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Personalized Cancer Vaccines

Personalized Cancer Vaccines. Willem W. Overwijk Department 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 ↓

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Personalized Cancer Vaccines

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

  6. Tumor-Associated Antigens 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 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 (www.clinicaltrial.gov) 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 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 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.

  30. Mutation rates in different cancers

  31. Mutation rates in different cancers

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

  33. Further reading

  34. 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

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