Cancer Immunotherapy

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Bacteria as anticancer agents to initiate potent
antitumor immunityMaria Rescigno
How to improve immunotherapy protocols for
melanoma?
2
Immunosurveillance and immunoescape
From Dunn et al. Immunity 21, 2004, Pages 137-148
3
Transform the tumor site into an infected site
Salmonella typhimurium Avoid immune-escape
mechanisms Increase visibility of the tumor
site
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
B16
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Salmonella as anti-cancer agent
INVASIVE Strain SL7207 SL3261AT
Unable to replicate in vivo
NON INVASIVE Strain SL3261ATK
B16
C57BL/6 mice
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Immunotherapy approach
Vaccination DC
DC SL GST
In situ
PBS
PBS
SL3261InvA
SL3261InvA
SL3261
SL3261
50
Plt0,01
20
20
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What is the systemic response?
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Salmonella induces a systemic anti-tumor response
F. Avogadri et al. Cancer Res. 2005
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Can we improve the Salmonella-based protocol?
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Can we direct anti-tumor T cells to untreated
lesions?
Avogadri et al EJI 2008
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Generate intelligent missiles to target tumor
cells
VHH/scFv clone specific for tumor antigens
U
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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

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Clinical Results
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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
Melanoma Unit Francesco Ferrucci Alessandro
Testori IEO, Milan