discover personalized medicine: oliver dorigo, md, phd

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

California

Stanford

UCLA

San Diego,

Sidney Kimmel

Cancer Center

http://www.google.com/url?sa=i&rct=j&q=california+map&source=images&cd=&cad=rja&docid=aZRmMyx5KeULOM&tbnid=yclSdD_1EpK32M:&ved=0CAUQjRw&url=http://www.lib.utexas.edu/maps/california.html&ei=atCSUeXGEevRiALUwYG4Bg&bvm=bv.46471029,d.cGE&psig=AFQjCNElizwFs1x41L1Wtkg2Wev_LQ8dSQ&ust=1368662498596062

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 adaptation to antigens

(infectious pathogens or cancer) through

maturation in response to antigens

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

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

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.

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

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

Cancer Cell

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

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.

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

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

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 Response to

Immune check point inhibition

Presented By Adil Daud at 2015 ASCO Annual Meeting

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

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 Cell T Cell



Antigen



Antigen T Cell

Receptor



Retrovirus

Antigen T Cell

Receptor

T Cell Receptor

Gene



Retrovirus

Antigen T Cell

Receptor

T Cell Receptor

Gene

Which Antigen should we target

in Ovarian Cancer?



Retrovirus

NY-ESO-1 NY-ESO-1

T Cell

Receptor

NY-ESO-1

T Cell Receptor

Gene

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 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

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

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

discover personalized medicine: oliver dorigo, md, phd

Health & Medicine