Personalized Cancer Vaccines

Willem W. OverwijkDepartment of Melanoma Medical Oncology

10/22/2014

Texas Fresh AIR

Therapeutic Cancer Vaccines

The Idea

Vaccinate against Cancer

↓(re)Activate and (re)Educate Immune System

↓Kill Cancer Cells

↓Life-Long Immunological Memory against Recurrence

Therapeutic Cancer Vaccines

The Idea

Vaccinate against Cancer

↓(re)Activate and (re)Educate Immune System

↓Kill Cancer Cells

↓Life-Long Immunological Memory against Recurrence

limiting step incheckpoint blockade therapy?

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

peptide

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Non-mutated antigens (normal)

Self Ags - ubiquitous, not tumor-specific (eg. actin, vimentin) > 98%

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Non-mutated antigens (normal)

Self Ags - ubiquitous, not tumor-specific (eg. actin, vimentin) > 98%

Tissue differentiation Ags (eg. gp100, Tyrosinase, MART-1/Melan-A)

Cancer / testis Ags (eg. MAGE, GAGE, NY-ESO-1)

Over-expressed in tumors (eg. KIT, HER2, HERV)

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

Cancer Vaccines: Moving Parts

1

9-10 aa

2

Clinical Trials of Cancer Vaccines

402 open studies (USA only) using cancer vaccines (www.clinicaltrial.gov)

1. Study of Peptide Vaccination With Tumor Associated Antigens Mixed With Montanide in Patients With CNS Tumors2. CpG 7909/Montanide ISA 720 With or Without Cyclophosphamide in Combination Either With NY-ESO-1-derived

Peptides or the NY-ESO-1 Protein for NY-ESO-1-expressing Tumors 3. Vaccine Therapy in Treating Patients With Non-Small Cell Lung Cancer (NSCLC) Stages IIIB/IV 4. Randomized Study of Adjuvant WT-1 Analog Peptide Vaccine in Patients With Malignant Pleural Mesothelioma (MPM)

After Completion of Combined Modality Therapy5. Immunotherapy of Stage III/IV Melanoma Patients6. A Clinical Trial of Autologous Oxidized Tumor Cell Lysate Vaccine For Recurrent Ovarian, Fallopian Tube or Primary

Peritoneal Cancer7. Vaccine Therapy and Monoclonal Antibody Therapy in Treating Patients With Stage III or Stage IV Melanoma That

Cannot Be Removed by Surgery8. Safety Study of Multiple-Vaccine to Treat Metastatic Breast Cancer9. IDO Peptide Vaccination for Stage III-IV Non Small-cell Lung Cancer Patients.10.Survivin Vaccine Therapy for Patients With Malignant Gliomas11.Phase I Oncovir Poly IC:LC and NY-ESO-1/gp100/MART (Melanoma)12.A Phase I Study of WT1 Peptides to Induce Anti-Leukemia Immune Responses Following Autologous or Allogeneic

Transplantation for AML, CML, ALL, MDS, and B Cell Malignancies13.Vaccination of High Risk Breast Cancer Patients14.MAGE-A3/HPV 16 Vaccine for Squamous Cell Carcinoma of the Head and Neck15.Novel Adjuvants for Peptide-Based Melanoma Vaccines

The QuestionWhy do many vaccinated cancer patients not

experience tumor regression despite increased

levels of cancer antigen-specific T cells?

Modeling peptide vaccination in mice

inject naive gp100-specific CD8+ T cells: pmel-1 Tg

vaccinate s.c. with gp100 peptide in IFA

follow pmel-1 T cells in blood

measure s.c. B16 melanoma growth

Incomplete Freund’s Adjuvant= water-in-oil emulsion

Vaccine site is a sink for T cellsgp100/IFA

control/IFA

Hailemichael et al., Nat. Med. 13, 2013

Vaccine site is a sink for T cells

gp100/IFA

control/IFA

gp100/IFA

control/IFA

Hailemichael et al., Nat. Med. 13, 2013

Where are the T cells?

Rabinovich et al., Proc. Natl. Acad. Sci., 2009

gp100/IFA s.c. + eLuc-transduced pmel-1 T cells i.v.

