0-1

N=512

R

Sipuleucel-T

N=341

2:1

The primary end point:

•Overall Survival

Secondary end points:

•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.



Research Institute

57

Efficacy Results

Overall Survival (months)

Median Survival (months)

3-Year Survival

Time to Disease Progression

PSA reduction of >50%

Sipuleucel-T Placebo

25.8

21.7

Hazard Ratio 0.78 (95% CI 0.61

– 0.98, p=0.032)

25.8

21.7

37.1%

3.7

23%

3.6 months

Hazard Ratio, 0.95 (95% CI, 0.77 - 1.17, p = 0.63)

2.6% 1.6%



Research Institute

58

Overall Survival – Kaplan Maier Curves



Research Institute

59

Toxicities That were different btw 2 groups

Advers Event Sipuleucel-T (%)

All Grades

54.1

Grade 3-5

1.2

Chills

Fever

Headache

29.3

16

9.8

Flu-Like

Symptoms

Myalgia

HTN

9.8

7.4

Hyperhydrosis 5.3

Groin Pain 5.0

0.3

0.3

0

0.6

0.6

0

0

Anorexia

Depression

Flank Pain

7.1

2.4

2.7

Hydronephrosis 3.8

0.3

0.3

0

4.8

3.0

0.6

2.4

16.1

6.5

6.0

7.1

All Grades

12.5

Placebo (%)

Grade 3-5

0

13.7

4.8

3.6

1.8

0

0

0

0

0

0

1.8

0

0



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



Research Institute

61

21 centers

Stage III-IV

Melanoma

Expression of

HLA-A0201+

No brain mets

Stratification:

Site of disease

(sub) cutaneous vs. other

N=185

R gp100 – Phase III Study

IL-2

720,000 IU/kg q8h**

The primary end point:

•Clinical Response (assessed q6weeks)

1:1

Secondary end points:

•Safety

•Progression Free Survival

•Immunologic Response

•Quality of Life

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 - 209217(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



Research Institute

62

Response

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



Research Institute

63

Progression and Overall Survival

Progression Free Survival

(95% Confidence Interval)

Overall Survival

(95% Confidence Interval)

IL-2

1.6 months

(1.5 – 1.8)

11.1 months

(8.7 – 16.3)

IL-2 + gp 100

2.2 months

(1.7 – 3.9)

17.8 months

(11.9 – 25.8)



Research Institute

P-value

0.008

0.06

64

Safety



Research Institute

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



Research Institute

66

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)



Research Institute

67

Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex

Pertuzumab

III

I

IV

II

 Inhibits HER2 dimerization with other HER family receptors (particularly HER3)

 Activates ADCC

 Inhibits multiple HER-mediated signaling pathways

III

I

II

Dimerization domain

IV

Trastuzumab

 Activates ADCC

 Inhibits HER-mediated signaling pathways

 Prevents HER2 domain cleavage

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



Research Institute

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

.



Research Institute

69

Administration Schedule

Cohort

3

4

1

2

Dose

0.25 mg

0.5 mg

1.0 mg

1.5 mg

Schedule # of doses

Every 3 weeks 3

Every 3 weeks 3

Every 3 weeks 3

Every 3 weeks 3


.



Research Institute

70

Study Population


.



Research Institute

71

Grade 3-4 Toxicity

Toxicity

Diarrhea

Pain

Cardiac Toxicity

Deaths

Hospitalization

Number

1

1

0

1*

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



Research Institute

72

The Vaccine Induces IgG Response


.



Research Institute

73

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



Research Institute

74

The Antibodies Inhibit Growth of BT474

Breast Cancer Cells


.



Research Institute

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.

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



Research Institute

76

MUC1 and Normal Tissues

Tissue

Spleen

Smooth/Striated Muscle

Lung Epithelium

Breast Epithelium

Prostate Epithelium

Colon Epithelium

Stomach Epithelium

Pancreas Epithelium

Uterus Epithelium

Ovary Epithelium

Liver Epithelium

Kidney Epithelium

Testis Epithelium

Brain Epithelium

Connective Tissue

Zhang et al. Clin Cancer Res 1998;4:2669-2676

Expression

+/-

2+

1+

2+

1+

1+

-

-

2+

1+

-

-

-

-

2+



Research Institute

77

MUC 1 on Normal vs. Malignant Cells

Feature

Polarity

Malignant Cells

Diffuse expression

Amount of Carbohydrate Low

Type of Glycosylation Simple

Normal Cells

Apical surface only

High

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



Research Institute

78

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




Research Institute

79

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




Research Institute

80

Study Population




Research Institute

81

Toxicity




Research Institute

82

Immune Reaction




Research Institute

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.



Research Institute

84

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



Research Institute

85

Thank You For Your Attention

Questions?



Research Institute

86

New Developments in Cancer Vaccines

Overview

Immune System and Cancer

Immunosurveillance

MDSC Are Elevated in Spleens of

Tumor- Bearing Mice

Phase III MDX010-20 – 2

Line Tx

Phase III MDX010-20 – 2

Line Tx

Phase III MDX 010-24 – 1st Line Tx

PD-1 / PDL-1 Interaction

Pilot Study

Grade 3-4 Toxicity

Related documents

Products

Support

New Developments in Cancer Vaccines

Overview

Immune System and Cancer

Immunosurveillance

MDSC Are Elevated in Spleens of

Tumor- Bearing Mice

Phase III MDX010-20 – 2

Line Tx

Phase III MDX010-20 – 2

Line Tx

Phase III MDX 010-24 – 1st Line Tx

PD-1 / PDL-1 Interaction

Pilot Study

Grade 3-4 Toxicity

Related documents

Add this document to collection(s)

Add this document to saved

Suggest us how to improve StudyLib