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Oliver Dorigo, MD, PhD
Director and Associate Professor, Division Gynecologic Oncology
Director, Gynecologic Oncology Clin...
California
Stanford
UCLA
San Diego,
Sidney Kimmel
Cancer Center
Sidney Kimmel Cancer Center, San Diego, CA
Development of First Genetically Modified Tumor Cell Vaccines
The Immune System
Innate immunity does not require
adaptation to react to foreign
antigens
Adaptive Immunity requires adap...
The Cancer-Immunity Cycle – Targeting Opportunities
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cyc...
The Cancer-Immunity Cycle – Targeting Opportunities
Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cyc...
Clinical Evidence for the Potential of Ovarian Cancer Immunotherapy
Study Patients Treatment # Patients Response Survival
...
The World Map of Ovarian Cancer Immunotherapy
Source:
https://www.clinicaltrials.gov/ct2/results/map?term=%22immunotherapy...
Pardoll DM. The blockade of immune checkpoints in cancer
immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64
Immune Ch...
The Cancer Cell’s Shield against the Immune System
Macrophages
T Cells
Natural Killer
Cells
Cancer Cell
The Cancer Cell’s Shield against the Immune System
Macrophages
T Cells
Natural Killer
Cells
PDL1
CD47
Macrophages
T Cells
...
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64
Targeting...
Safety and Tumor Responses with Lambrolizumab
(Anti–PD-1) in Melanoma
• 135 patients with advanced melanoma
• Response rat...
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fuji...
Nivolumab (3mg/kg) in bulky clear cell carcinoma
CA125 (U/ml)
1 2
(day)
316
16 10
0
200
400
0 50 100 150
SAE with Fever
Ti...
Presented at 2015 ASCO Annual Meeting
PD-L1 Expression and Relationship With Response
Presented By Adil Daud at 2015 ASCO Annual Meeting
Expression of PDL1 and ...
Blocking CD47 inhibits Ovarian Cancer Tumor Growth
Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, F...
Blocking CD47 inhibits Ovarian Cancer Tumor Growth
Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, F...
Blocking CD47 inhibits Ovarian Cancer Tumor Growth
Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, F...
Adoptive Cell Therapy: Directing the Immune System
to Recognize and Attack Ovarian Cancer Cells
Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
Antigen
Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
AntigenT Cell
Receptor
Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
Retrovirus
AntigenT Cel...
Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
Retrovirus
AntigenT Cel...
Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
Retrovirus
NY-ESO-1NY-E...
The Clinical Application of Adoptive Cell
Transfer with Genetically Modified T Cells
Cancer cell
1. The immune system offers unprecedented opportunities to
target ovarian cancer and achieve clinically meanin...
Brigid Miralda
Gynecologic Oncologic
Nurse Practitioner
Arati Jairam-Thodla
Gynecologic Oncologic
Nurse Practitioner
Nelso...
Stanford Gynecologic Oncology Service
Stanford Women’s Cancer Center and Stanford Cancer Institute
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Discover Personalized Medicine: Oliver Dorigo, MD, PhD

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Discover Personalized Medicine: Oliver Dorigo, MD, PhD

