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
Outer muscle layer
Inner muscle layer
Lamina propria
Papillary tumor
Mucosa
Carcinoma in situ
Prostate gland
Urethra
surgery
BCG
1 wk
BCG – something extraordinary….
Carcinoma-in-situ (CIS)
Complete Resolution
BCG Treatment
Induction
(6 weeks)
Maintenance
(3weeks)
BCG induction
surgery
week 1
week 4
BCG maintenance
week 6
week 12
Progression-free survival
BCG therapy: one of the few examples of
successful immunotherapy in the clinic
1.0
0.9
0.8
0.7
surgery + BCG
0.6
0.5
0.4
0.3
0.2
0.1
surgery alone
0.0
0
5
10
15
20 years
Superficial cancer (T1G3 stage)
Adapted from Herr, 1997
Current proposed model of BCG therapy
in bladder cancer
BCG
tumor cells
Bladder
urothelium
1
attachment and invasion
of the urothelium
4
cytolysis of bladder tumor
cells by CD8+ T cells
T cells
Neutrophils
2
Monocytes
attraction of innate immune cells
and release of cytokines / chemokines
3
attraction and activation of T cells
Adapted from Albert, 2014
BCG adjuvant therapy remains the standard-of-care
for high-risk superficial bladder cancer
Outer muscle layer
Inner muscle layer
Lamina propria
Papillary tumor
Mucosa
Carcinoma in situ
Prostate gland
Urethra
surgery
BCG
1 wk
Boosted cytokines after repeated instillations of BCG
surgery
BCG
week 1
week 4
week 6
PRIME/BOOST Concept
Intradermal vaccine prior to intravesical instillation could improve
resonse to intravesical BCG
MB49 animal model for BCG studies
High-resolution ultrasound:
Baseline
Week 1
BCG Instillation
• Dwell time: 2hrs
• BCG Dose:
– ~ 3 x 106 CFUs per mouse
(2% of human dose)
BCG
Week 1
Week 2
Week 3
s.c. immunization prior to intravesical challenge results
in rapid bladder T cell infiltration at 1st intravesical instillation
Repeated
Weeks 1 to 4
Single
Week 1
BCG s.c.
*
-21
0
*
-21
7
14
21
0
Single
*0
Week 4
33-35
33-35
21
33-35
Instillation: PBS BCG BCG PBS BCG BCG BCG
Week(s) of treatment: W1-4 W1-4 W1 W1-4 W1-4 W1
W4
Ø
BCG s.c. 21 days prior
to instillation
Biot et al. Science Transl Med. 2012
Pre-existing BCG-specific immunity improves anti-tumor
response in a mouse model for bladder cancer
BCG s.c.
*
-19
80,000 MB49
(+ poly-L-lysin)
0
Intravesical PBS or BCG
2
9
16
23
30
days
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
Patients with
high-risk bladder
tumor
Surgery
BCG therapy
Clinical
outcome?
PPD test
+ +
+
+
100
Recurrence-free survival (%)
90
80
70
+
+
+
++
+
60
50
+
40
+ +
+
30
20
+
10
Censored
PPD + (n=23)
PPD - (n=32)
0
0
10
50
20
30
40
Time until recurrence (months)
*
60
Biot et al. Science Transl Med. 2012
PRIME
SWOG 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