IMMUNOISOLATED CELLS IMPLANTS: FROM XENOTRASPLANTATION TO LOCOREGIONAL CHEMOIMMUNOTHERAPY THROUGH MI

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IMMUNOISOLATED CELLS IMPLANTSFROM
XENOTRASPLANTATION TO LOCOREGIONAL
CHEMO-IMMUNOTHERAPY THROUGH MICROFABRICATED
BIOCAPSULES
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CELL IMMUNOISOLATION
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Insulin secretion after intraperitoneal
implantation
Desai T.A. et al. Biomedical Microdevices, 1999
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• Microfabricated systems
• to drug delivery

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Sustained-release drug delivery
Intravenous drug administration
Sustained drug delivery helps to achive a zero
order release profile ( )
in which the release rate is constant
Kindly provided by Mark Cheng

Sharma S. et al.
Expert Opin. Drug Deliv. 2006 modified
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Sustained-release drug delivery in loco through
implantable systems
Different routes of administration Reduction of
systemic toxicity Peak drug level achieved
directly at the target site Predictable and
extended duration of action
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Nanochannel delivery system - nDS1
Kindly provided by Mark Cheng


Ferrari M. Nanotecnology, 2004 modified
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Release through nDS1
Interferon alpha
Glucose
Kindly provided by Mark Cheng


Sharma S. et al. Expert Opin. Drug Deliv. 2006
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• Translation of
• immunoisolated cell system
• for immuno- chemiotherapy
• drug delivering

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COMBINATION THERAPY OF CANCER

• The field of combination therapy of cancer
  continues to evolve rapidly.
• New evidence during the past years clearly
  establishing the benefit of the combination
  chemo-immunotherapy in cancer treatment.
• Cancer treatment in becoming a matter of strategy
  rather than a traditional drug therapy.
• Role of immune response is of increasing
  interest, especially for the development of
  cancer vaccines.

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COMBINATION THERAPY OF CANCER

• Problems with chemotherapy
• Insufficient response
• Depression of immune response
• Problems with immunotherapy
• Cytokines and chemokines act locally and given
  sistemically are potentially toxic and less
  effective
• Non-specific immune response
• Impaired killer-cell/tumor-cell ratio
• Insufficient immunogenicity of the tumor
• requires simultaneously an antigenic stimulation
  toward the tumor

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Liver Metastasis Colorectal Cancer Model

• Effect of combination chemo-immunotheraphy
• Effect of peptide vaccine
• Effect of Combination of the two

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Liver Metastasis Colorectal Cancer Model

• Weak points
• Thymosin alpha1 dose and timing
• IL-2 dose and timing
• 5-FU dose

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Effect of sustained release of Thymosin-alpha 1
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DRUG PRODUCING CELLS
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IMMUNOISOLATED CELL FOR DRUG DELIVERY
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Locoregional therapy throught Immunoisolated
cells producing IL-2 and Thymosin alpha1

• Expected advantage
• Enhanced CTL response by TA1 continuos release
• Sustained CTL, NK response by IL-2/TA1 continuos
  release
• Improved chemotherpy effect due to accelerated
  bone marrow recovery
• Reduced toxicity

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HEK-293 TRANSFECTED CELL LINES IL-2 production
per cell in 24h (ELISA test)
pg/ml
number of cells
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PRESENCE OF IL-2 IN THE SUPERNATANT FROM
TRANSFECTED HEK-293 (Flow Cytometry)
HEK-PS
HEK-IL2
IL-2
gt 5000 pg/ml
0 pg/ml
Cytokine increment
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HUMAN PBMC EXPOSED TO SUPERNATANT FROM IL-2
PRODUCING FIBROBLAST
HEK-PS
HEK-IL2
CD25-Pe
MHC-II fitc
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• Utilizing a tumor-directed therapy, higher
  concentrations of the agent can be achieved in
  loco with minimal systemic exposure, reducing
  toxicity and increasing the agent availability in
  concentration and time-dose.
• The immunoisolated cell implants induce a
  moderate tissue reaction and do not require
  concomitant immunosoppression to avoid rejection.

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• Application of chemo-immunotherapy in nanoscale
  devices offer the opportunity to introduce
  promising novel approaches to cancer therapies,
  delivering multiple drugs in a timed manner and
  at different locations in the body.

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Acknowledgments
INMM-CNR Claudia Matteucci, PhD Pasquale
Pierimarchi, PhD Dr. Roberta Sorrentino
UT-University of Texas Houston Brown
Foundation IMM - Nanomedicine Prof. Mauro
Ferrari Ass.Prof. Mark Ming-Cheng Xuewu Liu, PhD
Istituto Superiore di Sanità Prof. Enrico Garaci
Department of Experimental Medicine and
Biochemical Science University of Rome Tor
Vergata Prof. Paola Sinibaldi Vallebona