Immunotherapy and Recurrent Ovarian Cancer: Time for New Paradigms!

IMMUNOTHERAPY AND RECURRENT OVARIAN CANCER:

TIME FOR NEW PARADIGMS!

ROBERT P. EDWARDS MDCHAIR OF OB/GYN/RS

CO-DIRECTOR WOMEN’S CANCER PROGRAM UNVERSITY OF PITTSBURGH

MWRI AND UPCIDIRECTOR WOMEN’S HEALTH SERVICE LINE OF UPMC

IMMUNOTHERAPY FOR

RECURRENT OVARIAN CANCER

• Introduction• Inflammation and

Cancer• Historical Vaccine

Experience• New Paradigms• The Promise of

Checkpoints

Ovarian Cancer:

Highest Mortality of All Gynecologic Malignancies

BALANCE OF INFLAMMATION AND

DEATH

ZOU, 2004

Inflammation• Inflammation is integral to

most carcinogenesis• Most tumors induce

measurable immunity during carcinogenesis

• “Bad” inflammation is there from the beginning

Healthy Individuals

Premalignancy CancerDiagnosis

Treatment Survivorship

Improved early detection and prevention…through better understanding of ovarian cancer precursors

Endometriosis is a chronic inflammatory disease that increases the risk for ovarian cancer

Endometriosis Atypical Endometriosis

Endometriosis-Associated Ovarian

Cancer (EAOC)

Atypical Endometriosis Transitions to Ovarian Cancer

Clear Cell

Tumor

Atypical Cells

normal

cancer

Atypical transition

Inflammation drives ovarian cancer development

Stromal inflammation

T CELLS INFILTRATES

ZHANG, 02

0 20 40 60 80 100 120 140Overall Survival (Months)

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ulat

ive

Sur

viva

l

Intraepithelial CD8+ TILlowest tertileall others

Log Rank test P=0.009

Median survival: 55 Vs 26 monthsHazard ratio: 0.33 (p = 0.0003)Sato et al, PNAS. 2005, 102:18538

Evolution of the RPCI-UPCI Ovarian SPORE: High Intraepithelial CD8+ TILs is associated with

improved survival

Clinical Course Overview

DiseaseBurden

Low

NED

High

Time (months)0 1 7 19 31 60

CA125 35

Death

CA125 >35

“Watchful waiting”

Surgery

Chemotherapy(platinum/taxol)

Clinical Recurrence

“Watchful Waiting”

“Recurrent Disease”

06/0715

10 0812

Galluzzi et al, Oncotarget, 5 (24) 2015

Ovarian Cancer Immunotherapy

Budiu, Edwards, Vlad et al,Cancer Imm Immunother 2011, 2012

IP IL-2

Budiu, Kalinski, Edwards, et al,Oncogene 2013

MUC1

Mony, Vlad, Edwards et al,Cancer ImmunolImmunother 2015

aPD-L1

SPORE: EDWARDS/KALINKSI

IDO,CHEMOTHERAPY

CANCER VACCINES• Prophylactic• Therapeutic

o Peptides and proteins• Free peptide*• HSP-peptide• Dendritic cell-loaded peptides

o Antibodies• Anti-idiotype• Hybrid engineering

o Whole tumor

Antigens (rank/reference number and name)

Cumulative score

Therapeutic function (0.32)

Immunogenicity (0.17)

Oncogenicity (0.15)

Specificity (0.15)

Expression level and % positive cells (0.07)

Stem cell expression (0.05)

No. patients with antigen-positive cancers (0.04)

No. epitopes (0.04)

Cellular location of expression (0.02)

1. WT1 0.81 0.75 (fair) 1.0 (trials) 1.0 (o) 0.54 (o) 0.37 (hm) 1.0 (st) 1.0 (mphl) 1.0 (mu) 0.95 (iMHC)

2. MUC1 0.79 0.75 (fair) 1.0 (trials) 1.0 (o)

0.23 (posttranslational changes) 1.0 (ha) 1.0 (st) 1.0 (mphl) 1.0 (mu) 0.25 (sc)

3. LMP2 0.78 0.75 (fair) 1.0 (trials) 0.34 (pv) 1.0 (ab) 0.37 (hm) 1.0 (st) 1.0 (mphl) 1.0 (mu) 0.95 (iMHC)

4. HPV E6 E7 0.77 0.89 (mixed) 1.0 (trials) 0.34 (pv) 1.0 (ab) 0.23 (la)

0.73 (all stages, 11; stem cells, 3) 0.16 (mpll) 1.0 (mu) 0.95 (iMHC)