Rabinovich et al., PNAS 2008

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User: Group: Experiment: Comment1: Comment2:

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x10 6

Color BarMin = 1.6605e+06Max = 1.7101e+07

bkg subflat-fieldedcosmic

WARNING: Saturated Luminescent Image

Click # YH20090727143921Mon, Jul 27, 2009 14:39:21Em filter=OpenBin:M (8), FOV19.7, f1, 30sCamera: 23210, EEV

User: Group: Experiment: Comment1: Comment2:

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1200

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Color BarMin = 179.64Max = 1542

bkg subflat-fieldedcosmic

Click # YH20090730153808Thu, Jul 30, 2009 15:38:8Em filter=OpenBin:M (8), FOV19.7, f1, 30sCamera: 23210, EEV

User: Group: Experiment: Comment1: Comment2:

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Color BarMin = 57

Max = 534

bkg subflat-fieldedcosmic

day 0 gp100/IFA

day –30 gp100/IFA

day 4 day 7 day 10

tumor

day 0 saline/IFA

Water-based vaccines permitT cell accumulation in tumor

Water-based vaccines permitT cell accumulation in tumor

Water-based vaccines permitT cell accumulation in tumor

Tumor therapy with long-lived vs. short-lived vaccine : self antigen

Hailemichael et al., Nat. Med. 13, 2013

Tumor therapy with long-lived vs. short-lived vaccine : self antigen

VT

VT

Hailemichael et al., Nat. Med. 13, 2013

ipiipi + gp100/IFAgp100/IFA

IFA-based vaccination does not synergize with anti-CTLA-4 therapy

Yared Hailemichael

IFA-based vaccination sequestersT cells induced by anti-CTLA-4 therapy

Yared Hailemichael

IFA-based vaccination sequestersT cells induced by anti-CTLA-4 therapy

Yared Hailemichael

Virus-based vaccinationsynergizes with anti-CTLA-4 therapy

Yared Hailemichael

Tumor therapy with long-lived vs. short-lived vaccine: self antigen .

VT

VT

Hailemichael et al., Nat. Med. 13, 2013

Tumor therapy with long-lived vs. short-lived vaccine: non-self antigen

0

50

100

150

200

0 10 20 30T

um

or s

ize

(mm

2)

Days After Vaccination

OVA/saline + covax

OVA/IFA + covax

covax

0

20

40

60

80

100

0 10 20 30

OT

-I (%

of C

D8

+)

Days After Vaccination

OVA/saline + covax

OVA/IFA + covax

covax

.

Hailemichael et al., Nat. Med. 13, 2013

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Non-mutated antigens (normal)

Mutated antigens (aberrant)

Self Ags - ubiquitous, not tumor-specific (eg. actin, vimentin) > 98%

Tissue differentiation Ags (eg. gp100, Tyrosinase, MART-1/Melan-A)

Cancer / testis Ags (eg. MAGE, GAGE, NY-ESO-1)

Over-expressed in tumors (eg. KIT, HER2, HERV)

Single point mutations

Deletions / insertions / frameshifts

Fusion peptides / mis-spliced / intron translation

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Non-mutated antigens (normal)

Mutated antigens (aberrant)

Self Ags - ubiquitous, not tumor-specific (eg. actin, vimentin) > 98%

Tissue differentiation Ags (eg. gp100, Tyrosinase, MART-1/Melan-A)

Cancer / testis Ags (eg. MAGE, GAGE, NY-ESO-1)

Over-expressed in tumors (eg. KIT, HER2, HERV)

Single point mutations

Deletions / insertions / frameshifts

Fusion peptides / mis-spliced / intron translation

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

Self

Foreign

Immuno-genicity

T cell

Tumor cell lysisCytokine release

Tumor cell

TCR

MHC class I

Mutated antigens (aberrant)

Single point mutations

Deletions / insertions / frameshifts

Fusion peptides / mis-spliced / intron translation

Tumor-Associated Antigens

Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

Self

Foreign

Immuno-genicity

Mutation rates in different cancers

Mutation rates in different cancers

From mutation to vaccine

adapted from Overwijk et al., JITC, 2013

Further reading

This work was funded by:

NIH/NCI: R01-CA143077

NIH/NCI: PO1 CA128913

Melanoma Research Alliance

Cancer Vaccine LaboratoryDpt. of Melanoma Medical OncologyHiep KhongZhimin Dai, M.D.Yared Hailemichael, Ph.D.Manisha Singh, Ph.D.

Patrick Hwu, M.D.

Bethyl LaboratoriesJohn Carwile, D.V.M, and team