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. California
Stanford
UCLA
San Diego,
Sidney Kimmel
Cancer Center

3. Sidney Kimmel Cancer Center, San Diego, CA
Development of First Genetically Modified Tumor Cell Vaccines

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. 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. 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. 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. 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. 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. The Cancer Cell’s Shield against the Immune System
Macrophages
T Cells
Natural Killer
Cells
Cancer Cell

11. The Cancer Cell’s Shield against the Immune System
Macrophages
T Cells
Natural Killer
Cells
PDL1
CD47
Macrophages
T Cells
Cancer Cell

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. 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. 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. 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. Presented at 2015 ASCO Annual Meeting

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. 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. 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. 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. Adoptive Cell Therapy: Directing the Immune System
to Recognize and Attack Ovarian Cancer Cells

22. Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell

23. Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
Antigen

24. Directing the Immune System to Recognize and Attack
Ovarian Cancer Cells
Ovarian Cancer CellT Cell
AntigenT Cell
Receptor

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. 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. 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. The Clinical Application of Adoptive Cell
Transfer with Genetically Modified T Cells

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. 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. Stanford Gynecologic Oncology Service
Stanford Women’s Cancer Center and Stanford Cancer Institute