immunotherapy and recurrent ovarian cancer: time for new paradigms!
TRANSCRIPT
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