PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG...
-
Upload
diane-barber -
Category
Documents
-
view
216 -
download
1
Transcript of PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG...
![Page 1: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/1.jpg)
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
![Page 2: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/2.jpg)
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)
![Page 3: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/3.jpg)
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
![Page 4: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/4.jpg)
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
![Page 5: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/5.jpg)
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)
![Page 6: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/6.jpg)
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
![Page 7: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/7.jpg)
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
![Page 8: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/8.jpg)
surgery BCG
week 4 week 6 week 1
Boosted cytokines after repeated instillations of BCG
![Page 9: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/9.jpg)
PRIME/BOOST Concept
Intradermal vaccine prior to intravesical instillation could improve resonse to intravesical BCG
![Page 10: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/10.jpg)
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
![Page 11: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/11.jpg)
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
![Page 12: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/12.jpg)
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
![Page 13: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/13.jpg)
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
![Page 14: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/14.jpg)
PRIMESWOG Trial Schema
![Page 15: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/15.jpg)
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
![Page 16: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/16.jpg)
PRIME/BOOST Trial Schema
![Page 17: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/17.jpg)
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
![Page 18: PRIME / BOOST A trans-atlantic collaboration studying T cell priming and boosting with BCG vaccination Rob S. Svatek, MD, MSCI The University of Texas.](https://reader035.fdocuments.in/reader035/viewer/2022062421/56649d345503460f94a0b781/html5/thumbnails/18.jpg)
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