prime / boost a trans-atlantic collaboration studying t cell priming and boosting with bcg...
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PRIME / BOOST
A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination
Rob S. Svatek, MD, MSCI
The University of Texas Health Science Center
San Antonio
Prime/Boost Participants
Europe •Cyril Rentsch (University Hospital of Basel, Switzerland)•Matthew Albert (Institut Pasteur, Paris)•George Thallman (Inselspital, Bern, Switzerland)EORTC•Richard Sylvester (Senior Statistician)•Julie Hermans (Operations)Sanofi Pasteur•Andrew Farrow (Director, Franchise Liaison)SAKK•Celine Genton (SAKK)SWOG•Rob Svatek (San Antonio)•Seth Lerner (Houston)•Cathy Tangen (Senior Statistician)
BCG adjuvant therapy remains the standard-of-care for high-risk superficial bladder cancer
surgery
1 wk
BCG
Inner muscle layer
Lamina propria
Mucosa
Prostate gland
Urethra
Carcinoma in situ
Papillary tumor
Outer muscle layer
BCG – something extraordinary….
Carcinoma-in-situ (CIS)
BCG TreatmentInduction (6 weeks)
Maintenance (3weeks)
Complete Resolution
surgery BCG induction BCG maintenance
week 4 week 6 week 1 week 12
BCG therapy: one of the few examples of successful immunotherapy in the clinic
Adapted from Herr, 1997
1.0
0.9
0.8
0.7
0.2
0.0
Pro
gres
sion
-fre
e su
rviv
al
50 10 15 20 years
0.6
0.5
0.4
0.3
0.1
surgery + BCG
surgery alone
Superficial cancer (T1G3 stage)
Bladderurothelium
tumor cellsBCG
1 attachment and invasion of the urothelium
Monocytes
2 attraction of innate immune cells and release of cytokines / chemokines
Neutrophils
4 cytolysis of bladder tumor cells by CD8+ T cells
T cells
3 attraction and activation of T cells
Current proposed model of BCG therapy in bladder cancer
Adapted from Albert, 2014
BCG adjuvant therapy remains the standard-of-care for high-risk superficial bladder cancer
surgery
1 wk
BCG
Inner muscle layer
Lamina propria
Mucosa
Prostate gland
Urethra
Carcinoma in situ
Papillary tumor
Outer muscle layer
surgery BCG
week 4 week 6 week 1
Boosted cytokines after repeated instillations of BCG
PRIME/BOOST Concept
Intradermal vaccine prior to intravesical instillation could improve resonse to intravesical BCG
MB49 animal model for BCG studies
BCG Instillation
•Dwell time: 2hrs
•BCG Dose: – ~ 3 x 106 CFUs per mouse
(2% of human dose)
High-resolution ultrasound:
Baseline Week 1
Week 1
BCG
Week 2 Week 3
s.c. immunization prior to intravesical challenge results in rapid bladder T cell infiltration at 1st intravesical instillation
RepeatedWeeks 1 to 4 0 7 14 21
BCG s.c.
33-35
SingleWeek 1
SingleWeek 4
-21*
0 33-35 -21*
0 33-35*
21
Instillation: PBS BCG BCG BCG BCGPBS
Week(s) of treatment: W1-4 W1-4 W1-4 W1 W4W1-4
Ø BCG s.c. 21 days prior to instillation
BCG
W1
Biot et al. Science Transl Med. 2012
Pre-existing BCG-specific immunity improves anti-tumor response in a mouse model for bladder cancer
days-19 9
BCG s.c.
0
80,000 MB49 (+ poly-L-lysin)
3023162 *
Intravesical PBS or BCG
BCG s.c. Intravesical ttt
+-+-
BCG (n=9)BCG (n=8)PBS (n=9)PBS (n=8)
**
Biot et al. Science Transl Med. 2012
Pre-existing BCG-specific immunity improves anti-tumor response in patients
PPD + (n=23)
PPD - (n=32) *
+ Censored
Time until recurrence (months)
0 10 20 30 40 50 60
0
10
20
30
40
50
60
70
80
90
100
Re
curr
en
ce-f
ree
su
rviv
al (
%)
+++
+
+
+
+++
+
+++
+
Patients with high-risk bladder
tumor
PPD test
Surgery BCG therapyClinical
outcome?
Biot et al. Science Transl Med. 2012
PRIMESWOG Trial Schema
PRIME/BOOST
PRIME–U.S.–PPD negative
BOOST–Europe–PPD negative/positive–A significant proportion of European patients are PPD negative, despite childhood vaccination–Stratify – PPD expression
PRIME/BOOST Trial Schema
Correlative Studies
Impact of prime/boost on immune responses– Monitor blood and urine protein biomarkers using multiplexed immunoassays
Validate prior models and identify novel molecular determinates of BCG responsiveness
• Systemic/local immune responses following therapy
• Urine based Cell-lineage specific gene expression profiles
• Tissue-based IHC
Conclusions
PRIME / BOOST
A trans-atlantic collaboration studying T cell priming and
boosting with BCG vaccination
• BCG immunotherapy is effective but currently we have no reliable determinants of therapy response
• Intradermal BCG vaccination – a cost-effective means to improve response?
• Opportunity for correlative studies