1. Personalized Cancer Vaccines
Willem W. Overwijk
Department of Melanoma Medical Oncology
10/22/2014
Texas Fresh AIR

2. Therapeutic Cancer Vaccines The Idea
Vaccinate against Cancer ↓
(re)Activate and (re)Educate Immune System
Kill Cancer Cells
Life-Long Immunological Memory against Recurrence

3. 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 in
checkpoint blockade therapy?

4. Tumor-Associated Antigens
T cell
TCR
Tumor cell lysis
Cytokine release
MHC
class I
Tumor cell
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

5. Tumor-Associated Antigens
T cell
peptide
TCR
Tumor cell lysis
Cytokine release
MHC
class I
Tumor cell
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

6. Tumor-Associated Antigens Non-mutated antigens (normal)
T cell
TCR
Tumor cell lysis
Cytokine release
Non-mutated antigens (normal)
MHC
class I
 Self Ags - ubiquitous, not tumor-specific (eg. actin, vimentin) > 98%
Tumor cell
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

7. Tumor-Associated Antigens Non-mutated antigens (normal)
T cell
TCR
Tumor cell lysis
Cytokine release
Non-mutated antigens (normal)
MHC
class I
 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)
Tumor cell
 Over-expressed in tumors (eg. KIT, HER2, HERV)
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

8. Cancer Vaccines: Moving Parts
9-10 aa 1 2

9. Clinical Trials of Cancer Vaccines
402 open studies (USA only) using cancer vaccines (
Study of Peptide Vaccination With Tumor Associated Antigens Mixed With Montanide in Patients With CNS Tumors
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
Vaccine Therapy in Treating Patients With Non-Small Cell Lung Cancer (NSCLC) Stages IIIB/IV
Randomized Study of Adjuvant WT-1 Analog Peptide Vaccine in Patients With Malignant Pleural Mesothelioma (MPM) After Completion of Combined Modality Therapy
Immunotherapy of Stage III/IV Melanoma Patients
A Clinical Trial of Autologous Oxidized Tumor Cell Lysate Vaccine For Recurrent Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Vaccine Therapy and Monoclonal Antibody Therapy in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery
Safety Study of Multiple-Vaccine to Treat Metastatic Breast Cancer
IDO Peptide Vaccination for Stage III-IV Non Small-cell Lung Cancer Patients.
Survivin Vaccine Therapy for Patients With Malignant Gliomas
Phase I Oncovir Poly IC:LC and NY-ESO-1/gp100/MART (Melanoma)
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 Malignancies
Vaccination of High Risk Breast Cancer Patients
MAGE-A3/HPV 16 Vaccine for Squamous Cell Carcinoma of the Head and Neck
Novel Adjuvants for Peptide-Based Melanoma Vaccines

10. The Question
Why do many vaccinated cancer patients not experience tumor regression despite increased levels of cancer antigen-specific T cells?

11. 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

12. Vaccine site is a sink for T cells
Hailemichael et al., Nat. Med. 13, 2013

13. Vaccine site is a sink for T cells
Hailemichael et al., Nat. Med. 13, 2013

14. gp100/IFA s.c. + eLuc-transduced pmel-1 T cells i.v.
Rabinovich et al., PNAS 2008
Where are the T cells?
day 0 gp100/IFA
day 0 saline/IFA
tumor
day –30 gp100/IFA
day 4
day 7
day 10
Rabinovich et al., Proc. Natl. Acad. Sci., 2009

15. Water-based vaccines permit T cell accumulation in tumor

16. Water-based vaccines permit T cell accumulation in tumor

17. Water-based vaccines permit T cell accumulation in tumor

18. Tumor therapy with long-lived vs. short-lived vaccine : self antigen
Hailemichael et al., Nat. Med. 13, 2013

19. Tumor therapy with long-lived vs. short-lived vaccine : self antigen
Hailemichael et al., Nat. Med. 13, 2013

20. ipi
ipi + gp100/IFA
gp100/IFA

21. IFA-based vaccination does not synergize with anti-CTLA-4 therapy
Yared Hailemichael

22. IFA-based vaccination sequesters
T cells induced by anti-CTLA-4 therapy
Yared Hailemichael

23. IFA-based vaccination sequesters
T cells induced by anti-CTLA-4 therapy
Yared Hailemichael

24. Virus-based vaccination synergizes with anti-CTLA-4 therapy
Yared Hailemichael

25. Tumor therapy with long-lived vs. short-lived vaccine: self antigen .
Hailemichael et al., Nat. Med. 13, 2013

26. Tumor therapy with long-lived vs. short-lived vaccine: non-self antigen
Hailemichael et al., Nat. Med. 13, 2013

27. Tumor-Associated Antigens Non-mutated antigens (normal)
T cell
TCR
Tumor cell lysis
Cytokine release
Non-mutated antigens (normal)
MHC
class I
 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)
Tumor cell
 Over-expressed in tumors (eg. KIT, HER2, HERV)
 Single point mutations
 Deletions / insertions / frameshifts
 Fusion peptides / mis-spliced / intron translation
Mutated antigens (aberrant)
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

28. Tumor-Associated Antigens Non-mutated antigens (normal)
T cell
TCR
Tumor cell lysis
Cytokine release
Non-mutated antigens (normal)
MHC
class I
Self
 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)
Tumor cell
Immuno-genicity
 Over-expressed in tumors (eg. KIT, HER2, HERV)
 Single point mutations
 Deletions / insertions / frameshifts
 Fusion peptides / mis-spliced / intron translation
Foreign
Mutated antigens (aberrant)
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

29. Tumor-Associated Antigens
T cell
TCR
Tumor cell lysis
Cytokine release
MHC
class I
Self
Tumor cell
Immuno-genicity
 Single point mutations
 Deletions / insertions / frameshifts
 Fusion peptides / mis-spliced / intron translation
Foreign
Mutated antigens (aberrant)
Adapted from Dr. Gregory Lizee, Melanoma Med. Oncol.

31. Mutation rates in different cancers

32. Mutation rates in different cancers

33. From mutation to vaccine
adapted from Overwijk et al., JITC, 2013

34. Further reading

35. Cancer Vaccine Laboratory
Dpt. of Melanoma Medical Oncology
Hiep
Khong
Zhimin
Dai, M.D.
Yared
Hailemichael
, Ph.D.
Manisha Singh, Ph.D.
Patrick
Hwu, M.D.
Bethyl Laboratories
John Carwile, D.V.M, and team
This work was funded by:
NIH/NCI: R01 -
CA143077
NIH/NCI: PO1 CA128913
Melanoma Research Alliance