5. EGFRvIII 0.76 0.76 (mixed) 1.0 (trials)

0.62 (o), 8; uncertain but decreased survival, 7) 1.0 (ab) 0.37 (hm) 1.0 (st)

0.11 (high level, small subset) 0.13 (s) 1 (slc MHC)

6. HER-2/neu 0.75 0.85 (adequate) 1.0 (trials) 1.0 (o) 0.35 (oe) 0.37 (hm) 0.66 (al)

0.11 (high level, small subset) 1.0 (mu) 0.25 (sc)

7. Idiotype 0.75 0.76 (mixed) 1.0 (trials) 0.12 (d) 1.0 (ab) 1.0 (ha) 0.66 (al) 0.14 (unique) 1.0 (mu) 1.0 (slc MHC)

8. MAGE A3 0.71 0.79 (mixed) 1.0 (trials) 0.25 (ubds) 0.54 (of) 0.37 (hm) 1.0 (st) 1.0 (mphl) 1.0 (mu) 0.95 (iMHC)

9. p53 nonmutant 0.67 0.42 (mixed) 1.0 (trials) 1.0 (o) 0.35 (oe) 0.37 (hm) 1.0 (st) 1.0 (mphl) 1.0 (mu) 0.95 (internal MHC)

10. NY-ESO-1 0.66 0.75 (fair) 1.0 (trials) 0.25 (ubds) 0.54 (of) 0.37 (hm) 1.0 (st)

0.11.0 (high level, small subset) 1.0 (mu) 0.95 (iMHC)

The Prioritization of Cancer Antigens: A National Cancer Institute Pilot Project for the Acceleration of Translational Research

Clin Cancer Res 2009; 15 (17).N=75

REVIEW OVARIAN CANCER

THERAPEUTIC VACCINES • 36 English language trials most uncontrolled phase I/II

o 3 Randomized placebo-controlled trials (oregovamab trials)

o 6 randomized allocation studieso Median patient number (2 to 371)

• Outcome measures highly variable (2010)o Immunologic response endpoints 34o Clinical response measures 21o Survival 25o Toxicity 28

• Current Trials Open (Clinical Trials.gov)o 23 Trials nation-wide involving a vaccine or

immunotherapyLEFFLER, 2010

CANCER VACCINES• Prophylactic Vaccines

o Peptideo VLP

• Therapeutic Vaccineso Peptide and DC/cytokineo VLPo Antibodies

• Immune Adjuvantso Co-stimulatory moleculeso Cytokineso Anti T Regulatory/Myeloid Suppressor strategies

TARGET ANTIGENS

• Monoclonal antibodyo CA125o EpCAMo Membrane folate receptoro MUC1o Her2/neu

PEPTIDE-BASED• P53• NY-EOS-1• HER2/NEU• CEA• MUC-1

OVARIAN CANCER REMISSION

• Is this the right setting for vaccination?o Prior chemotherapy induced involutionoNo primary cytotoxic or biologic therapy has

been shown to extend overall survival in this cohort

o Expensive trials to demonstrate efficacy (RCT require 300 to 400 subject

Oregovomab (OvaRex®)

• Oregovomab forms xenotypic complexes with CA125 in circulation

• Immune complexes are taken up by antigen-presenting cells

• Oregovomab enhances the activation of T cells by:– Increasing uptake– Cross-presenting on HLA

Class I and II– Activating T helper cells

and CTL– Stimulating immune

function by exposure to foreign antibody

CA-125-specific monoclonal antibody to induce anti-tumor immunity

1 Gordon et al. Gynecol Oncol 2004;94(2):340-351.

OvaRex® Clinical Trial Overview

DiseaseBurden

Low

NED

High

Time (months)0 1 7 19 31 60

CA125 35

Death

CA125 >35

“Watchful waiting”

Surgery

Chemotherapy(platinum/taxol)

Clinical Recurrence

“Watchful Waiting”

“Recurrent Disease”

06/0715

10 0812

ADJUVANT TRIAL DESIGN

Berek, JCO. 2008

RESULTS OF OREGOVOMAB TRIALS

o Consolidation• Phase III Trial with

2:1Randomization• Double-blinded• Placebo-controlled• 373 subjects• Unither stops development

Adapted from Cancer Genome Atlas Research Network. "Integrated genomic analyses of ovarian carcinoma." Nature 474.7353 (2011): 609-615.

