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