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Bacteria as anticancer agents to initiate

potent antitumor immunity


How to improve immunotherapy protocols for
melanoma?
Maria Rescigno

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Immunosurveillance and immunoescape

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From Dunn et al. Immunity 21, 2004, Pages 137-148

Transform the tumor site into an infected site

Salmonella typhimurium:
Avoid immune-escape mechanisms
Increase visibility of the tumor site

DC

Gr

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Use of bacteria in cancer therapy


1893: first observation of tumor regression in individuals with concomitant bacterial infection.
[Coley, WB]
1935-1969: BCG anti-cancer efficacy was studied in different tumor settings, such as
lymphoblastoid leukaemia [Mathe, G].
1976-1980: intralesional instillation of BCG for the treatment of superficial bladder cancer
[Morales, A; Lamm, DL].
1955-1985: Clostridium can selectively accumulate in tumors in vivo and nonpathogenic
strains of Clostridium prove attractive delivery systems to target therapeutic agents to the
tumor site. [Malmgren, RA; Mose, JR]
1967: first Clinical trials with Clostridium spores [Carey RW]
1980: Bifidobacterium injected i.v. localised within tumors, but no anti-tumor effect was
found. [Kimura, NT]
Salmonella and

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Tumor cell infection hypothesis


Salmonella

X
X

X
X X
X

X
X

B16

TCR
Anti-Salmonella CTL
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Salmonella as anti-cancer agent


INVASIVE
Strain
SL7207
SL3261AT

Recombinant
attenuated
S. typhimurium

NON INVASIVE
Strain
SL3261ATK

Unable to
replicate
in vivo

AroA

AroA

InvA

108 inv+/invSalmon
Anti salmonella T cells

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C57BL/6 mice

B16

Immunotherapy approach

Vaccination:
In situ:

DC

DC+ SL GST

PBS
SL3261InvA
SL3261

100
80

80

60

60

40

40

20

20%

PBS
SL3261InvA
SL3261

100

50%

P<0,01

20

20%

10

20

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30

40

50

60

70

10

20

30

40

50

60

70

What is the systemic response?

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Salmonella induces a systemic anti-tumor response

Intra-tumor
treatment

P<0,01

Vaccinated
mice

Survived mice develop vitiligo,


and are protected (75%) to
subsequent melanoma
challenges

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F. Avogadri et al. Cancer Res. 2005

Can we improve the Salmonella-based protocol?

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Can we direct anti-tumor T cells to untreated lesions?

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Avogadri et al EJI 2008

Generate intelligent missiles to target tumor cells

VHH/scFv clone
specific for tumor
antigens

U UU

U U

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pVUB4 plasmid
pVUB4 plasmid
U

Conclusions I

Salmonella impacts on the growth of untreated lesions


I.t. Salmonella induces the cross-presentation of tumor antigens and
the development of anti-tumor response
Coupling of I.T. Salmonella and radiotherapy has a strong anti-tumor
property
Salmonella can be used to target tumor cells.

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From mouse to man: 2-step protocol


Oral Vaccination (3 administrations at alternate days)
after 14 days
Anti-salmonella titers (2-fold higher than basal level)
Intratumoral injection in two metastases
4 injections every 3-4 days
(eventually additional cycle)
Biopsies before and after treatment
PBMC for antitumor response

S
vaccination

-7

intratumoral injections
3 weeks

135

25 29

I
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PBMC/serumm

PBMC/serum

32 36

39

I+II

43

II

46

II

1 week

53 d

Clinical Results
PI

PN

DOB

Oral Vaccination

I cycle completed

STATUS

01

F-C

13/01/1932

Completed

no

Not Immunized

02

A-L

15/09/1948

Not Done

no

Screened but not enrolled due


to liver metastasis

03

F-G

26/04/1944

Completed

yes

PD

04

R-C

27/06/1944

Completed

no

Not treated due to PS >2-3

05

G-A

11/01/1949

Completed

no

Not Immunized

06

I-F

07/11/1919

Completed

no

SD but SAE

07

A-B

28/07/1972

Completed

no

Not Immunized

08

G-D

28/02/1946

Completed

yes

PD

09

R-R

12/07/1966

Completed

no

SAE

10

A-O

04/08/1934

Completed

no

11

C-M

03/05/1964

Completed

yes

SD

12

S-A

12/03/1953

Completed

no

Not Immunized

13

A-F

26/02/1939

Completed

no

SAE

14

S-R

20/05/1953

Ongoing

no

Not evaluable

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Not Immunized

Conclusions II

Nearly 50% of the patients are vaccinated against Salmonella


Salmonella is safe when administered intratumorally in patients
We could observe an effect on the treated masses and some clinical
response
The immunomonitoring will tell us whether there was an induction of
a systemic anti-tumor response

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Acknowledgements

Immunotherapy Unit
Francesca Avogadri
Chiara Martinoli
Fabiana Saccheri
Paul Massa
Aida Paniccia
Erika Mileti
IEO, Milan

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Melanoma Unit
Francesco Ferrucci
Alessandro Testori
IEO, Milan