No survival difference for any of the transcriptional subtypes

The Cancer Genome Atlas (TCGA)Identification of an “immunoreactive” group

in high grade serous ovarian cancer

Immune Profiling the OVCA TCGA Dataset • N=327 genes with known immune functions, mostly associated with T cell (also

B and NK cell) immunity• N=92 (28%) - immune effector/cytotoxic genes • N=123 (38%)- immune regulation• N=10 (3%) immune checkpoint

Cytotoxicity

T cell migration

Immune checkpoint

Immune suppression

OVARIAN CANCER

Effector and Inhibitory Molecules show positive correlation in the tumor microenvironment

CD3CD4IFNG

TBX21EOMESCXCL9

CXCL10FASLGPRF1GZMAGZMBLAG3TIM3PD1

PDL1

George Tseng, PhDCharles Ma

OVARIAN BREAST KIDNEY GLIOBLASTOMA

Supervised Clustering Identifies Patients with Decreased Survival

Hemorrhagic ascites

Injected ovary

Diaphragm implants

Uninjected ovary (control)

A C DB

Ovarian tumor

Normal Ovaries

OSE

Serous Clear CellEndometrioid

MU

C1

More than 80% of epithelial ovarian tumors overexpress MUC1

MUC1-C acts and oncogenD. W Kufe Cancer Biology & Therapy 8:13, 1197-1203; 1 July 2009

MUC1: Well defined tumor associated antigen, oncoprotein and vaccine candidate

Mucinous

Ovarian Cancer Standard of Care: Surgery + Platinum/Taxane Chemotherapy

Combination Chemo-Immuno Therapy

CHEMOIMMUNOTHERAPY• Debulking tumor burden also debulks stromal support

cells and consequently fascilitating inflammation• T regulatory cells suppress in the existing new T cell

activation at tumor sites• “ Wiping the slate clean with surgery and chemotherapy

allows naïve T cell recruitment as the tumor dies• Synergy with chemotherapy and immunotherapy is

counter-intuitive but many groups are now adopting

Cisplatin Upregulates Human Tumor PD-L1 Expression in vitroOVCA420

(Resistant)OVCA432(Sensitive)

Cisplatin Upregulates Murine Tumor PD-L1 Expression

PD-L1 5.87%

PD-L1 14.2%

PD-L1 9.33%

PD-L1 20.2%

2F8 Ctrl 2F8 Cisplatin 2F8Cis Ctrl 2F8Cis Cisplatin

2F8 PD-L1

10X

40X

2F8Cis PD-L1

10X

40X

2F8 2F8cis

Cisplatin Increases T Cell Infiltration in vivo

3684T(Anti-PD-L1) CD3

3797T(Anti-PD-L1) CD3

3874T(Cisplatin) CD3

3873T(Cisplatin) CD3 3906T(Cis/Anti-PD-L1) CD3

3905T(Cis/Anti-PD-L1) CD3

10X

10X10X 10X

10X 10X

40X

40X40X40X

40X40X

Grabosch et al, In preparation.

Celecoxib Improves Overall Survival in Combination with

Cisplatin and Anti-PD-L1

• Cyclooxygenase-2 (COX-2)o Proinflammatory enzyme expressed by ovarian cancero Poor prognostic markero Product prostaglandin E2 (PGE-2) associated with invasion

• Celecoxibo Selective COX-2 Inhibitor

0 10 20 30 40 500

50

100

Survival proportions: Control vs Cisplatin/Celecoxib/Anti-PD-L1

Time

Perc

ent s

urvi

val

ControlCis/Cele/PD-L1p=0.0027*

Roswell Park Cancer Institute

University of Pittsburgh Cancer Institute

PD-L1 is present in areas of T cell infiltration

PD-L1

CD8

DAPI

Frances Zeng

AcknowledgmentsShannon Grabosch, MD Jyothi Mony, PhD Frances Zhang Lixin Zhang, MD PhDJoan Brozick, MHAMirna Bulatovic, PhD

• Tianzhou Ma, MS-University of Pittsburgh, Dept of Statistics• George Tseng PhD- University of Pittsburgh, Dept of Statistics• Esther Elishaev, MD- Magee-Womens Hospital

NIH R01 CA163462NIH P50 RPCI-UPCI SPOREDOD Ovarian Cancer Academy – OC093429 Developmental Research Project- UPCI/RPCI Ovarian Cancer SPORE

Anda Vlad , MD, PhD

Pawel Kalinski, MD PhD