  1. 1. Oliver Dorigo, MD, PhD Director and Associate Professor, Division Gynecologic Oncology Director, Gynecologic Oncology Clinical Care Program, Stanford Women’s Cancer Center Director Mary Lake Polan Gynecologic Oncology Research Laboratory Department of Obstetrics and Gynecology, Stanford University Ovarian Cancer National Conference, San Diego, July 25th, 2015 Using the Immune System to Target Ovarian Cancer
  2. 2. California Stanford UCLA San Diego, Sidney Kimmel Cancer Center
  3. 3. Sidney Kimmel Cancer Center, San Diego, CA Development of First Genetically Modified Tumor Cell Vaccines
  4. 4. The Immune System Innate immunity does not require adaptation to react to foreign antigens Adaptive Immunity requires adaptation to antigens (infectious pathogens or cancer) through maturation in response to antigens
  5. 5. The Cancer-Immunity Cycle – Targeting Opportunities Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 Jul 25;39(1):1-10
  6. 6. The Cancer-Immunity Cycle – Targeting Opportunities Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013 Jul 25;39(1):1-10
  7. 7. Clinical Evidence for the Potential of Ovarian Cancer Immunotherapy Study Patients Treatment # Patients Response Survival Vald, Edwards Cancer Immunol Immunother 2010 Recurrent, platinum resistant ovarian Cancer Interleukin-2 i.p. 6 x 105 IU/ml weekly x 16 24 CR: 4 PR: 2 SD: 7 Median Survival: Non-Responder: 1.5 years Responders: not reached (24 -120+ months) Hodi, Dranoff PNAS 2008 Recurrent metastatic ovarian cancer CTLA-4 Blockade: Ipilupimab i.v. 3mg/kg q 2 – 3 months 9 CR: 0 PR: 1 SD: 3 Duration of Response: SD: 2,4,6+ Months PR: 35+ Months Diefenbach, Dupont Clin Cancer Res 2008 “High Risk” ovarian cancer after surgery and 1st line chemo NY-ESO-1b peptide (position 157-165; 100 μg) + 0.5 mL Montanide ISA-51 s.c. q 3 weeks x 5 9 NA Median PFS: 13 months 6/9 patients recurred 3 patient disease free after 25, 38, and 52 Fujita,Tanaka Clin Cancer Research 1995 NED after surgery and 1st line chemo 1.0 – 4.4 x 109 TIL after 1st line chemo 13 TIL 11 Control NA 3-year DFS: TIL: 82.1% Control:54.5% 3-year DFS, residual disease after surgery TIL: 76.2% Control:33.3% Chester C, Dorigo O, Berek JS, Kohrt H. Immunotherapeutic approaches to ovarian cancer treatment. Journal for Immunotherapy of Cancer. 2015 Mar 24;3:7
  8. 8. The World Map of Ovarian Cancer Immunotherapy Source: https://www.clinicaltrials.gov/ct2/results/map?term=%22immunotherapy%22+AND+%22ovarian+cancer%22 58 studies worldwide; 39 in the United States.
  9. 9. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64 Immune Checkpoint Targeting in Ovarian Cancer: PD1 and PDL1 Inhibitors
  10. 10. The Cancer Cell’s Shield against the Immune System Macrophages T Cells Natural Killer Cells Cancer Cell
  11. 11. The Cancer Cell’s Shield against the Immune System Macrophages T Cells Natural Killer Cells PDL1 CD47 Macrophages T Cells Cancer Cell
  12. 12. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64 Targeting the PD-L1/PD-1 Immune Checkpoint in Ovarian Cancer
  13. 13. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma • 135 patients with advanced melanoma • Response rate across all dose cohorts 38% (highest dose: 52%) • Responses were durable in the majority of patients • Median progression-free survival longer than 7 months. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44 • 135 patients with advanced melanoma • Response rate across all dose cohorts 38% (highest dose: 52%) • Responses were durable in the majority of patients • Median progression-free survival longer than 7 months.
  14. 14. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3360-5. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003 Jan 16;348(3):203-13. CD8 T -lymphocytes and PD-L1 Expression Ovarian Cancer
  15. 15. Nivolumab (3mg/kg) in bulky clear cell carcinoma CA125 (U/ml) 1 2 (day) 316 16 10 0 200 400 0 50 100 150 SAE with Fever Timeline Day Target Lesion Response Pre-Treatment -19 6.2 cm 1. Treatment 79 0 CR 2. Treatment 123 0 CR Efficacy of Nivolumab in Platinum-Resistant Ovarian Cancer – Impressive Single Patient Responses ! Presented by Hamanishi et al ASCO 2014
  16. 16. Presented at 2015 ASCO Annual Meeting
  17. 17. PD-L1 Expression and Relationship With Response Presented By Adil Daud at 2015 ASCO Annual Meeting Expression of PDL1 and Response to Immune check point inhibition Presented By Adil Daud at 2015 ASCO Annual Meeting
  18. 18. Blocking CD47 inhibits Ovarian Cancer Tumor Growth Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11103-8 Macrophages T-Cells Natural Killer Cells PDL1 CD47
  19. 19. Blocking CD47 inhibits Ovarian Cancer Tumor Growth Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11103-8 Macrophages T-Cells Natural Killer Cells PDL1 CD47
  20. 20. Blocking CD47 inhibits Ovarian Cancer Tumor Growth Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB, Seita J, Inlay MA, Weiskopf K, Miyanishi M, Weissman IL. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11103-8 Macrophages T-Cells Natural Killer Cells PDL1 CD47
  21. 21. Adoptive Cell Therapy: Directing the Immune System to Recognize and Attack Ovarian Cancer Cells
  22. 22. Directing the Immune System to Recognize and Attack Ovarian Cancer Cells Ovarian Cancer CellT Cell
  23. 23. Directing the Immune System to Recognize and Attack Ovarian Cancer Cells Ovarian Cancer CellT Cell Antigen
  24. 24. Directing the Immune System to Recognize and Attack Ovarian Cancer Cells Ovarian Cancer CellT Cell AntigenT Cell Receptor
  25. 25. Directing the Immune System to Recognize and Attack Ovarian Cancer Cells Ovarian Cancer CellT Cell Retrovirus AntigenT Cell Receptor T Cell Receptor Gene
  26. 26. Directing the Immune System to Recognize and Attack Ovarian Cancer Cells Ovarian Cancer CellT Cell Retrovirus AntigenT Cell Receptor T Cell Receptor Gene Which Antigen should we target in Ovarian Cancer?
  27. 27. Directing the Immune System to Recognize and Attack Ovarian Cancer Cells Ovarian Cancer CellT Cell Retrovirus NY-ESO-1NY-ESO-1 T Cell Receptor NY-ESO-1 T Cell Receptor Gene
  28. 28. The Clinical Application of Adoptive Cell Transfer with Genetically Modified T Cells
  29. 29. Cancer cell 1. The immune system offers unprecedented opportunities to target ovarian cancer and achieve clinically meaningful responses. 2. Immune checkpoint inhibitors have shown impressive efficacy in solid tumors like melanoma. Clinical trials investigating the efficacy of these drugs in ovarian cancer patients are underway. 3. Our ability to genetically modify cells of the immune- system can increase targeting efficiency for ovarian cancer related antigens (adoptive cell therapy). Using the Immune System to Target Ovarian Cancer
  30. 30. Brigid Miralda Gynecologic Oncologic Nurse Practitioner Arati Jairam-Thodla Gynecologic Oncologic Nurse Practitioner Nelson N.H. Teng, MD, PhD Jonathan S. Berek, MD, MMS Laurie Krause Lacob Professor and Chair Director, Stanford Women's Cancer Center Shannon MacLaughlan-David, MD Amer Karam, MD Associate Director, Division Gynecologic Oncology Oliver Dorigo, MD, PhD Director, Division Gynecologic Oncology The Stanford Women’s Cancer Center
  31. 31. Stanford Gynecologic Oncology Service Stanford Women’s Cancer Center and Stanford Cancer Institute

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